Microneedle arrays with heterogeneous needles, and systems and components thereof

Abstract

A microneedle array system with heterogeneous needles, designed for the enhanced transdermal delivery of bioactive agents for therapeutic and diagnostic purposes. This system includes a variety of microneedle 140 configurations, such as primary and secondary microneedles that differ in size, shape, and material to optimize delivery and functionality. Secondary needles are specifically designed with additional features such as sensors, specialized coatings, and microelectronics to perform tasks beyond simple delivery, such as in-situ detection and measurement of physiological responses, and stimulation for enhanced drug absorption and therapeutic effect.

Description

MICRONEEDLE ARRAYS WITH HETEROGENEOUS NEEDLES, AND SYSTEMSAND COMPONENTS THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 675,689, filed July 25, 2024, the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure pertains to systems and methods involving microneedle arrays engineered for intradermal and / or transdermal delivery of molecules, for diagnosis, treatment of immune-mediated diseases and other diseases and ailments, via the skin. Particularly, the disclosure relates to systems and methods for a heterogeneous microneedle array (h-MAP) device comprising multiple needle types, with primary and secondary needles.BACKGROUND

[0003] The skin is ideally suited for the delivery of treatments including the activation of immunological responses. Traditionally, drug delivery, including for immunization and desensitization of immune-mediated diseases and other ailments, are administered using hypodermic needle-based injections to intramuscular tissue or oral tablets to the gut mucosa. However, these methods fail to deliver biologies reproducibly and precisely to targeted immune-rich, skin microenvironments, resulting in suboptimal efficacy, high doses of biologies with high toxicity, and inefficient treatment strategies. Furthermore, hypodermic needle-based injections consist of several challenges, including the need for trained healthcare personnel for injection, low patient compliance due to needle phobia, risk of disease transmission, risk of “sharps” injuries, and substantial costs associated with cold storage and transportation of underlying treatments.SUMMARY OF THE DISCLOSURE

[0004] In some embodiments, an apparatus comprises a plurality of microneedles configured to be inserted into a skin of a subject to deliver a treatment under the skin, the plurality of microneedles including a first set of microneedles and a second set of microneedles different than the first set of microneedles; and a base structure coupled to the plurality of microneedles and configured to support the plurality of microneedles during insertion into the skin, a tip ofeach microneedle of the plurality of microneedles extending away from the base structure such that the base structure remains outside of the skin when the plurality of microneedles are inserted into the skin.

[0005] In some embodiments, an apparatus comprises a plurality of microneedles configured to be inserted into a skin of a subject to deliver a treatment under the skin, the plurality of microneedles disposed in a predetermined arrangement; a base structure coupled to the plurality of microneedles and configured to support the plurality of microneedles during insertion into the skin, a tip of each needle of the plurality of needles extending away from the base structure such that the plurality of needles can be inserted under the skin while the base structure remains outside of the skin; and a transducer coupled to the base structure and configured to vibrate the base structure to facilitate insertion of the plurality of microneedles into the skin and / or to separate the base structure from the plurality of microneedles.

[0006] In some embodiments, a method comprises receiving a force at a first surface of a base structure of a microneedle array patch such that a plurality of microneedles coupled to the base structure are inserted into a skin of a subject, the plurality of microneedles including a first set of microneedles and a second set of microneedles different than the first set of needles; anchoring, via the plurality of microneedles, the microneedle array patch relative to the skin; releasing a bioactive agent from at least one of the first set of microneedles or the second set of microneedles to a target layer of the skin; and activating a portion of the microneedle array patch to separate the base structure from the plurality of microneedles.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Some embodiments of the present disclosure are depicted for illustrative purposes and are not constrained by the figures of the accompanying drawings. In these drawings, like reference numerals may denote similar elements across the various views:

[0008] FIG. l is a schematic block diagram of a microneedle array, according to embodiments.

[0009] FIG. 2A depicts an isometric view of one example of a microneedle array with heterogeneous needles, according to embodiments.

[0010] FIG. 2B illustrates a side view of the example embodiment of a microneedle array with heterogeneous needles as depicted in FIG 2A.

[0011] FIG. 3 is a schematic illustration of an example system for a microneedle array with heterogeneous needles with electrical stimulation and indication.

[0012] FIG. 4 depicts an isometric view of an example of a microneedle array with heterogeneous needles of varying dimensions, locations, and purposes, according to various embodiments described herein.

[0013] FIG. 5 illustrates an isometric view of an example of a microneedle array with heterogeneous needles of varying dimensions, locations, and purposes, according to various embodiments described herein.

[0014] FIG. 6 shows a side profile view of an example of a microneedle array with heterogeneous needles of varying dimensions, locations, and purposes, according to various embodiments described herein.

[0015] FIGS. 7A and 7B illustrate the anatomy of the skin and placement of a microneedle array.

[0016] FIG. 8 shows a side profile view of an example of a microneedle array with heterogeneous needles of varying dimensions, locations, and purposes, according to various embodiments described herein.

[0017] FIG. 9 depicts a side profile view of an example of a microneedle array with heterogeneous needles of varying dimensions, locations, and purposes, according to various embodiments described herein.

[0018] FIG. 10 is a flow chart diagram of an example method of delivering a bioactive agent under the skin using a microneedle array patch, according to embodiments.DETAILED DESCRIPTION OF THE DISCLOSURE

[0019] The skin, a complex and multifunctional organ, serves not only as a protective barrier and thermal regulator but is readily accessible tissue ideally suited for the delivery of treatments including the activation of immunological responses. An active immune organ, the skin contains a rich, high-density network of antigen-presenting and immune-accessory cells, making it a preferred anatomic target site to “train” the immune-responsive system to modulate pathogenic-specific protective immunity (immunization) and / or anti-inflammatory tolerance (desensitization). The skin is also an ideal entryway to the body’s circulatory system.

[0020] Traditionally, drug delivery, including for immunization and desensitization of immune-mediated diseases and other ailments, are administered using hypodermic needlebased injections to intramuscular tissue or oral tablets to the gut mucosa. However, these methods fail to deliver biologies reproducibly and precisely to targeted immune-rich, skin microenvironments, resulting in suboptimal efficacy, high doses of biologies with high toxicity, and inefficient treatment strategies. Furthermore, hypodermic needle-based injectionsconsist of several challenges, including the need for trained healthcare personnel for injection, low patient compliance due to needle phobia, risk of disease transmission, risk of “sharps” injuries, and substantial costs associated with cold storage and transportation of underlying treatments.

[0021] To overcome the formidable physical barrier of the skin (stratum corneum) and deliver molecules to the epidermis and upper layers of the dermis, where the highest concentration of immune-responsive cells resides, various microneedle array-based systems and methods disclosed herein have been developed to enhance the diagnosis and treatment of immune- mediated diseases.

[0022] The systems and methods disclosed herein include an advanced heterogeneous microneedle array designed for the broad-based intradermal and / or transdermal delivery of biologically active molecules to the skin, applicable to a wide range of cosmetic, aesthetic, therapeutic, diagnostic, and / or testing applications. The heterogeneous microneedle arrays are engineered with diverse specifications such as size, tip shapes, needle location, spacing, length, and material properties to optimize insertion, durability, efficacy, and delivery confirmation. These arrays may comprise varying needle dimensions and primary functions, with various needles designated as primary for delivery of a bioactive agent and other needles designated as secondary for purposes inclusive or exclusive of biologic delivery. Such purposes may include embedded sensors and physical mechanisms for in-situ detection of chemical and biochemical markers, wound healing, pain amelioration, neurostimulation, tissue anchoring, and multi- biological cargo delivery.

[0023] The comprehensive details, objectives, features, and advantages of the present disclosure are further elucidated in the detailed description that follows, which is accompanied by figures illustrating the heterogeneous microneedle array system.

[0024] This detailed description covers specific example embodiments related to the design and use of microneedle arrays (MNAs) with heterogeneous needles. While the examples focus on particular MNAs, it is important to understand that the systems and methods described here are applicable to various other types of MNAs. For the purpose of clarity and to ensure a thorough understanding, numerous specific details are included in this description. However, it is evident to those skilled in the art that the principles outlined may be practiced in the absence of these specific details.

[0025] The terminology utilized in this document is intended solely for describing specific embodiments and should not be seen as limiting the scope of the disclosure. The term "and / or" as used herein encompasses any possible combination of one or more of the listed items.Similarly, the singular terms "a," "an," and "the" include both their singular and plural forms unless the context explicitly indicates otherwise. As used herein, the terms “biologic,” “drug,” “active component,” “bioactive agent” refers to active pharmaceutical agents (APIs), such as anesthetic agents, immunostimulating agents, immunosuppressive agents, cytotoxic agents, antigens, adjuvants, antihistamines, corticosteroids, allergens, monoclonal antibodies, antioxidants, peptides, hydrating agents, exfoliants, lightening agents, cholinergic agents, dopaminergic agents, GABAergic agents, and the like. The bioactive agent may include materials that are dissolvable, materials that are insoluble yet dispersible, as well as natural or engineered macro, micro, and nano particulates. Additionally, it can consist of combinations of two or more dissolvable, dispersible, and insoluble materials, along with natural or synthesized macro, micro, and nano particulates. It is also understood that the terms "comprises" and "comprising" are inclusive in this specification, indicating the presence of stated features, elements, operations, and components while allowing for the addition of others.

[0026] This description of the present disclosure acknowledges various techniques and steps, each offering distinct advantages and capable of being used in combination with others. For clarity, not every potential combination of these steps is detailed explicitly; however, it should be recognized that such combinations are contemplated within the scope of the present disclosure and the accompanying claims.

[0027] The present disclosure is to be considered as an exemplification of the present disclosure, and is not intended to limit the disclosure to the specific embodiments illustrated by the figures or description below. Additionally, for clarity, the accompanying illustrations may not depict all possible configurations and combinations (which are readily apparent to those of ordinary skill in the art based on this disclosure) in which the described system, method, and apparatus can be employed alongside other systems, methods, and apparatuses. Furthermore, this description occasionally employs terms like "produce" and "provide" to depict the operations of the disclosed method. These terms represent generalized actions, and the specific operations they entail can differ according to the particular implementation. These operations are, however, readily identifiable by one of ordinary skill in the art from the information provided in this disclosure.

[0028] The present disclosure will be described by referencing the appended figures representing some but not all preferred embodiments of a microneedle array with heterogeneous needles, comprising primary and secondary needles with similar and / or differing functions.

[0029] FIG. 1 is a schematic block diagram of a microneedle array (MNA) patch 136, according to embodiments. The MNA patch 136 can include a microneedle array 140, a skin adhesive 134, a base structure 132 (e.g., a base plate), and may optionally include an identifier 138 (e.g., an near-field communication (NFC) Chip, radio frequency identification (RFID), quick-response (QR) code, etc.), one or more sensors 142, and / or one or more transmitters 144. The base structure 132 may be a flexible or rigid backing coupled to the plurality of microneedles. The microneedle array 140 may include a first surface including a plurality of absorbable needles and a second surface opposite the first surface that is configured to be coupled to the skin adhesive 134 and / or the base structure 132. In embodiments, the second surface opposite the first surface may be substantially flat, non-conformable, and composed of non-dissolving and / or absorbable material. In embodiments, the second surface opposite the first surface may be substantially flat, conformable, and composed of the same material as the first surface and / or absorbable needles. In embodiments, the microneedle array 140 may be coupled to the base structure 132 via any suitable mechanism (e.g., built-in snapfits, friction fit, adhesive, clips, magnets, threading, etc.). The skin adhesive 134 may include a first surface (e.g., a distal surface) configured to secure or adhere the microneedle array 140 to the skin of the user for a period of time while the microneedle array 140 dissolves and the agent is delivered.Microneedles:

[0030] The MNA comprises a plurality of microneedles. In some embodiments, the plurality of microneedles can be the same type of microneedle. In some embodiments, the plurality of microneedles can include different types of microneedles (e.g., microneedles with different lengths, sizes, configurations, structural polymers, and / or agents). In some embodiments, some microneedles are designated as secondary needles while others are designated primary or standard needles and are configured to deliver a bioactive agent. The primary needles and secondary needles can vary in microneedle length, thickness, tip shape, spacing between microneedles, and relative positioning and clustering in the microneedle array 140. The secondary needles can be, for example, a type of microneedle on a microneedle array designed to complete and / or serve additional, specialized functions within a microneedle array. These secondary microneedles may comprise and / or be equipped with features such as electrical, chemical, biological and / or physical sensors, specialized coatings, vibration, microelectronics, biodissolvable materials, tissue anchoring, skin tightening, multi-cargo bioactive agents, and the like. The standard or primary needles can be, for example, a needle of a microneedle arraywith the primary function of delivering a bioactive agent to the epidermis and / or dermis of the skin.

[0031] In embodiments, the microneedles can be about 50 pm to about 1000 pm in length and about 50 pm to about 350 pm in width or thickness, inclusive of all ranges and subranges therebetween. In embodiments, the microneedles can be about 200 pm to about 800 pm in length and about 150 pm to about 200 pm in width, inclusive of all ranges and subranges therebetween. In some embodiments, at least some of the plurality of microneedles may have a length of about 50 pm, about 200 pm, about 400 pm, 600 pm and / or about 750 pm.

[0032] In some embodiments, one or more of the microneedles are in the shape of a square obelisk, with a square stem structure and a pyramid tip structure. In embodiments, an agent is loaded into and / or resides in the pyramid tip structure of the microneedle of the MNA. In embodiments, one microneedle can be configured to deliver about 1 to about 30 nanoliters (nL) of agent, inclusive of all ranges and subranges therebetween.

[0033] In some embodiments, the tip of one or more of the microneedles may be shaped as an arrowhead (e.g., be arrow-shaped) or with an undercut feature capable of improving penetration of the stratum corneum and / or providing positional stability once the microneedle array has been inserted. The arrowhead and / or undercut features provide an anchoring point for the microneedle array to stay in place after application. For example, the undercut feature may prevent the microneedle array from being pulled out of the skin such that the microneedles are maintained at a desired depth under the skin. In some embodiments, the undercut feature may have a maximum width (e.g., the width at the base of the arrow or pyramid shape) in a range of about 180 pm to about 350 pm, inclusive of all ranges and subranges therebetween. In some embodiments, the undercut feature may have a maximum width in a range of about 225 pm to about 275 pm, inclusive of all ranges and subranges therebetween. In some embodiments, the undercut feature may have a maximum thickness or width of about 250 pm. In some embodiments, the undercut feature may be disposed at a distal end of a microneedle having a thickness in a range between about 100 pm to about 200 pm, inclusive of all ranges and subranges therebetween. In some embodiments, the undercut feature may be disposed at a distal end of a microneedle having a thickness of about 175 pm. In some embodiments, the undercut feature (e.g., the base of the arrowhead or pyramid) may be a predetermined amount thicker than the thickness of the microneedle. For example, the undercut feature may be about 10% thicker, 20% thicker, 30% thicker, 40% thicker, 50% thicker, 60% thicker, 70% thicker, 80% thicker than the microneedle thickness, inclusive of all values and ranges therebetween.

[0034] In embodiments, one or more of the microneedles are filleted at the base. In embodiments, the microneedles have a fillet radius of between about 10 and about 100 pm, inclusive of all subranges and values therebetween. In embodiments, the microneedles have a fillet radius of between about 10 gm and about 50 gm, inclusive of all subranges and values therebetween. In embodiments, the microneedles have a fillet radius of about 20 gm and about 40 gm, inclusive of all subranges and values therebetween.

[0035] The microneedles can be fabricated from a structural polymer and / or an agent. In embodiments, the microneedles can be fabricated from only a structural polymer. In embodiments, the microneedles are fabricated from a structural polymer and an agent, including bioactive, non-active, and / or functional, only. In embodiments, the microneedles are fabricated from a bioactive agent only. In embodiments, the microneedles are fabricated from a non-active agent only. In embodiments, the microneedles are fabricated from a functional agent only. In embodiments, the microneedles are fabricated from an agent that is water-soluble only. In embodiments, the microneedles are fabricated from an agent that is non-water-soluble only.

[0036] In embodiments, the structural polymer is biocompatible. In embodiments, the biocompatible polymer is biodegradable or absorbable. In embodiments, the biocompatible polymer is non-biodegradable or not absorbable. In embodiments, the structural polymer is water-soluble. In embodiments, the microneedles are formed from or include biocompatible, absorbable and / or dissolvable polymers and are used for transdermal and / or intradermal delivery of various agents such as but not limited to carbohydrates, lipids, vitamins, minerals, hormones, antibodies, nucleic acids (e.g., DNA, RNA), small molecules, biologies, peptides, proteins, fillers and / or, humectants. In embodiments, the structural polymer is carboxymethylcellulose (CMC), trehalose, sucralose, polyvinylpyrrolidone (PVP), maltodextrin, silk, hyaluronic acid, polyvinyl alcohol, polyethylene glycol, poly(lactic-co- glycolic acid), poly(lactic acid), or a mixture thereof. In embodiments, the microneedles are fabricated from carboxymethylcellulose, polyvinylpyrrolidone, or hyaluronic acid. In embodiments, the microneedles are fabricated from hyaluronic acid or carboxymethylcellulose. Absorbable and / or dissolvable microneedles are used for transdermal and / or intradermal delivery of various agents for applications such as, but not limited to, cosmetics, aesthetics, and / or therapeutics.

[0037] The microneedles can be designed, manufactured, and / or formulated to overcome the physical barrier of the skin, the stratum corneum. In embodiments, the microneedles are solid microneedles that create microchannels through the stratum corneum for topical application ofagents to be delivered to the epidermis and dermis. In embodiments, the solid microneedles comprise a lacuna and / or channel for direct delivery of one or more agents to the skin of the subject (e.g. epidermis and / or dermis). In embodiments, the solid microneedles are coated with one or more agents that are dissolved into the epidermis and / or dermis of the skin after penetration of the stratum comeum. In embodiments, the microneedles are dissolvable, absorbable, and / or biodegradable. In embodiments, the microneedles are non-biodegradable. In embodiments, the microneedles are fabricated from the same material as the base plate of the MNA. In embodiments, the microneedles are fabricated from different materials as compared to the base plate of the MNA. In embodiments, the microneedles are fabricated from composites, metals, plastics, water-soluble, non-water-soluble, and / or dissolvable materials.Microneedle Array (MNA):

[0038] In embodiments, the microneedle array 140 may be any suitable microneedle array 140. For example, the microneedle array may be formed in any size or shape. The microneedle array may have any dimensions. For example, the microneedle may have a width between about 2 mm to about 30 mm, inclusive of all values and subranges therebetween. The microneedle array 140 may have a length between about 2 mm and about 30 mm, inclusive of all values and subranges therebetween. In embodiments, a needle density and / or a size of the microneedle array may depend on a treatment (agent) type and / or formulation (e.g., small molecule, peptide, protein, nucleic acid, etc.). While described as an array, the microneedles may be arranged in any suitable pattern (e.g., a circle, linearly, an irregular shape, a zig-zag, etc.) In embodiments, the microneedle array may be configured for any one of diagnostics, treatments, or testing (e.g., treatment evaluation). In embodiments, the microneedle array 140 may be multifunctional.

[0039] The microneedles are typically structured in an organized array (e.g., 10 by 10 configuration, 20 by 20 configuration, 10 by 30 configuration, etc.). Agents may be embedded within the structural polymer of the microneedles and / or premixed with the structural polymer of the microneedles. A single MNA may have one (i.e., single cargo) or multiple (i.e., multicargo) agents embedded and / or premixed (“loaded”) within the structural polymer of the microneedles. A single MNA with multiple agents may be referred to as a multi-cargo MNA. In embodiments, a single MNA may include multiple agents by having sets of different microneedles, e.g., a first set of microneedles that carry a first agent and a second set of microneedles that carry a second agent. In embodiments, a single MNA may include multiple agents by having microneedles that each carry multiple agents. A MNA may be designed with specific characteristics (e.g., microneedle geometry, tip sharpness, needle spacing) to (i) penetrate the stratum corneum without mechanical failure (e.g., needle fracture, needledeformation, etc.); (ii) target and reach the epidermis and / or dermis of the skin, which is about 200 to 750 pm below the stratum corneum (surface of the skin); and (iii) rapidly dissolve and / or absorb into the skin (e.g., via structural polymer) to deliver embedded and / or premixed agent(s). In embodiments, an MNA may include an array of needles having a stem structure and / or tip structure with specific geometry, e.g., to improve skin penetration, mechanical strength, etc. In embodiments, the MNA may include an array of needles having a square obelisk shape, with a square stem structure and a pyramid tip structure. In embodiments, an agent is embedded into and / or resides in the tip of the microneedle of the MNA.

[0040] In embodiments, the MNA comprises between about 1 microneedle and about 1000 microneedles, inclusive of all ranges and subranges therebetween. In embodiments, the MNA comprises 100 microneedles to about 750 microneedles, inclusive of all ranges and subranges therebetween. In embodiments, the MNA comprises 100 microneedles. In embodiments, the MNA comprises 200 microneedles. In embodiments, the MNA comprises 300 microneedles. In embodiments, the MNA comprises 400 microneedles. In embodiments, the MAN comprises 500 microneedles.

[0041] In embodiments, the microneedles are arranged on the MNA as 1-100 microneedles by 1-100 microneedles. In embodiments, the microneedles are arranged on the MNA as 10-75 microneedles by 10-75 microneedles. In embodiments, the microneedles are arranged on the MNA as 10-50 microneedles by 10-50 microneedles. In embodiments, the microneedles are arranged on the MNA as 10-30 microneedles by 10-30 microneedles. In embodiments, the microneedles are arranged as 10-20 microneedles by 10-20 microneedles. In embodiments, the microneedles are arranged in a 10 by 10 array. In embodiments, the microneedles are arranged in a 20 by 20 array. In embodiments, the microneedles are arranged on the patch in a 10 by 30 array.

[0042] The pitch of the microneedles is defined as a tip-to-tip distance between the microneedles. In embodiments, the microneedles are pitched about 5 pm to about 1000 pm apart, inclusive of all ranges and subranges therebetween. In embodiments, the microneedles are pitched at about 5 pm to about 800 pm apart on the MNA. In embodiments, at least some of the microneedles are pitched at about 5 pm to about 250 pm apart on the MNA. In embodiments, at least some of the microneedles are pitched at about 100 pm to about 1000 pm apart on the MNA. In embodiments, the microneedles are pitched 500 pm to about 725 pm apart on the MNA. In embodiments the microneedles are pitched 675pm apart on the MNA. In some embodiments, the microneedles (e.g., the primary microneedles) may be pitched between about 500 pm to about 800 pm apart, inclusive of all ranges and subranges therebetween. Insome embodiments, the pitch of the primary microneedles may be different than the pitch of the secondary microneedles.

[0043] In embodiments, the microneedles are pitched between about 0.005 mm and about 50 mm apart on the MNA, inclusive of all subranges and values therebetween. In embodiments, the microneedles are pitched 0.005-40 mm apart on the MNA. In embodiments, the microneedles are pitched 0.005-25 mm apart on the MNA. In embodiments, the microneedles are pitched 0.005-10 mm apart on the MNA. In embodiments, the microneedles are pitched 0.005-1 mm apart on the MNA.

[0044] In embodiments, the MNA comprises one or more pluralities of microneedles, each plurality of microneedles comprises microneedles of differing lengths, shapes, and / or compositions. In embodiments, the MNA comprises one or more pluralities of microneedles, each plurality of microneedles comprises microneedles of the same lengths and / or compositions. In embodiments, the MNA comprises five pluralities of microneedles. In embodiments, the MNA comprises four pluralities of microneedles. In embodiments, the MNA comprises three pluralities of microneedles. In embodiments, the MNA comprises two pluralities of microneedles. In embodiments, all of the microneedles comprised within the MNA are of the same length.

[0045] In embodiments, the MNA comprises at least two pluralities of microneedles. For example, the MNA can include the primary microneedles and the secondary microneedles. In some embodiments, the primary microneedles and the secondary microneedles may have the same length (or other characteristics). In some embodiments, the primary microneedles and the secondary microneedles may have different lengths (or other characteristics).

[0046] In embodiments, when the MNA is applied to the skin of a subject, the first plurality of microneedles reach the epidermis of the subject and / or the second plurality of microneedles reaches into the dermis. In embodiments, the MNA comprises microneedles, such as, for example, shorter microneedles (e.g., primary microneedles) that are between about 50 pm and about 250 pm in length, inclusive of all sub-ranges and values therebetween. In some embodiments, the MNA comprises microneedles, such as, for example, longer microneedles (e.g., secondary microneedles) that are between about 250 pm and about 850 pm in length, inclusive of all subranges and values therebetween. In some embodiments, the first plurality of microneedles (e.g., the primary microneedles) can comprise microneedles about 100 pm to about 250 pm in length, inclusive of all ranges and subranges therebetween. The second plurality of microneedles (e.g., the secondary microneedles) can comprise microneedles about 500 pm to about 800 pm in length, inclusive of all ranges and subranges therebetween.

[0047] In some embodiments, the plurality of microneedles may extend at an angle relative to the based of the MNA (or the base structure 132.) In some embodiments, the plurality of microneedles may extend at an angle less than about 60 degrees relative to the base structure. In some embodiments, the plurality of microneedles may extend at an angle of about 15 degrees, about 30 degrees, or about 45 degrees. In some embodiments, the primary microneedles and the secondary microneedles may extend at different angles. In some embodiments, the primary microneedles may extend perpendicular to the MNA, and the secondary microneedles may extend at an angle less than about 60 degrees from the MNA. In some embodiments, the secondary microneedles may be positioned near a border or edge of the MNA and extend at an angle (e.g., toward the center of the MNA).

[0048] In some embodiments, the microneedles may be arranged in a predetermined pattern or formation. For example, the secondary microneedles may be disposed around at least a portion of a border or edge of the MNA to help anchor the MNA into the skin after penetration. In some embodiments, the primary microneedles and the secondary microneedles may alternate across one or both axes (e.g., x axis or rows and y axis or columns) of the MNA. For example, the MNA may have an order across the rows and the columns of primary microneedle, secondary microneedle, primary microneedle, secondary microneedle, and so on. In some embodiments, the primary microneedles and the secondary microneedles may alternate every other microneedle. In some embodiments, the primary microneedles and the secondary microneedles may alternate every 2 microneedles, every 3 microneedles, every 4 microneedles, every 5 microneedles, etc.

[0049] In some embodiments, the secondary microneedles may be arranged in one or more clusters, and all other microneedles on the MNA may be primary microneedles. In some embodiments, the cluster may have a predetermined dimensions such as, for example, 2 by 2 microneedles, 3 by 3 microneedles, 4 by 4 microneedles, 5 by 5 microneedles, 6 by 6 microneedles. In some embodiments, the secondary microneedles may be arranged in one cluster disposed around the center of the MNA and / or in a central portion of the MNA. In some embodiments, the MNA may include a plurality of clusters of secondary microneedles, and each cluster may be disposed at or near a corner of the MNA. In some embodiments, the MNA may include a first set of clusters of secondary microneedles and a second set of clusters of primary microneedles, and the first set of clusters and the second set of clusters may alternate across one or both axes of the MNA.MNA Patch:

[0050] In embodiments, the microneedle array 140 and the skin adhesive 134 may be coupled to the base structure 132. The base structure 132 provides a support for MNA patch 136 (e.g., the skin adhesive 134, the base structure 132, and / or the identifier 138). For example, the base structure 132 may support the microneedles during insertion into the skin. In some embodiments, a distal tip (e.g., a sharp end or tip) of the microneedles may extend away from the base structure 132 such that the base structure 132 remains outside of the skin while the microneedles are inserted into the skin. The base structure 132 may be configured to receive a force from actuator(s) of an applicator. The base structure 132 may include a rigid material to prevent deformation of the base structure 132 when the force is applied. For example, the base structure 132 may resist deformation in response to the force applied by the actuator(s) to push the microneedle array 140 into the skin (e.g., about 5 Newtons (N) to about 20 N, inclusive of subranges and values therebetween). The base structure 132 may increase or ensure uniform transmission of the force to the microneedle array 140, such that the microneedle array 140 follows a substantially linear path into the skin during penetration. In embodiments, the base structure 132 may have a cross-sectional area that spans a total area of the microneedle array 140 such that force is applied uniformly to the microneedle array 140 from the base structure 132. For example, if the microneedle array 140 has a first area (e.g., 15 mm by 15 mm area), the base structure 132 may include a second area configured to cover at least the first area (e.g., at least 225 mm2).

[0051] In embodiments, the base structure 132 may include any suitable material configured to resist deformation and / or uniformly transfer force or pressure. The base structure 132 may include, for example, a metal, a polymer, a plastic, ceramic, or a suitable combination thereof. For example, the base structure 132 may include a polypropylene, polystyrene, nylon, polycarbonate, methacrylate, etc. The skin adhesive 134 may include any suitable material configured to comfortably adhere to the skin of the patient.

[0052] In embodiments, the base structure 132 may include suitable materials and electronics to enable closed-loop feedback for application, delivery, and treatment evaluation. The electronics may communicate with embedded sensors integrated and / or adjacent to the plurality of absorbable microneedles in contact with the skin. In embodiments, the embedded sensors may detect changes in skin impedance, temperature, pH, and / or other physiological parameters to provide confirmation to the user. In embodiments, the sensors may detect specific and / or disease specific markers (“biomarkers”) to evaluate the absorbable MNA treatment. While the electronics can be embedded in the base structure 132, the electronics (or a portion thereof) can embedded in other locations, e.g., in the needles (e.g., secondary microneedles of themicroneedle array 140). Details of embedded sensors are described in further detail below. The transmitter(s) 144 of the MNA patch 136 may be configured to receive data from the sensor(s) 142 and to send the data to an external device (e.g., a processor of a third-party device.)

[0053] In some embodiments, the base structure 132 can be actuated to push the MNA patch toward the skin surface such that the microneedles are inserted into the skin. In embodiments, the microneedle array 140 is partially inserted into the skin, e.g., approximately one-fifth of the microneedle array (e.g., backing layer) may not be in the skin but resting on a surface of the skin. The skin adhesive 134 can then be disposed around the microneedle array 140 and in contact with the skin. Once the microneedle array 140 is inserted into the skin, the base structure 132 may protect the microneedle array 140 from external forces and / or from being dislodged, dislodged. The base structure 132 may enable the user to easily remove the skin adhesive 134 and any other material left on the skin after the treatment has been absorbed.

[0054] In embodiments, the MNA patch comprises an array of microneedles that are arranged on a base structure in an area between about 1-100 mm in width and between about 1-100 mm in length, inclusive of all subranges and values therebetween. In embodiments, the MNA comprises an array of dissolvable and / or absorbable microneedles that are arranged on a base plate in an area 1-50 mm in width by 1-50 mm in length. In embodiments, the MNA comprises an array of microneedles that are arranged on a base plate in an area 5-40 mm in width by 5- 40 mm in length. In embodiments, the MNA comprises an array of microneedles that are arranged on a base plate in an area 10-30 mm in width by 10-30 mm in length. In embodiments, the MNA comprises an array of microneedles that are arranged on a base plate in an area of 10 mm by 10 mm. In embodiments, the MNA comprises an array of microneedles that are arranged on a base plate in an area of 15 mm by 15 mm. In embodiments, the MNA comprises an array of microneedles that are arranged on a base plate in an area of 10 mm by 30 mm. In embodiments, the MNA comprises an array of microneedles that are arranged non-uniformly (i.e., not structured as an array) on a base plate.

[0055] In embodiments, the MNA patch is fabricated from silicone and / or another flexible material. In embodiments, the MNA patch further comprises an adhesive.

[0056] In embodiments, the base structure is flexible and / or conformable to the curvature of the skin. In embodiments, the base plate is rigid and / or non-conformable. In embodiments, the base plate comprises a circular shape. In embodiments, the base plate comprises a rectangular shape. In embodiments, the base plate comprises a square shape. In embodiments, the base plate comprises an irregular shape including but not limited to a star, bean, or triangle.

[0057] In embodiments, a first plurality of microneedles can be disposed on a first base plate, while a second plurality of microneedles can be disposed on a second base plate separate from the first base plate. One or more additional pluralities of microneedles can also be disposed on one or more additional base plates. In embodiments, a MNA patch can comprise one, two, three, four, or more MNAs. In embodiments, each MNA disposed on a MNA patch comprises microneedles of different lengths, compositions, and / or cargos. In embodiments, each MNA disposed on the MNA patch comprises microneedles having the same lengths, compositions, and / or cargos. In embodiments, some of the MNAs disposed on the MNA patch comprises microneedles having the same lengths, compositions, and / or cargos, and some of the MNA disposed on the MNA patch comprises microneedles of different lengths, compositions, and / or cargos.

[0058] In some embodiments, the MNA and the microneedles are fabricated from carboxymethylcellulose or polyvinylpyrrolidone, and the MNA patch is fabricated with a medical adhesive

[0059] The identifier 138 can include a near-field communication chip that allows for wireless communication between one or more devices (the MAP and user device). In some embodiments, the identifier 138 may be scannable to register a treatment contained on the microneedle array 140. In some embodiments, the identifier 138 may be configured to send additional information relating to the treatment (e.g., a progress of absorption). For example, the MNA patch may include one or more sensors configured to measure penetration and / or absorption, and the identifier 138 may be configured to send this information to the user device such that the user device can display this information to the user. The identifier 138 may include a coupling mechanism or connector (e.g., an adhesive) on one side in order to couple the identifier 138 to the ridged backing 132. The identifier 138 may be coupled to the skin adhesive 134 with a second coupling mechanism or connector (e.g., a permanent double-sided adhesive). Alternatively or additionally, the identifier 138 may be disposed on or in a packaging in which the MNA patch 136 is delivered. In some embodiments, the identifier 138 may include a scannable code (NFC, RFID, or QR code) provided by a medical professional.

[0060] The user may scan the identifier 138 on the packaging and / or a scannable code at the medical office and / or at home to register the treatment. In some embodiments, the identifier 138 may be scanned to register the treatment such that the user and / or a medical professional can track treatments the user has undergone, effectiveness of the treatments, user compliance (e.g., receipt, use disposal), etc. In some embodiments, a user interface may be configured to display (e.g., when the user scans the identifier 138) information such as instructions, consentforms, permission forms, drug information, side effects, warnings, links to disease information and / or patient-specific content, provider information, appointment scheduling options, diagnostic results, disease management, etc. In some embodiments, the identifier 138 may be configured to send stability information related to the treatment. In some embodiments, the user interface may allow the user to input side effects and / or issues with the MNA patch 136. The user interface may additionally store individual data and / or aggregate data and / or send this information to a server or database.

[0061] In embodiments, the MNA patch 136 further comprises a vibration unit or vibration device. In embodiments, the vibration unit applies controlled mechanical vibrations during administration that enhance skin contact and reduce insertion force. In embodiments, the vibration unit improves the uniformity of microneedle penetration across diverse skin types and anatomical regions. In embodiments, the vibration assists in collagen production. In embodiments, the vibration device can include one or more transducers, piezoelectric elements or actuators, micro-motors, or other components configured to generate mechanical vibrations. The vibration device can be configured to generate vibration along one or more axes, e.g., an axis parallel to a direction of insertion and / or one or more axes perpendicular or set at a nonzero angle relative to the axis of insertion. The vibration device optionally has a tunable or adjustable intensity and / or frequency of vibration. In embodiments, the vibration device can be disposed on and / or integrated into a base structure of a MNA patch 136.

[0062] In some embodiments, the vibration unit may generate vibrations having a predetermined frequency. In some embodiments, the vibration unit may generate vibrations at a frequency between about 100 Hz and about 200 Hz, inclusive of all ranges and subranges therebetween. In some embodiments, the vibration unit may generate vibrations at about 100 Hz, about 125 Hz, about 150 Hz, about 175 Hz, about 200 Hz, inclusive of all values and ranges therebetween. In some embodiments, the predetermined frequency of vibration may stimulate natural production of biological materials such as adjuvant, collagen, etc. in the skin. In some embodiments, the vibration unit may generate high frequency vibrations (e.g., ultrasonic frequencies).

[0063] In some embodiments, the vibration unit may generate vibrations having a predetermined amplitude. In some embodiments, the vibration unit may generate vibrations having an amplitude in a range between about 0.05 mm to about 2 mm, inclusive of all ranges and subranges therebetween. In some embodiments, the vibration unit may generate vibrations having an amplitude in a range between about 0.2 mm to about 1 mm, inclusive of all ranges and subranges therebetween. In some embodiments, the vibration unit may generate vibrationsin a range between about 0.2 and about 0.5 mm, inclusive of all ranges and subranges therebetween. The vibration amplitude may be below an upper threshold to ensure safe skin penetration. The vibration amplitude may be sufficiently large to enable effective skin penetration.

[0064] In some embodiments, the vibration unit may be configured to vibrate before and / or during the insertion of the MNA to help reduce a total force required to penetrate the skin such that the microneedles more easily penetrate the skin. In some embodiments, the vibration unit may be configured to vibrate during and / or after insertion (e.g., when the microneedles are disposed in the skin to facilitate production of natural adjuvant, collagen, etc.). In some embodiments, the vibration unit may be configured to vibrate after insertion to separate the base structure 132 from the MNA 140.

[0065] In some embodiments, the vibration unit may include one or more actuators or motors (e.g., rotational or linear) to generate the vibrations. For example, the vibration unit may include an eccentric rotating mass (ECM) including a motor (e.g., a direct current (DC) motor) and an off-center weight to generate vibration at a predetermined frequency during rotation of the ECM. In some embodiments, the vibration unit may include a linear actuator such as a linear resonant actuator (LRA). In some embodiments, the linear actuator may include a mass coupled to a spring driven by alternating current (AC) at a resonant frequency.

[0066] In some embodiments, the vibration unit may be coupled to a plate coupled to a surface of the MNA to generate vibration (e.g., uniformly) across the entire MNA. In some embodiments, the vibration unit may be coupled to the base structure 132 such that the vibration is uniform across the entire MNA 140. In some embodiments, the vibration unit may be configured to direct vibration only to a subset of microneedles. For example, the vibration unit may be coupled to the MNA via one or more attachment mechanisms such that the vibration unit is configured to direct vibration to the secondary microneedles. In some embodiments, a first subset of the microneedles may be configured to move (e.g., relative to the base plate,) while a second subset of the microneedles may be configured to remain stationary (e.g., relative to the base plate,) and one of the subsets may be configured to vibrate in the skin in response to vibrations from the vibration unit. In some embodiments, the primary microneedles may be configured to move (e.g., relative to the base plate,) and the secondary microneedles may be configured to remain stationary (e.g., relative to the base plate.) In some embodiments, the secondary needles may be configured (e.g., relative to the base plate,) and the primary microneedles may remain stationary (e.g., relative to the base plate.) In someembodiments, the base plate may be vibrated. In some embodiments a different surface or plate in the MNA may be vibrated.

[0067] In some embodiments, the one or more sensors 142 of the MNA may be coupled to the base structure. In some embodiments, the one or more sensors 142 of the MNA may be coupled to or embedded in one or more of the plurality of microneedles. In some embodiments, the one or more sensors 142 of the MNA may be coupled to or embedded in the secondary microneedles.

[0068] In some embodiments, the one or more sensors 142 may be configured to measure physiological parameters including impedance, interstitial fluid amount, pH, temperature, concentration of biomarkers or other compounds, etc. In some embodiments, the sensor data can be processed (e.g., by a processor external to the MNA patch) to determine at least one of administration confirmation, adherence or compliance, performance of the MNA patch, efficacy of treatment, or side effects. In some embodiments, the sensor data may be processed to confirm the MNA patch has been administered and that the MNA patch has been administered correctly (e.g., “administration confirmation” or “application confirmation.”) For example, the one or more sensors 142 may be configured to measure a change in a physiological or biological parameter (e.g., a skin condition) such as skin electrical impedance before and after the secondary microneedles penetrate the skin. The one or more sensors 142 may include electrodes disposed on a portion of the secondary needles and may obtain a baseline measurement of skin impedance when the secondary needle tips are first in contact with the skin. The one or more sensors 142 may be configured to obtain continuous (or periodic) measurements as the secondary microneedles are pushed into the skin until a predetermined delta is measured, indicating all of the microneedles of the MNA 140 have penetrated the stratum comeum and / or reached the target skin layer. In some embodiments, the one or more sensors 142 may be configured to measure pH, temperature, transepidermal water loss in addition to or as an alternative to skin impedance. In some embodiments, a sensor 142 may be disposed on the base structure and a sensor 142 may be disposed on the MNA, and a relative position of the sensors may be tracked to determine when the base structure has been removed from the MNA.

[0069] In some embodiments, the one or more sensors 142 may be configured to confirm delivery of the microneedles of the MNA 140 and / or the treatment disposed therein. For example, the one or more sensors may be configured to monitor (e.g., continually or periodically) a skin condition (e.g., the skin impedance, pH, temperature, level of interstitial fluid, compounds, etc.) until a predetermined delta is reached, indicating the primarymicroneedles and / or secondary microneedles have dissolved and that the treatment was delivered. In some embodiments, the sensor(s) may be configured to measure concentrations of one or more compounds or immediate reactive skin conditions (e.g., skin impedance, pH, temperature change, etc.) to determine that the microneedles have dissolved and the treatment has entered the target layer of the skin (e.g., the stratum corneum, epidermis, dermis). Information relating to whether the secondary microneedles have dissolved can be used to determine that the MNA patch was administered properly and the treatment has been delivered. In some embodiments, the sensor(s) can be configured to detect breakage of the microneedles, indicating the MNA patch has not been administered properly.

[0070] In some embodiments, adherence or compliance refers to tracking that the user is administering the MNA patch as prescribed and / or is administering the MNA patch correctly. Adherence can be determined by tracking the administration of the MNA patch based on the sensor data. For example, adherence can be determined based on the application confirmation (e.g., confirmation patch was properly administered).

[0071] In some embodiments, the sensor data can be used to determine efficacy of a treatment. For example, the one or more sensors may be configured to sense physiological parameters and / or biological parameters including tissue impedance and / or disease-specific biomarkers or skin reactions after treatment delivery to determine an efficacy of the treatment. These physiological parameters can be transmitted (e.g., via the transmitter(s)) to a processor and analyzed to determine that the treatment loaded into the MNA patch is working properly. For example, the sensor may detect a change in concentration of disease-specific biomarkers and use this data to evaluate improvement of the condition. In embodiments, the sensor 142 may be configured to sample specific markers present in the delivery layer of the skin and the MNA patch 140 with marker sample may be removed and tested outside of the skin to evaluate treatment efficacy.

[0072] In some embodiments, the sensor data can be used to detect side effects from the MNA patch 140 by measuring physiological parameters indicative of swelling, scar tissue build up, immune responses, etc. For example, the sensor(s) may track scar tissue build up using impedance measures and / or immune responses based on a concentration of immune cells.

[0073] In some embodiments, the sensor data may be used to determine a performance of the MNA patch. For example, the physiological parameters such as impedance can be used to determine at which layer under the skin the microneedles are disposed. Therefore, it can be determined whether the treatment is being delivered to the target layer of skin.

[0074] FIG. 2A depicts an isometric view of the elements that may comprise a heterogeneous microneedle array system (h-MNA) according to various embodiments of the present disclosure. In preferred embodiments, some microneedles are designated as secondary needles 203 while others are designated primary or standard needles 202 and are configured to deliver a bioactive agent with each of the elements of the h-MNA configured to optimize and improve the functionality of microneedle arrays for cutaneous, intradermal and / or transdermal delivery of bioactive agents for diagnosis and treatment, which can vary, according to FIG. 2B in microneedle length, thickness, tip shape 204, spacing between microneedles, and relative positioning and clustering in the array of microneedles. The secondary needles can be, for example, a type of microneedle on a microneedle array designed to complete and / or serve additional, specialized functions within a microneedle array. These secondary microneedles may comprise and / or be equipped with features such as electrical, chemical, biological and / or physical sensors, specialized coatings, vibration, microelectronics, biodissolvable materials, tissue anchoring, skin tightening, multi-cargo bioactive agents, and the like. The standard or primary needles can be, for example, a needle of a microneedle array with the primary function of delivering a bioactive agent to the epidermis or dermis of the skin. These primary and secondary microneedles can be made of solid materials such as composites, metals, and plastics and / or water-soluble, dissolvable materials. The primary and secondary microneedles may protrude from a base plate 201 that can be made of a similar or different material as the secondary and / or primary microneedles.

[0075] The heterogeneous microneedle array system (h-MNA) can be made from different materials (metal, plastics, ceramics, and / or biodissolvable matrix) and may be manufactured as: a rigid, solid microneedle array to penetrate the stratum comeum of the skin and create microchannels to the epidermis for topical application of a bioactive agent; a hollow, solid microneedle array resembling hypodermic needle-based delivery for delivery of bioactive agents through micro lumens in the needles; a coated, solid microneedle array with individual needles coated with an bioactive agent; and / or dissolvable, biodegradable microneedle arrays formed with a biodissolvable, water soluble matrix with embedded thermostable, solid-state bioactive agents.

[0076] In one embodiment, the heterogeneous microneedle array system (h-MNAs) may be manufactured from a biodissolvable matrix. The primary and secondary microneedles of the hMNA may comprise various dissolvable materials formulations, compositions, and concentrations of varying dissolution rates to suit specific applications and desired delivery vectors. These dissolvable materials may comprise of substances such ascarboxymethylcellulose, trehalose, sucralose, polyvinylpyrrolidone, maltodextrin, silk, hyaluronic acid, polyvinyl alcohol, polyethylene glycol, poly(lactic-co-glycolic acid), poly(lactic acid), or a mixture of any of these. The backing layer of the h-MNA may be manufactured from similar and / or differing materials as the primary and secondary microneedles. In one embodiment, the base plate of the h-MNA may be manufactured from a non-dissolvable, flexible material such as silicone.

[0077] In one embodiment, the heterogeneous microneedle arrays may have designated secondary needles 203 integrated with and / or coupled to electronic and / or indication systems. In some embodiments, the electronic and / or indication systems can be housed in the base plate 201 of the microneedle array. Certain details of the MNA patch in FIG. 2 may be structurally and / or functionally similar to the MNA patch 136, and therefore, certain details of the MNA patch in FIG. 2 are not described again.

[0078] FIG. 3 depicts an example of an electronic and / or indication system, according to embodiments. The system may include indication systems 302 reactive to interstitial fluid (or biomarkers disposed therein) residing in the skin 303 for diagnosis and / or confirmation of bioactive agent delivery. The indication system 302 can include sensor(s) configured to measure a physiological metric. The transmitter(s) may be disposed on the MNA patch and configured to receive data from the senor(s) and to send the data to an external device. The system may also include electronic systems such as a control unit 320. The control unit 320 may be configured to vibrate the secondary and / or primary microneedles during insertion and / or delivery of bioactive agents. The vibration can be implemented via a vibration device 301 (e.g. a transducer) coupled to or disposed in the base plate 201 (i.e., h-MAP Base Plate). The control unit 320 can include a memory 321, a processor 322, and an input / output (I / O) device 323. The memory 321 can be, for example, a random-access memory (RAM), a memory buffer, a hard drive, a flash memory, a read-only memory (ROM), an erasable programmable read-only memory (EPROM), and / or the like. In some instances, the memory 321 can store, for example, one or more software programs and / or code that can include instructions to cause the processor 322 to perform one or more processes, functions, and / or the like. The processor 322 can be, for example, a hardware based integrated circuit (IC), or any other suitable processing device configured to run and / or execute a set of instructions or code. For example, the processor 322 can be a general-purpose processor, a central processing unit (CPU), an accelerated processing unit (APU), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), a programmable logic array (PLA), a complex programmable logic device (CPLD), a programmable logic controller (PLC) and / or the like. Insome embodiments, the memory 321 and processor 322 may be implemented on a single chip, while in other embodiments, the memory 321 and processor 322 may be implemented on separate chips but be in operative communication with one another. The I / O device 323 can include an input device and / or an output device, such as, for example, a display (e.g., Cathode Ray tube (CRT) display, Liquid Crystal Display (LCD), Light Emitting Diode (LED) display, Organic Light Emitting Diode (OLED) display, and / or the like), camera, microphone, touchscreen, button, and / or the like. For example, the I / O device 323 may include an input device for a user to input information or instructions and / or an output device for a user to receive an output. In some embodiments, the I / O device 323 can be used to provide alerts to a user. In some embodiments, the control unit 320 can control a signal generator 330 to generate a signal that causes the vibration device 301 to generate vibration. In some embodiments, the signal generator 330 can be coupled to a potentiometer 331, which can be configured to adjust a voltage output to the vibration device 301 to control vibration of the vibration device 301. Vibrational stimulation reduces the total force required to penetrate the stratum corneum and may enhance the secondary needles’ 203 ability to perform active functions such as, for example, scarification (e.g., process of creating micro punctures in the skin using, for example, physical or electrical stimulation) for enhanced natural adjuvant production, improvement of the deposition of bioactive agents and / or vaccines, etc. In some embodiments, vibrational stimulation from the base plate may cause both and / or one of the secondary microneedles and / or primary microneedles to break away from the base plate 201. Therefore, the vibration device 301 may be configured to provide vibrational stimulation that separates the microneedles from the base plate 201 such that the microneedles remain at least partially under the epidermis while the base plate remains outside of the epidermis and can be removed from the microneedles. While certain components of FIG. 3 are described as a singular part or as multiple parts, it can be appreciated that any one of the components depicted in FIG. 3 can include a single part or multiple parts that together form the component and / or perform all or a portion of the functions associated with that component.

[0079] In another embodiment, the heterogeneous microneedle arrays may have designated secondary needles 203 integrated with electronic and / or indication systems or portions thereof (e.g., one or more indication systems 302, control unit 320, signal generator 330, and / or potentiometer 331) housed in one or more of the needles 203 themselves. These electronic and / or indication systems may carry sentinel cargos, bioactive agents, or sensors that react chemically with interstitial fluid located in the skin present after penetration of the stratum corneum for in-situ detection and measurement of temperature, humidity, chemicalcomposition, and biochemical markers indicating whether an intended reaction has occurred. In embodiments, this may facilitate precise monitoring, indication, confirmation, and control over bioactive agent delivery and immune responses.

[0080] In another embodiment, the secondary microneedles of the heterogeneous microneedle array may be manufactured from a biodissolvable matrix with primary microneedles, comprising of a different biodissolvable material, concentration, and / or formulation from the biodissolvable material / matrix used for the formation of the secondary microneedle and to embed the thermostable, solid-state bioactive agent. The biodissolvable material of the primary microneedles may be configured to dissolve within two to twenty minutes after the heterogeneous microneedle array has penetrated the skin. The secondary microneedle biodissolvable material may be configured or formulated to dissolve faster or slower than the primary microneedle dissolvable material. In an example embodiment, a slower dissolvable secondary microneedle could deliver tissue healing agents such as Vitamin E after the delivery of a bioactive agent once the primary microneedle has dissolved.

[0081] In an example embodiment, the secondary microneedles 402 of the heterogeneous microneedle array may be located in various locations and / or clusters around or within the primary microneedles 401 of the microneedle array. As shown in FIG. 4, the secondary microneedles 402 may be arranged or clustered in a circular or rectangular pattern at or near a center of the microneedle array, and the primary microneedles 401 may be distributed around the secondary microneedles 402. Certain details of the MNA patch in FIG. 4 may be structurally and / or functionally similar to the MNA patch 136, and therefore, certain details of the MNA patch in FIG. 4 are not described again.

[0082] In another embodiment as shown in FIG. 5, the secondary microneedles 502 may be distributed at or around the corners and / or along the border or near a perimeter of the microneedle array. In some embodiments, the secondary microneedles may be arranged independently or may be clustered together. In some embodiments, the secondary microneedles may be disposed around the primary microneedles 501. In other words, the secondary microneedles 502 may be disposed closer to the border of the microneedle array than at least some of the primary microneedles 501. For example, the secondary microneedles 502 may be arranged in clusters (e.g., square, rectangular, triangular, and / or circular clusters) at each corner of the microneedle array. In some embodiments, the primary microneedles 501 may be arranged in a cross formation (e.g., a “+” or “x” shape), as shown in FIG. 5. In some embodiments, the plurality of microneedles (e.g., the secondary microneedles 502) that are disposed near the corners of the microneedle array may have a longer length than the pluralityof microneedles disposed in a central portion of the microneedle array. In this way, the microneedles with the longer length may anchor the microneedle array in the skin and prevent dislodging of the microneedle array and / or and to ensure microneedles configured to deliver treatment are at a target depth or layer of the skin. For example, the secondary microneedles may anchor the microneedle array in the skin such that the primary microneedles 501 are aligned with a target layer of the skin for delivering treatment. Certain details of the MNA patch in FIG. 5 may be structurally and / or functionally similar to the MNA patch 136, and therefore, certain details of the MNA patch in FIG. 5 are not described again.

[0083] The location of the secondary microneedles 502 on the microneedle array and the spacing between adjacent primary microneedles 501 may allow for (i) improved insertion, (ii) positional stability after application (e.g., being securely in place and / or anchored after it has penetrated the skin without adverse shifting or dislodging), and / or (iii) delivery of either sentinel cargos or bioactive components in primary 501 and / or secondary microneedles 502. For example, as shown in FIG. 2A, the primary and secondary microneedles may be distributed on the microneedle array patch with equal spacing, or equal microneedle tip-to-tip distance, between adjacent microneedles. Such a configuration can allow for uniform distribution of force across the microneedles of the array during skin penetration. The spacing between adjacent microneedles may range from about 200pm to about 750pm, including all values and sub-ranges therebetween.

[0084] FIG. 6 is an example of one embodiment of a heterogeneous microneedle array with a base plate 601, which may include a series of primary microneedles 602 with a needle height suitable for delivery of a bioactive agent to the epidermis and dermis of the skin (FIG. 7A-7B), with dedicated secondary needles 603 of varying height, angle of protrusion off the base plate, width, and / or tip shape. In some embodiments, the height of the needles primary 502 and / or secondary needles 603 can be between about 50 pm and about 900 pm, including all values and sub-ranges therebetween. The secondary microneedles 603 may have a total height that is similar to, less than, or greater than the height of the primary microneedles 602. In one embodiment, the secondary microneedles 603 may have a needle height greater than the primary microneedles 602 such that the secondary microneedles 603 can penetrate the nerves present in the lower layers of the dermis (FIG. 7A) to deliver a local anesthetic for pain amelioration and localized numbing. In some embodiments, the secondary microneedles 603 may have a needle height greater than the primary microneedles to provide positional stability of the microneedle array 601 after application, providing an anchoring point to any layer of the skin (FIG. 7b). Therefore, the secondary microneedles 603 may provide mechanical stabilityof the heterogeneous microneedle array 601 to have improved mechanical stability and allow for the strategic placement of its components to allow the device to conform to different types of skin contours.

[0085] In another embodiment of FIG. 8, the secondary microneedles 803 may protrude from the base plate 801 at an angle from the base plate 801. In some embodiments, the angle may be greater than 0 degrees and less than about 45 degrees, inclusive of all values and sub-ranges therebetween. In some embodiments, the secondary microneedles 803 may extend at an angle directed towards the center of the microneedle array and / or primary microneedles 802, such that, once the microneedle array has been inserted into the skin, the angled secondary microneedles 803 would support healing functions such as wound closure, where the secondary microneedles 803 may pull skin around a wound together and / or catalyze pore closure. Certain details of the MNA patch in FIG. 8 may be structurally and / or functionally similar to the MNA patch 136, and therefore, certain details of the MNA patch in FIG. 8 are not described again.

[0086] FIG. 9 shows another embodiment of a heterogeneous microneedle array including a base plate 901, primary microneedles 902, and secondary microneedles 903, where the tip shape of the secondary microneedles 903 differs from that of the primary microneedles 902. The tip of the secondary microneedles 903 may be shaped as an arrowhead (e.g., be arrowshaped) or with an undercut feature capable of improving penetration of the stratum comeum and / or providing positional stability once the microneedle array has been inserted. The arrowhead and / or undercut features provide an anchoring point for the microneedle array to stay in place after application. For example, the undercut feature may prevent the microneedle array from being pulled out of the skin such that the microneedles are maintained at a desired depth under the skin. In some embodiments, the secondary microneedles 903 may include one undercut feature (e.g., at a base of the distal tip). In some embodiments, the secondary microneedles 903 may include a plurality of undercut features to anchor to surrounding tissue. In some embodiments, the secondary microneedles 903 may include the arrowhead tip shape and may additionally be longer than the primary microneedles 902. Certain details of the MNA patch in FIG. 9 may be structurally and / or functionally similar to the MNA patch 136, and therefore, certain details of the MNA patch in FIG. 9 are not described again. For example, undercut features may be structurally and / or functionally similar to the undercut features described in FIG. 1, and therefore certain details are not described with respect to FIG. 9.

[0087] FIG. 10 is a flow chart diagram of an example method of delivering a bioactive agent under skin of a subject using a microneedle array patch, according to embodiments. The method may be carried out using any of the MNA patches described herein. The method mayinclude receiving a force at a first surface of a base structure of a microneedle array patch to insert a plurality of microneedles into the skin of the subject, at 1002. For example, the base structure may be configured to receive a force (e.g., from an applicator) and evenly distribute the force across the MNA such that the plurality of microneedles are inserted into the skin. In some embodiments, the plurality of microneedles may include a first set of microneedles (e.g., primary microneedles) and a second set of microneedles (e.g., secondary microneedles) different than the first set of microneedles. The method may include anchoring the microneedle array patch relative to the skin, at 1004. In some embodiments, the MNA patch may be anchored via the plurality of microneedles. In some embodiments, the secondary microneedles may be configured to anchor the MNA patch relative to the skin such that the primary microneedles align with a target layer of the skin. In some embodiments, the skin adhesive of the MNA patch may be configured to anchor the MNA patch relative to the skin (e.g., for a period of time until the plurality of microneedles dissolve.) The method may include, releasing a bioactive agent from the plurality of microneedles to a target layer of the skin, at 1006. In some embodiments, the bioactive agent may be released from at least one of the primary microneedles or the secondary microneedles. In some embodiments, the bioactive agent may be released from the primary microneedles. In some embodiments, the bioactive agent may be released from the primary microneedles at the target layer of skin (e.g., the epidermis or the dermis). In some embodiments, the method may include activating a portion of the microneedle array patch to separate the rigid backing from the plurality of microneedles. In some embodiments, the activating the portion of the MNA patch includes activating a transducer coupled to the base structure to cause vibration of at least a portion of the MNA patch to separate the base structure from the microneedles. In some embodiments, the portion of the MNA patch may be activated before or during insertion into the skin. In some embodiments, the method may optionally include sensing, via sensors disposed on the MNA patch, a skin condition (e.g., skin impedance and / or presence of biomarkers in the skin.) In some embodiments, the sensors may be disposed on or embedded in the secondary microneedles.Method of Fabrication:

[0088] In embodiments, the MNA is fabricated via a mold. In embodiments, the agent is dissolved into a solution, added into the wells of the mold, and then the structural polymer is loaded into the mold to form the microneedles and the base plate. In embodiments, the agent dissolved in the solution is added into the wells of the mold manually. In embodiments, the agent dissolved in the solution is added into the wells via spin casting. In embodiments, the agent dissolved in the solution is added into the wells via vacuum. In embodiments, the agentdissolved in the solution is added into the wells via a robot. In embodiments, the agent dissolved is added into the wells via direct into tip loading (DIT). In embodiments, the agent is collagen, and the collagen is dissolved in water and added into the wells via vacuum or spin casting. In embodiments the agent is a combination of collagen and a MMPi.

[0089] In embodiments, the agent is only added to the tip of the microneedle. In embodiments, the agent is added to the entire microneedle.

[0090] It should be understood that the disclosed embodiments are not intended to be exhaustive, and functional, logical, operational, organizational, structural and / or topological modifications can be made without departing from the scope of the disclosure. As such, all examples and / or embodiments are deemed to be non-limiting throughout this disclosure. The drawings primarily are for illustrative purposes and are not intended to limit the scope of the subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the subject matter disclosed herein can be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference characters generally refer to like features (e.g., functionally similar and / or structurally similar elements).

[0091] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. That the upper and lower limits of these smaller ranges can independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0092] As used herein, the terms “about” and / or “approximately” when used in conjunction with numerical values and / or ranges generally refer to those numerical values and / or ranges near to a recited numerical value and / or range. In some instances, the terms “about” and “approximately” may mean within ± 10% of the recited value. For example, in some instances, “about 100 [units]” may mean within ± 10% of 100 (e.g., from 90 to 110). The terms “about” and “approximately” may be used interchangeably.

Claims

CLAIMS1. An apparatus, comprising: a plurality of microneedles configured to be inserted into a skin of a subject to deliver a treatment under the skin, the plurality of microneedles including a first set of microneedles and a second set of microneedles different than the first set of microneedles; and a base structure coupled to the plurality of microneedles and configured to support the plurality of microneedles during insertion into the skin, a tip of each microneedle of the plurality of microneedles extending away from the base structure such that the base structure remains outside of the skin when the plurality of microneedles are inserted into the skin.

2. The apparatus of claim 1, wherein the first set of microneedles are configured to deliver a bioactive agent, and the second set of microneedles are configured to facilitate tissue anchoring.

3. The apparatus of claim 1, wherein the first set of microneedles have a first length, and the second set of microneedles have a second length greater than the first length.

4. The apparatus of claim 1, wherein the first length is in a range between about 500 pm and about 800 pm and the second length is in a range between about 50 pm and about 250 pm.

5. The apparatus of claim 1, wherein the microneedles are arranged in an area having a width between 2 mm and 30 mm and a length between 10 mm and 30 mm.

6. The apparatus of claim 1, wherein the first set of microneedles are disposed in a central portion of the base structure, and the second set of microneedles are disposed around a border of the base structure or near corners of the base structure.

7. The apparatus of claim 1, wherein the base structure includes a transducer configured to vibrate the base structure and the plurality of microneedles.

8. The apparatus of claim 7, wherein the transducer is configured to vibrate the base structure before or during insertion of the plurality of microneedles into the skin of the subject to reduce a total force to penetrate the surface of the skin.

9. The apparatus of claim 7, wherein the transducer is configured to vibrate the base structure after the plurality of microneedles are inserted into the skin of the subject to separate the plurality of microneedles from the base structure.

10. The apparatus of claim 1, further comprising: one or more sensors configured to measure at least one of electrical impedance of the skin or biomarkers in the skin; and microelectronics coupled to the one or more sensors and configured to determine at least one of (i) the plurality of microneedles have reached a target skin layer, (ii) the plurality of microneedles have dissolved, (iii) the treatment has been delivered under the skin, or (iv) a treatment efficacy of the treatment delivered.

11. The apparatus of claim 10, wherein the one or more sensors are embedded in the second set of microneedles.

12. The apparatus of claim 1, wherein the needles include a square obelisk shape.

13. An apparatus, comprising: a plurality of microneedles configured to be inserted into a skin of a subject to deliver a treatment under the skin, the plurality of microneedles disposed in a predetermined arrangement; a base structure coupled to the plurality of microneedles and configured to support the plurality of microneedles during insertion into the skin, a tip of each needle of the plurality of needles extending away from the base structure such that the plurality of needles can be inserted under the skin while the base structure remains outside of the skin; and a transducer coupled to the base structure and configured to vibrate the base structure to facilitate insertion of the plurality of microneedles into the skin and / or to separate the base structure from the plurality of microneedles.

14. The apparatus of claim 13, the plurality of microneedles including a first set of microneedles and a second set of microneedles different than the first set of microneedles.

15. The apparatus of claim 13, wherein the first set of microneedles are configured to deliver a bioactive agent, and the second set of microneedles are configured to facilitate tissue anchoring.

16. The apparatus of claim 13, wherein the first set of microneedles have a first length, and the second set of microneedles have a second length greater than the first length.

17. The apparatus of claim 13, wherein the first length is in a range between about 500 pm and about 800 pm and the second length is in a range between about 50 pm and about 250 pm.

18. The apparatus of claim 13, wherein the microneedles are arranged in an area having a width between 2 mm and 30 mm and a length between 10 mm and 30 mm.

19. The apparatus of claim 13, wherein the first set of microneedles are disposed in a central portion of the base structure, and the second set of microneedles are disposed around a border of the base structure or near corners of the base structure.

20. The apparatus of claim 19, wherein the transducer is configured to vibrate the rigid before or during insertion of the plurality of microneedles into the skin of the subject to such that the plurality of microneedles to reduce a total force to penetrate the surface of the skin.

21. The apparatus of claim 19, wherein the transducer is configured to vibrate the base structure after the plurality of needles are inserted into the skin of the subject to separate the plurality of needles from the base structure.

22. The apparatus of claim 13, wherein the transducer is configured to vibrate the base structure at a frequency between 100 Hz and 200 Hz.

23. The apparatus of claim 13, wherein the needles include a square obelisk shape.

24. A method, comprising: receiving a force at a first surface of a base structure of a microneedle array patch such that a plurality of microneedles coupled to the base structure are inserted into a skin of a subject, the plurality of microneedles including a first set of microneedles and a second set of microneedles different than the first set of needles; anchoring, via the plurality of microneedles, the microneedle array patch relative to the skin; releasing a bioactive agent from at least one of the first set of microneedles or the second set of microneedles to a target layer of the skin; and activating a portion of the microneedle array patch to separate the base structure from the plurality of microneedles.

25. The method of claim 24, wherein the anchoring the microneedle array patch relative to the skin includes anchoring, via the second set of microneedles, the microneedle array patch in the skin such that the first set of microneedles align with the target layer of skin.

26. The method of claim 24, further comprising: sensing, via sensors disposed on the second set of microneedles, a skin condition.

27. The method of claim 26, wherein the skin condition includes at least one of an electrical impedance or a biomarker in the skin.

28. The method of claim 24, wherein the activating the portion of the microneedle array patch includes activating a transducer coupled to the base structure to cause vibration of at least a portion of the microneedle array patch.

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