Microneedle tattooing patch and method

Abstract

The present invention relates to a microneedle patch for creating a tattooing image on skin wherein the microneedle patch comprises a backing layer and an array of microneedles extending from the backing layer wherein the microneedles each comprise a distal tip portion having a tattooing substance, wherein the microneedle is configured to be inserted into the skin of a subject and to release the tattooing substance in the skin, thereby creating a tattooing image visible to the human eye in the skin. Each microneedle in the array of microneedles may correspond to a point or pixel of the tattoo image or portion thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 322,636, filed on March 22, 2022, which is incorporated herein by reference. Background Art

[0003] Tattoos have been used for thousands of years in human societies and cultures around the world as a form of body modification that provides artistic, informational, spiritual meaning, or other attributes. Tattoos are widely used for medical or veterinary applications, as well as for ornamental, self-expressive, or cosmetic purposes. For example, medical tattoos are used to communicate chronic or life-threatening medical conditions (such as diabetes) to emergency personnel, to mark the location of repeated therapeutic treatments (such as radiation therapy), or the cosmetic results of treatments for medical conditions, such as dermatological color correction of vitiligo and simulated areola in nipple-areola reconstruction therapy. Animals are tattooed to indicate sterilization status or for individual identification and / or group monitoring of stray animals.

[0004] Tattoos are usually made by injecting pigment or ink into the skin using a needle or lancet. Modern tattoo machines use electromagnetic forces to repeatedly move a needle in and out of the skin at frequencies up to thousands of times per minute to deposit material in the skin, and the needle can penetrate the skin to a depth of several hundred microns to about 2 mm. Liquid tattoo ink is guided through the needle and deposited in the skin. Although many different tattoo methods have been developed throughout human history, the basic principle of introducing colored particles into the skin by needle puncture has remained largely unchanged.

[0005] Adverse reactions to tattoos have been reported in rates as high as 31% and 68%, with reports describing skin complications after receiving a tattoo, most commonly itching and / or bleeding. There is also a risk of infection, which is primarily bacterial and confined to the skin, with an incidence of infection of up to 5% in tattoo recipients.

[0006] Therefore, there is a need to provide new and improved methods and systems for applying tattoos. Summary of the invention

[0007] In one aspect, a microneedle patch for creating a tattoo image on the skin is provided, wherein the microneedle patch comprises a backing layer and an array of microneedles extending from the backing layer, wherein the microneedles each comprise a distal tip portion having a tattoo substance, wherein the microneedles are configured to be inserted into the skin of a subject and release the tattoo substance in the skin, thereby creating a tattoo image visible to the human eye in the skin. Each microneedle in the array of microneedles may correspond to a dot or pixel of the tattoo image or a portion thereof.

[0008] In another aspect, a kit for creating a tattoo image is provided, the kit comprising: two or more microneedle patches, each patch comprising: a backing layer; and an array of microneedles extending from the backing layer; wherein each microneedle in the array of microneedles comprises a distal tip portion, the distal tip portion comprising a tattoo substance, wherein the microneedles of each of the two or more microneedle patches are configured to be inserted into the skin to form a tattoo image. In a particular embodiment, the two or more microneedle patches are configured to cooperate to produce a composite tattoo, the composite tattoo being produced by selectively positioning the tattoo images from each microneedle patch relative to each other (adjacent to each other and / or overlapping each other).

[0009] In another aspect, a method for making a tattoo microneedle patch is provided. The method may include: casting a first composition in a mold having a cavity defining an array of microneedles, wherein the first composition includes a tattoo substance; and then solidifying the first composition in the mold to form the array of microneedles or at least the distal tip portion of the microneedles in the mold, wherein each microneedle in the array of microneedles corresponds to a dot or pixel of a predefined tattoo image or a portion thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Detailed description is set forth with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may or may not be present in various embodiments. Elements and / or components are not necessarily drawn to scale.

[0011] Figure 1 is a perspective view of a microneedle patch including an array of microneedles according to one or more embodiments of the present disclosure.

[0012] Figure 2A is a photomicrograph showing a perspective view of an array of tattoo microneedles according to one or more embodiments of the present disclosure.

[0013] Figure 2B It is a display Figure 2A A micrograph of a close-up of a tattoo microneedle is shown.

[0014] Figure 3A is a photomicrograph showing a perspective view of an array of remaining proximal portions of tattoo microneedles after the distal tip portions of the microneedles have dissolved according to one or more embodiments of the present disclosure.

[0015] Figure 3B It is a display Figure 3A A micrograph of a close-up of the remaining proximal portion of the tattoo microneedle is shown.

[0016] Figure 4A-4B2 are plan views of microneedle molds in a heart shape and a star shape, respectively, according to one or more embodiments of the present disclosure.

[0017] Figure 4C-4D According to one or more embodiments of the present disclosure, Figure 4A-4B A perspective view of a tattoo microneedle array fabricated from a mold is shown.

[0018] Figures 4E-4F According to one or more embodiments of the present disclosure, Figure 4C-4D A plan view of a tattoo image in the skin of an animal model made with a tattoo microneedle array is shown.

[0019] Figures 5A-5C is a plan view of a microneedle mold in the shape of a medical indicator according to one or more embodiments of the present disclosure.

[0020] Figures 5D-5F According to one or more embodiments of the present disclosure, Figures 5A-5C A perspective view of a tattoo microneedle array fabricated from a mold is shown.

[0021] Figure 5G-5I According to one or more embodiments of the present disclosure, Figures 5D-5F A plan view of a tattoo image in the skin of an animal model made with a tattoo microneedle array is shown.

[0022] Figure 6A-6B is a perspective view of a tattoo microneedle array utilizing a photoresponsive pigment according to one or more embodiments of the present disclosure.

[0023] Figure 6C-6E The use of the inspection under sunlight, darkness and UV light, and sunlight and UV light respectively according to one or more embodiments of the present disclosure Figure 6A-6B A plan view of a tattoo image in the skin of an animal model made with a tattoo microneedle array is shown.

[0024] Figure 7A-7B is a perspective view of a tattoo microneedle array utilizing thermoresponsive pigments according to one or more embodiments of the present disclosure.

[0025] Figure 7C-7D According to one or more embodiments of the present disclosure, the Figure 7A-7B A plan view of a tattoo image in the skin of an animal model made with a tattoo microneedle array is shown.

[0026] Fig. 8A A QR code pattern is shown that is used as the basis for a tattoo microneedle array according to one or more embodiments of the present disclosure.

[0027] Figure 8Bis a description of one or more embodiments of the present disclosure Fig. 8A A perspective view of a QR code tattoo microneedle array.

[0028] Figure 8C is the use according to one or more embodiments of the present disclosure Figure 8B A plan view of a tattoo image in the skin of an animal model made with a tattoo microneedle array is shown. DETAILED DESCRIPTION

[0029] Tattoo microneedle arrays and patches have been developed in which the array of microneedles (i) is configured, e.g., with geometric structures and mechanical properties, for insertion into the skin (or other mammalian tissue); and (2) is configured, e.g., with a suitable composition, for releasing tattoo substances in the skin to create a tattoo image in the skin.

[0030] Specifically, a tattoo image is an image that is directly visible to the human eye, i.e., visible to the "naked eye" (which may include using conventional glasses or contact lenses). As used herein, an image that cannot be seen in ambient light but only fluoresces in near infrared (NIR) wavelengths will not be considered "visible to the human eye."

[0031] The feasibility of applying tattoos to the skin with microneedle patches for a variety of medical and other applications has been demonstrated. Microneedle patches simplify the tattoo process by reducing the need for technical and process skills to apply tattoos, and improve the acceptability of the tattoo recipient to the process by shortening the time and eliminating pain to improve tolerance. The tattoo microneedle patches described herein can advantageously be provided as disposable sterile skin patches that do not generate biohazardous sharp waste. Microneedle patch tattoos can also respond to environmental cues such as light or temperature, which can be used for in-situ monitoring of physiological processes in the body for medical, research or other purposes. Microneedle patches can also apply complex tattoo patterns, such as QR codes.

[0032] One or more microneedle patches for creating a tattoo image on the skin are described herein. The microneedle patch generally comprises a backing layer and an array of microneedles extending from the backing layer, wherein the microneedles each have a distal tip portion comprising a tattoo substance, and the microneedles are configured to be inserted into the skin of a subject, and wherein the microneedles are configured to release the tattoo substance in the skin, thereby creating a tattoo image in the skin.

[0033] Each microneedle in the array of microneedles can correspond to a dot or pixel of a tattoo image or portion thereof. This may be particularly advantageous for assisting in creating tattoo images of a size and / or complexity that would require application of two or more microneedle patches to complete.

[0034] In some embodiments, the subject is a human, and the tattoo image can be placed on substantially any area of ​​the human skin where it is desired to have a tattoo image. In some other embodiments, the subject is a domestic animal, such as a pet (e.g., a dog or cat) or livestock (e.g., a cow, pig, sheep, or horse). For domestic animals, the tattoo image can contain identification information (e.g., the name or tracking number of the animal's owner and / or the animal), or medical status information (e.g., vaccination or sterilization status). In some embodiments, the tattoo image contains medical / veterinary warnings or medical / veterinary record information selected from the following: vaccination status, allergies, blood type, medical conditions (e.g., asthma, epilepsy, diabetes), medications (e.g., blood thinners, vaccinations, sterilization), medical devices (e.g., pacemakers), do not rescue orders and contact information, and / or encoded personal health information.

[0035] In one specific example, a tattoo image providing a sterilization status is placed under the ear or on the abdomen near the incision site for sterilization surgery on a dog, cat or other animal. In another specific example, a tattoo image providing a medical warning status is placed on a person's hand, wrist or arm so that the tattoo image can be prominently displayed or at least easily seen by, for example, emergency medical workers. Because these medical tattoo patches can be easily applied and read, they can enable patients to provide valuable medical information to health care workers, such as first responders, in emergency situations involving, for example, massive blood loss or severe hypoglycemia events where the patient may be unresponsive or slurred, thereby potentially replacing the need for conventional medical warning bracelets.

[0036] Tattoo images may include any symbols, numbers, letters, and other medical / decorative images applied to the skin. Tattoo images may be pictorial in nature, depicting representative, abstract, or other images. Tattoo images may involve representations of geometric patterns, real or imagined, living or inanimate physical objects. Tattoo images may function as makeup to enhance the appearance of the face or other body parts, such as eyeliner, eyebrows, lipstick, scalp micro-pigmentation, etc. Tattoo images may contain encoded information, i.e., information that has been converted into a specific visual form, such as a machine-readable form, such as a barcode or QR code. For example, the encoded information may be a URL. Creating a QR code with a microneedle patch has the advantage of storing more information or providing a link to essentially unlimited information on the cloud compared to simpler tattoo patterns.

[0037] The tattoo images produced by the microneedle patch can be substantially permanent or temporary, for example, depending on the tattoo material / microneedle formulation and the amount and location of the tattoo material delivered into the skin. For some cosmetic or clothing-related tattoos, temporary tattoo images may be particularly desirable.

[0038] One benefit of the tattoo microneedle patches described herein is that they can be configured for people to self-apply tattoo images. The microneedle patches of the present invention are also advantageously essentially dry systems in that they do not require the user to handle or inject liquid ink or other liquid forms of tattoo substances as with conventional tattoos.

[0039] Microneedle patch

[0040] Figure 1 An example of a tattoo microneedle patch having an array of microneedles is depicted in . The microneedle patch 100 includes a base substrate 110 from which microneedles 120 in a 10x 10 array extend. The phrase "base substrate" and the term "substrate" or "backing" are used interchangeably herein. Each microneedle 120 has a proximal end 122 that is directly or indirectly attached to the base substrate 110 via one or more proximal portions 124, and a distal tip 126 that is sharp and can effectively penetrate biological tissue. The microneedle 120 has a tapered sidewall 128 located between the proximal end 122 and the distal end 126 of the microneedle 120. Other geometric structures are possible. Figure 2A-2B An exemplary photograph of a tattoo microneedle array as disclosed herein is shown in FIG.

[0041] The microneedles may be coated or uncoated. In some embodiments, the uncoated microneedles or at least the distal tip portions of the microneedles are completely water-soluble. In some other embodiments, the microneedles or at least the distal tip portions of the microneedles comprise water-soluble components (e.g., a coating comprising a tattoo substance) and other components that are not water-soluble (e.g., an underlying microneedle structure on which a coating is disposed). For example, the underlying microneedle structure may be made of metal, polymer, or silicon, and the underlying microneedle structure is coated with a water-soluble composition comprising a tattoo substance. This may be important because coated microneedles can generally be stronger (e.g., made of metal), which enables them to be thinner and therefore can be made with a much higher microneedle density per microneedle patch area. A high-resolution tattoo image may require a certain microneedle density in an array of a microneedle patch, and such density and image resolution may be achieved using coated microneedles.

[0042] The microneedles of a microneedle patch are typically designed to be inserted into the skin, but may also be inserted into another suitable biological tissue.

[0043] In some embodiments, the length of the microneedle can be between about 50 μm and 2 mm, about 100 μm to about 2000 μm, about 100 μm to about 1500 μm, about 200 μm to 1000 μm, or ideally between about 500 μm and 1000 μm. In some embodiments, the array of microneedles comprises 10 to 50,000 microneedles, 25 to 10,000 microneedles, 25 to 1000 microneedles, 50 to 500 microneedles, or 100 microneedles (e.g., an array of 10×10 microneedles).

[0044] The microneedle density of the microneedle patch in the array can be 10 microneedles / cm 2 Up to 20,000 microneedles / cm 2 In some embodiments, the area density can be 50 microneedles / cm 2 Up to 5,000 microneedles / cm 2 , or 100 microneedles / cm 2 Up to 1000 microneedles / cm 2 .

[0045] In some embodiments, the array of microneedles is configured to be inserted to about 0.5 cm 2 To about 10cm 2 in the tissue area.

[0046] The tattoo material used in the microneedles of the microneedle patches described herein can be any material known in the art that is suitable for forming tattoos in the skin. For example, the tattoo material can be tattoo ink particles or pigment particles known in the art for conventional tattoos. It can be a single-color ink, a multi-color ink, a color-changing ink, or a fluorescent ink (e.g., an ultraviolet (UV) visible tattoo ink that emits visible light when exposed to ultraviolet (UV) light, such as a black light tattoo ink). The tattoo material can also be a dye that may be associated with the particle formulation, or any other material that is visible when applied to the skin.

[0047] In some embodiments, the microneedle, or at least the distal tip portion of the microneedle, comprises a mixture of a tattoo substance and a biocompatible water-soluble polymer. Examples of such suitable water-soluble polymers include poly(acrylic acid), polyvinyl pyrrolidone, polyvinyl alcohol, and polysaccharides. However, essentially any suitable biocompatible material may be used that can provide the mechanical properties required to form a structure that can be inserted into tissue and subsequently release the tattoo substance therein.

[0048] In some preferred embodiments, the composition of the distal tip portion of the microneedle comprises a tattoo substance and one or more excipient materials, wherein the tattoo substance is between 1% and 50% by weight of the composition of the distal tip portion of the microneedle. In some embodiments, the tattoo substance is between 5% and 40% by weight, or between 10% and 30% by weight of the composition of the distal tip portion of the microneedle.

[0049] In some embodiments, the microneedle comprises a hydrophobic matrix material that dissolves or disperses the tattoo substance. In some embodiments, the microneedle comprises a proximal portion between a backing layer and a distal tip portion. The proximal portion may be substantially free of the tattoo substance. The proximal portion of the microneedle may comprise a water-soluble material, such as polyvinyl pyrrolidone, polyvinyl alcohol, a sugar such as sucrose, or a combination thereof.

[0050] In some embodiments, the backing layer (base substrate) of the microneedle patch contains a tattoo substance. This tattoo substance may not be delivered to the skin, but may be present in the backing layer due to the manufacturing process. Microneedle patches used to administer drugs to the skin usually have drugs only in the microneedles, and not in the backing layer, because controlling the dose of the drug administered is important for medical treatment. Therefore, it would be counterintuitive to locate a substance (e.g., a drug) that is intended to be delivered to the skin in the backing layer of the microneedle patch. In contrast, as long as the tattoo substance in the distal tip portion of the microneedle is delivered to the skin, the tattoo substance can be located in the backing layer, even if it is not delivered to the skin. Such embodiments may be desirable for, for example, making a microneedle patch using a single composition (e.g., a mixture of a drug and a water-soluble polymer), which can be used to mold the base substrate and the microneedles in a single casting process.

[0051] In some embodiments, the microneedles within a given array of microneedles all contain the same tattoo substance. In other embodiments, the microneedles within a given array of microneedles may contain different tattoo substances. For example, the tattoo substance in each microneedle may be different, such as a different color, in different rows of microneedles or sections / regions of the microneedle array, as desired to create a desired tattoo image.

[0052] The tattoo material may be a tattoo ink, or a natural or synthetic pigment. It may be in the form of particles, or in the form of a liquid (e.g., a solution, suspension or dispersion) or a paste (e.g., a gel or cream) containing such particles. Such particles may be small enough to be cleared from tissues, for example by macrophages, for example, of a size of 10 nm to 20 um, or 100 nm to 10 um or 500 nm to 5 um, or as particles large enough to reduce clearance from tissues, for example, 10 um to 300 um or 20 um to 100 um or 30 um to 70 um.

[0053] Tattoo substances can be molecules that can diffuse away from tissue (e.g., diffusion rate depends inversely on molecular weight) and / or can be retained in tissue, possibly by binding to other substances or components in the tissue (e.g., binding to the tissue). The degree of binding can affect the duration that the tattoo remains in the tissue.

[0054] Like conventional tattoos, the tattoo material can remain substantially permanently in the tissue. Permanence can be achieved by the size of the fragments / particles of the tattoo material, by the interaction of the tattoo material with other materials or components in the tissue, or other factors.

[0055] The tattoo material may be temporarily retained in the tissue. The temporary nature of the tattoo material being retained in the tissue may be achieved by methods known in the art for making temporary tattoos. This may be because the tattoo material is cleared from the tissue (e.g., by diffusion, clearance by macrophages) in a form that does not substantially change the properties of the tattoo material, or may be due at least in part to a change in the properties of the material, such as degradation of the tattoo material by breaking chemical bonds in the tattoo material (e.g., biodegradation), by dissolution of the tattoo material (i.e., from a solid to a dissolved state), by breaking the tattoo material into smaller fragments, or other mechanisms. For example, the tattoo material may be henna, jagua, genipin, or other materials known in the art for temporary or semi-permanent tattoos.

[0056] The tattoo material may be temporarily retained in the tissue due to an intervention that renders the tattoo reversible. This can be achieved by methods known in the art for removing tattoos, such as by using a laser-based process. The tattoo material properties may respond to changes in the environment (e.g., temperature, pH, tonicity), or may respond to energy input (e.g., laser, heat, ultrasound, light, electric field, magnetic field) to change the properties of the tattoo material, thereby increasing its rate of clearance from the tissue.

[0057] In some embodiments, the tattoo material is encapsulated within or otherwise associated with the particles that affects the duration that the tattoo remains in the tissue. This process can be mediated at least in part by diffusion of the tattoo material through the particles; binding of the tattoo material to the particles; and / or biodegradation, dissolution, or other mechanisms of dissociation of the material comprising the particles from the particles. The particles can be made of biodegradable polymers such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), or poly(caprolactone), or mixtures thereof.

[0058] Microneedles containing tattoo substances may contain other components that may also be delivered to the tissue or may be removed from the tissue after the tattoo substance is delivered. In some embodiments, the microneedle design may involve a microneedle core that does not contain tattoo substances and a coating on part or all of the surface of the core containing tattoo substances. In this case, the coating on the microneedle remains mostly or completely in the tissue. The core may also remain in the tissue or may be mostly or completely removed. The microneedle design may alternatively involve microneedles that include a mixture of tattoo substances and other components, or may be made primarily or entirely of tattoo substances. In this case, most or all of the microneedles remain in the tissue. The other components may dissolve in the tissue and be cleared from the tissue in a much shorter time scale than the possible clearance of the tattoo substance. In another scenario, some or all of the tattoo substance and other components may remain in the tissue for approximately the same amount of time (i.e., including being permanently retained in the tissue).

[0059] The microneedle patch may further include other structural elements that enhance the storage and availability of the microneedles ( Figure 1 For example, the patch may include a housing and / or other layers, such as a treatment layer, on a side of the base substrate opposite the microneedles. Examples of such other additional structural components are described in U.S. Pat. No. 10,265,511 to McAllister et al., which is incorporated herein by reference.

[0060] Method for making microneedle array

[0061] The array of microneedles described herein can be made by any suitable process. In a preferred embodiment, the array of microneedles is made using a molding process, which is advantageously scalable to a great extent. The filling and molding steps described herein may be referred to as "casting" in this article. In certain embodiments, casting methods, molds, and other equipment can be adapted according to casting methods, molds, and equipment known in the art, such as those described in U.S. Patent No. 10,828,478 to McAllister et al., which is incorporated herein by reference. The method for making microneedles is preferably performed under a minimum ISO 7 (10,000 grade) process or an ISO 5 (100 grade) process.

[0062] In some embodiments, the process comprises preparing a composition having a tattoo substance dispersed or dissolved in an excipient (e.g., a water-soluble polymer) with or without an aqueous solvent or an organic solvent; filling a mold having cavities defining a plurality of microneedles (e.g., an array of microneedles); and then solidifying the composition to form a plurality of microneedles. Solidification may involve drying to remove the solvent. In some embodiments, the process comprises preparing a first liquid composition comprising a tattoo substance dispersed in an excipient material, the first liquid composition being heated to a temperature greater than the melting point of the excipient material; casting the liquid composition in a mold having cavities defining the microneedles; and then cooling the composition in the mold to a temperature below the melting point of the excipient material to form the microneedles.

[0063] Centrifugation and / or vacuum can be used to assist in these processes, particularly in that centrifugation and / or vacuum can help maintain the microneedle shape defined by the mold as the tattoo material-vehicle composition solidifies.

[0064] In some embodiments, as mentioned above, a single casting process is used to manufacture the base substrate and the array of microneedles. That is, a single casting of the tattoo substance and excipient forms not only the distal tip portion of the microneedles, but also the proximal side of the microneedles and any funnel portions and connected base substrates from which the array of microneedles extends.

[0065] In some embodiments, a double casting or triple casting process is used. In these embodiments, the first casting of the tattoo substance and the excipient forms only the distal tip portion of the microneedle. The subsequent casting may involve filling the remaining space of the mold on top of the distal tip portion of the microneedle to form the proximal portion of the microneedle. In some embodiments, a second casting is applied to the microneedle mold before the microneedle is removed from the mold. In some embodiments, the second casting has a different composition than the first casting. For example, the second casting can be water-based so that it can dissolve in the body at the same time as the first casting composition. For example, the water-based casting can be made of a mixture of a polymer such as polyvinyl alcohol (PVA) or polyvinyl pyrrolidone (PVP) and a sugar such as sucrose. In some preferred embodiments, the second casting is equal parts 18% PVP (360 / 55) and sucrose, such as 18% PVP and 18% sucrose by weight. In some embodiments, the second casting is non-water-soluble, for example, comprising a polymer such as poly(styrene) or poly(methyl methacrylate).

[0066] After forming the first casting composition, it is transferred to the concave mold of the one or more microneedles (usually an array of microneedles between 10 and 1000). This may be referred to as the "first casting". The mold may then be centrifuged and / or evacuated to facilitate the displacement of any bubbles and the movement of the composition into the microneedle tips of the mold. The mold is then filled with a second composition suitable for forming a backing substrate and optionally the proximal portion of the microneedle. In some embodiments, this second casting material may be or may include one or more water-soluble materials. After filling, the mold may be centrifuged and / or evacuated to facilitate and accelerate the casting process.

[0067] The filled mold is allowed to solidify and / or dry as needed. The filled mold can optionally be dried at an elevated temperature and / or in a desiccant chamber to facilitate removal of excess water or moisture from the patch. After the filling process, the filled mold can be brought to a lower temperature to phase change the material filled into the mold from a liquid to a solid. After the casting is substantially solidified and / or dried, the tattoo microneedle patch can be removed from the mold.

[0068] In some embodiments, the microneedle patch is made using a three-cast process, wherein the first cast is a tattoo substance-matrix composition that forms the distal tip portion of the microneedle, the second cast is an excipient that forms the proximal portion of the microneedle and / or the connector / funnel portion between the microneedle and the base substrate, and the third cast is a composition suitable for forming the base substrate. In these embodiments, the second cast excipient may dissolve after insertion and may act as a spacer between the distal tip portion (which may or may not dissolve in the skin) and the backing substrate (which may or may not dissolve in or on the skin). In some embodiments, it may be preferred to prevent the tattoo substance matrix composition and the base composition from contacting or mixing with each other.

[0069] In some embodiments, the preparation of the microneedle array involves a coating process. For example, a microneedle array that does not include a tattoo substance is made by molding, additive manufacturing, subtractive manufacturing, etching, 3D printing, or other methods known in the art. Then, the coating is applied to the surface of the microneedles. The microneedles can be solid, or the microneedles can have indentations, pores, grid structures, or other geometric features that can be located on the inside of the microneedles to provide a surface for coating or a cavity for filling. The coating including the tattoo substance is applied to the microneedles by dipping, spraying, electrodeposition, or other methods known in the art for coating a solid surface with a liquid coating. The coating is solidified by drying, phase change, or other methods.

[0070] How to use

[0071] The microneedle arrays described herein can be used to deliver tattoo materials to a tissue site in a human or other mammal, typically by applying a microneedle patch comprising an array of microneedles to the surface of the skin so that the microneedles penetrate the stratum corneum and enter the viable epidermis and possibly the dermis. In some embodiments, delivery to the dermis is preferred.

[0072] As used herein, the phrase "penetrating a tissue surface" includes penetrating a biological tissue surface with at least the distal tip of the microneedle. After the microneedle is separated from the substrate, the proximal end of the microneedle can be above the tissue surface, substantially flush with the tissue surface, or below the tissue surface. The phrase "biological tissue" generally includes any human or mammalian tissue. The biological tissue can be the skin or mucosal tissue of a human or other mammal. It is contemplated that the devices and methods of the present invention can also be adapted for other biological tissues and other animals.

[0073] Microneedle patches can be self-administered or administered by another individual.

[0074] The methods described herein further include a simple and effective method for tattooing a person or animal with a microneedle patch. The method may include identifying the application site, and preferably disinfecting the area before applying the microneedle patch (e.g., wiping with alcohol). The microneedle patch is then applied to the skin / tissue of the person, and manually pressed into the patient's skin / tissue (e.g., using a thumb or finger) or using a device that facilitates the application of the patch so that the microneedles penetrate the tissue surface. An applicator can be used, the applicator (i) does not contain any stored energy (i.e., the energy required to press the microneedles into the tissue comes from the user), but guides the process of applying the patch to the tissue, or (ii) contains stored energy (e.g., a compression spring), which provides part or all of the force required to press the microneedles into the tissue.

[0075] After delivery of the tattoo material, at least in embodiments where the substrate remains intact, the substrate (and the remaining microneedle patch structure) can be removed from the patient's skin / tissue.

[0076] In some embodiments, the microneedle patches described herein are used to deliver tattoo substances into the skin by inserting the microneedles through the stratum corneum (the outer 10 to 20 microns of the skin, which is a barrier to transdermal delivery) and into the viable epidermis and possibly the dermis. The small size of the microneedles enables them to cause little to no pain and target the intradermal space. The microneedles can dissolve once in the intradermal space to release the tattoo substance into the interstitial fluid and skin.

[0077] For microneedles that do not dissolve in the skin, the tattoo material can be released according to several mechanisms, such as diffusion, dissolution, and / or degradation. In embodiments, the microneedles can be manufactured such that the tattoo material is released through the intact microneedles. In other embodiments, the microneedles can be formed of excipients that are configured to degrade, such as through hydrolysis, enzymatic activity, or other similar mechanisms. This allows the tattoo material to be released at a rate that depends at least in part on the degradation rate.

[0078] The information encoded by the tattoo substance can be pictures or symbols in nature (e.g., similar to conventional tattoos used for artistic or cosmetic purposes). It can be placed anywhere on the body. It can be letters, words or characters in English or any other language (e.g., Chinese, pictograms). It can be numbers. It can be other symbols.

[0079] In some preferred embodiments, the tattoo substance is a substance that can be used as a cosmetic agent. For example, it can be permanent makeup, where the makeup can be permanent in nature or can be temporary, but at least long-lasting (e.g., longer than a day or a week or a month or more). The tattoo substance can enhance or replace anatomical features, such as eyebrows, lips, hair (e.g., scalp micropigmentation), cheeks, eyelids (e.g., mascara, eye shadow), and other aspects of the face and head, as well as features on other parts of the body.

[0080] Cosmetic tattoos typically cover large areas of skin and require custom artistry, but microneedle patches can quickly and painlessly provide small tattoos with simple designs. Self-application is also possible, and in these cases, the use of temporary tattoo inks may be particularly appropriate.

[0081] Medical tattoos can be very small and simple, such as tattoos used to mark body parts for repeated treatments (such as radiation therapy) or veterinary tattoos used to mark the sterilization status of animals. Microneedle patch tattoos may be ideally suited for such scenarios. More complex but relatively standardized designs, such as nipple-areola reconstruction therapy or dermatological color correction of vitiligo, can also be performed using the microneedle patch tattoos described herein, which apply multiple patches over larger areas and are custom colored based on the patient's skin color.

[0082] Many patients with chronic conditions wear medical warning bracelets, which in some cases can be replaced by tattoos. The tattoo images described herein can provide information about blood type or diabetes status and other health care situations, including medical conditions (asthma, epilepsy), medications (blood thinners, allergies), medical devices (pacemakers), do-not-rescue orders, Internet sites, and contact information.

[0083] The tattoo images described herein may be useful in the field of public health, especially in environments where health care resources and medical record keeping are limited. Information about important medical interventions can be recorded through small and precise tattoos. For example, microneedle patch tattoos can be used to indicate the year or date when a vaccination was administered, and such tattoos can be combined into dual-function patches that are also used to administer vaccines. Such tattoos can serve as evidence of vaccination status to identify unvaccinated people during vaccination campaigns, such as for infectious disease control, elimination or eradication.

[0084] Microneedle patch tattoo images can also provide dynamic information in response to environmental changes. For example, tattoos can be designed to respond to changes in light and / or heat. There are also a large number of documents on materials with properties that respond to a variety of physical and molecular inputs, such as blood glucose responsive materials that change color or appearance to report blood glucose levels of concern to people with diabetes. Other materials are known to respond to changes in pH, enzymes, binding reactions, redox states, ionic strength, mechanical stress or other stimuli, and the materials can be formulated into granular form and applied to the skin as microneedle patch tattoos. Such environmentally responsive tattoos may be a convenient and sophisticated method for patients to continuously monitor their health status.

[0085] Larger microneedle patch tattoo images can contain more information for direct readout of words, numbers or symbols, or for electronic readout, such as using a QR code containing digitized information including possible links to Internet sites. Although QR codes are standardized, other scan codes can also be used when combined with a suitable electronic reader.

[0086] In some embodiments, the microneedle patch can deliver a tattoo material into the tissue that encodes information that can be read from outside the body (i.e., a tattoo). The information can be in the form of a picture (e.g., an artistic or cosmetic tattoo with an image), letters / numbers, a pattern (e.g., a QR code or RFID), or other arrangement of pieces of tattoo material in the tissue, where the location and properties (e.g., color, absorptivity / emission of electromagnetic, acoustic, or other energy) of the pieces of tattoo material encode the information.

[0087] Reading the information can be done visually by the eye - unaided or aided by an instrument that facilitates the eye to see the tattoo material - or by a device without the involvement of the reader's eyes. The information being read can be in the form of visible light, such as in the form of color, intensity, spatial location and other characteristics. It can be invisible light, such as ultraviolet light or infrared light. The tattoo material can be fluorescent, so that when exposed to a specific wavelength of light (or energy from a non-optical part of the electromagnetic spectrum), it emits a different wavelength of light (or energy from a non-optical part of the electromagnetic spectrum), preferably light visible to the human eye.

[0088] The information may be from another portion of the electromagnetic spectrum that is not considered light. The reading may be performed by a detector of the portion of the electromagnetic spectrum of interest that can detect the wavelength, intensity, spatial location, and other characteristics of the tattoo material in the tissue. The information may be acoustic in nature using tattoo material having acoustic properties different from those of the surrounding tissue. The information may be obtained from the tattoo material in the tissue using imaging devices such as ultrasound, optical coherence tomography, x-ray, magnetic resonance imaging, x-ray computed tomography, positron emission tomography, radiography, elastography, photoacoustic imaging, near infrared spectroscopy, magnetic particle imaging, and the like.

[0089] The tattoo image can be applied using a single microneedle patch or a collection of two or more patches that together provide a complete body of information, a complete picture, etc.

[0090] For example, when it is desired to apply more than one patch, the microneedle patch can be provided as part of a kit. The kit may contain two or more microneedle patches and a template or alignment assembly that enables the user to position the microneedle patches relative to each other on the tissue surface. This will be useful when it is necessary to use multiple patches together to form a composite tattoo. The microneedle patches can be applied to the same area of ​​the tissue (e.g., each patch has a tattoo ink of a different color, and the tattoo inks together form an image with multiple colors, or each patch has a certain number of microneedles, each of which creates a pixel with a color in the tissue, and the use of multiple patches applies more microneedles that create more pixels to create an image with greater resolution (e.g., more pixels per area) or with greater intensity (e.g., more ink per area).

[0091] The microneedle patches can be applied together to an area larger than the area of ​​any individual patch. The total area can be less than, equal to, or greater than the sum of the areas of the individual patches. For example, if the patches are placed with their edges adjacent to each other, the area can be approximately equal to the sum of the areas of the individual patches. If there is overlap in the placement of each individual patch, the area can be less than the sum of the individual areas. If there is spacing between the edges of the patches, the area can be greater than the sum of the individual areas.

[0092] Alignment component can be applied to tissue and remain in place during application patch or remove before application patch.In the latter case, alignment component can leave mark or impression or other guide for placement patch on tissue surface.

[0093] In some embodiments, the kit specifies a particular arrangement of the patch on the tissue. In some other embodiments, the kit can be adapted to a variety of arrangements depending on how the user desires to use the patch, for example, enabling the user to customize a tattoo image according to their preferences.

[0094] In another embodiment, the kit may contain a collection of patches, each patch having, for example, one or more letters and / or numbers and / or symbols or other images. Combining two or more patches may create a collection of letters, numbers, symbols or other images that together form a specific tattoo image. Alternatively, the patches may be applied at locations away from each other so that they do not form a single tattoo image together, but rather two or more tattoo images. Patches from the same kit may also be applied to multiple different people, animals, etc. (e.g., matching a tattoo shared by two people, or a group of tattoos applied to multiple animals for marking purposes). Any given patch in the kit will only be applied to one person.

[0095] In some embodiments, two or more microneedle patches may be provided as a kit without an alignment component. This would allow a user to design their own tattoo image using the patch of interest positioned in a pattern of interest on tissue.

[0096] The microneedle patch design can be customizable, where customization can be performed at the time of manufacture or afterwards (e.g., by a user). For example, a patch can have a collection of microneedles, some of which are functional (i.e., capable of administering a tattoo substance into a tissue), and some of which are not functional. A microneedle patch can be manufactured with functional microneedles that are subsequently converted to non-functional microneedles. The conversion can be performed as part of the overall manufacturing process, or can be performed by the user of the microneedle patch after manufacture. Non-functional microneedles can be sites on a base substrate patch that have no microneedles at all.

[0097] Customization can also be done by controlling the location and composition of the microneedles in the patch, where most or all of the microneedles contain a tattoo substance. This customization can be done by making the patch in this way, or by making a patch with more microneedles on it and then removing some of the microneedles. Removal of the microneedles can be done as part of the overall manufacturing process, or can be done by the user of the microneedle patch after manufacturing.

[0098] Patterns can be encoded in microneedle patches in a variety of ways. A spatial pattern can be encoded by having a set of microneedles containing a tattoo substance in the pattern on one or more patches, which is then transferred to the tissue. Additional microneedles may be present on patches that do not contain ink. In this way, there can be an array of standard microneedles on a patch that is customized by placing ink into only a portion of the microneedles to achieve the pattern. The pattern can also encode different colors of ink or multiple types of tattoo substances with different properties (i.e., not just different colors). Each microneedle in the array can contain a tattoo substance with the same or different properties, or no tattoo substance.

[0099] Customization can be designed by the user (i.e., not the manufacturer) and implemented by the manufacturer. For example, the user can provide a design to the manufacturer, and the manufacturer makes a microneedle patch according to the design. The design can be communicated to the manufacturer in a digital format. Because the microneedle patch is digital in nature (i.e., the microneedle patch transfers the tattoo substance to the tissue at a collection of specific locations or pixels, and the specific locations or pixels together form an image), the user can communicate the design by identifying the characteristics of each pixel in the array of pixels. Each pixel can have a tattoo substance or not, and each pixel with a tattoo substance can have a specified property (e.g., color). Then, the instructions for each pixel can be used as instructions for the design of each microneedle. These instructions can be implemented by the manufacturer, and then the manufacturer provides the microneedle patch to the user according to the user's design, or can be implemented using an instrument operated by the user or other person at a location other than the microneedle patch manufacturing location (e.g., an instrument that selectively removes or deactivates the microneedle). In a specific embodiment, the digital design is transmitted from the user to the manufacturer via a network application or other computer or mobile device interface using hardware and software suitable or known in the art.

[0100] In some cases, it may be desirable to have two or more microneedle patches that encode the same information. In other cases, it may be desirable to have microneedle patches that encode unique information. These microneedle patches can be provided individually or as part of a multi-patch kit. The microneedle patch can contain tattoo materials as well as drugs, vaccines, or other compounds (collectively referred to as "drugs") of medical, veterinary or other therapeutic, diagnostic or preventive significance. If it is part of a multi-patch kit, one or more patches can have tattoo materials, and one or more other patches can have drugs, or the drug can be provided in the kit in a form that does not involve microneedles (for example, the drug is in tablets or is formulated for injection). The information encoded in the microneedle patch can be about the drug, including the type of drug, information about its manufacture (for example, batch number, location, date), information about its use time and / or location, information about the person receiving the drug, etc. The encoded information can be linked to a database or other information source about the drug, manufacture, use time / location, the person receiving the drug, etc.

[0101] Particularly in animals, it may be desirable to apply the microneedle patch to tissue that is hairless to facilitate application of the microneedles into the tissue and / or to facilitate inspection or other access to information encoded in the tissue (e.g., to see a tattoo). This may involve applying the microneedles to areas of tissue that naturally have very little hair, such as the underside of the ears, the nose, or certain areas of the underside of the animal (e.g., the abdomen / groin). It may also involve areas of tissue that have had hair removed for the purpose of applying the microneedle patch or for some other purpose (e.g., as part of a surgical or other procedure, such as neutering, spaying, or other sterilization methods).

[0102] The information encoded in the tattoo image can be directly understood by the viewer of the tattoo (e.g., words, numbers, pictures). The information can be in the form of a code that can be understood by an algorithm, such as a UPC code, QR code, and RFID.

[0103] The present invention may be further understood with reference to the following non-limiting examples.

[0104] Example 1. Fabrication of tattoo microneedle patch mold

[0105] A polydimethylsiloxane (PDMS) mold of the inverse of the desired shape of the microneedle patch was formed via laser cutting. First, a PDMS sheet was prepared by mixing two precursors of Sylgard 184 (Dow Corning, Midland, MI) in a ratio of 10:1. The mixture was degassed, poured into a flat-bottomed container to a thickness of approximately 2.5 mm, and cured at room temperature (20° C. to 25° C.) for 2 days and at 37° C. for another day.

[0106] The laser engraving process was performed in a VersaLaser engraver VLS 3.50 (Universal Laser Systems, Scottsdale, AZ) using carbon dioxide (CO 2 ) cutting laser drills the resulting solid PDMS sheet to generate an array of tapered cavities to form microneedles in the mold. The microneedle dimensions and positions were controlled by drawing in AutoCAD software (Autodesk, San Rafael, CA) so that each microneedle had a base diameter of approximately 550 μm base diameter and a length of approximately 1.1 mm, with each microneedle tapering to a tip with a radius of curvature of approximately 10 μm.

[0107] After the microneedle mold was formed, it was cleaned with a 20% (w / v) polyvinyl alcohol (PVA, 4-88, Millipore Sigma, Burlington, MA) solution in deionized water. This solution was applied to the drilled mold under vacuum and dried overnight at 40° C. to form a PVA film. Peeling off the PVA film removed burnt debris from the mold generated during laser drilling.

[0108] Example 2. Fabrication of tattoo microneedle patches

[0109] Tattoo microneedle patches are typically manufactured using a two-step molding process according to established methods, such as described in the following literature: Mistilis, MJ, Bommarius, AS, and Prausnitz, MR, "Development of a thermostable microneedle patch for influenza vaccination," Journal of Pharmaceutical Sciences (J. Pharm. Sci.), 104, 740-749 (2015); and Edens, C., Collins, ML, Goodson, JL, Rota, PA, and Prausnitz, MR, "A microneedle patch containing measles vaccine is immunogenic in non-human primates," Vaccine, 33, 4712-4718 (2015).

[0110] The tattoo ink dry powder was dispersed in an aqueous solution containing 10% (w / v) polyacrylic acid (PAA) (Polysciences, Warrington, PA) at a concentration of 5% (w / v) with the help of water bath sonication. This dispersion was used as the first solution to fill the mold under vacuum at room temperature (20° C. to 25° C.) for 20 minutes to form the ink-loaded microneedles. After this step, the excess liquid was removed from the mold surface.

[0111] Then a second casting solution consisting of 18% (w / v) polyvinyl alcohol (PVA) and 18% (w / v) sucrose (Sigma, St. Louis, MO) was applied to the mold and dried under vacuum at room temperature (20° C. to 25° C.) for 3 hours to form the backing layer of the microneedle patch. The filled mold was further dried at 40° C. overnight, and then the microneedle patch was demolded using tape (Scotch, 3M, St. Paul, MN). Figure 2A and 2B A microneedle patch formed according to this process is shown in FIG.

[0112] Example 3. Microneedles with various tattoo inks

[0113] Different types of tattoo inks or pigments are loaded into the microneedle patch to achieve different appearances and functions. The inks include: (1) visible colored dry tattoo powders (navy blue TN15, Chinese red TN31, and indigo black TN1, National Tattoo Supply, Allentown, PA); (2) UV visible tattoo ink (black light invisible, Bloodline, Carson City, NV); and (3) thermochromic ink that changes color when heated to about 31°C (UniGlow, Tampa, FL). These inks are loaded into the microneedle patch to obtain a solid color microneedle patch, a UV microneedle patch, and a thermal microneedle patch, respectively.

[0114] To make the microneedle patch, the dry ink powder was added directly to the casting solution and suspended in the casting solution. For liquid UV ink, the ink was centrifuged at approximately 5000 x g for 3 minutes to separate the ink particles. The ink particles were then washed with an equal volume of deionized (DI) water and dried at 37°C for two days to obtain dry ink powder.

[0115] Example 4. Applying a tattoo microneedle patch to tattooed skin

[0116] The feasibility of tattooing the skin with microneedle patches was examined by applying the tattoo microneedle patches to ex vivo excised porcine skin. The microneedle patches were briefly pressed against the skin for approximately 10 seconds and left in place for approximately 15 minutes before being peeled off. The deposition of ink into the skin was accompanied by the dissolution of the water-soluble microneedles, which renders the used backing free of biohazardous sharps. For example, Figure 3A and 3B The remaining backing and proximal portion of the tattoo microneedle after the distal tip portion dissolves to deposit the ink into the skin are shown. After application, the skin was gently cleaned with a tissue (Kimwipe, Kimberly-Clark Professional, Roswell, GA) to wipe the residual ink and microneedle patch dissolution products from the skin surface. Photos of the tattooed skin were taken from 20 cm or 1 m away by a digital camera (Canon EOS 60D, Tokyo, Japan).

[0117] Example 5. Symbol tattooing using a tattoo microneedle patch

[0118] Conventional microneedle patches for drug delivery are usually arranged as arrays of square or circular microneedles. To create microneedle patches with other shapes that can convey visual information, CO 2 A laser cutter drills conical cavities in the PDMS sheet to form a mold with any desired pattern. In this way, a microneedle patch is formed so that each microneedle behaves like a pixel or dot, together creating a tattoo shape or image. Each microneedle is made of a mixture of tattoo ink particles and a biocompatible, water-soluble polymer (e.g., poly(acrylic acid), PAA).

[0119] To demonstrate this method, Figure 4A and 4B As shown in Figure 2, heart-shaped and star-shaped microneedle patch molds were prepared. These molds were used to make microneedle patches with the same pattern, such as Figure 4C and 4D When pressed into the skin, tattoo ink is deposited into the skin through the microneedles to transfer a heart-shaped image (red) and a star-shaped image (blue) as skin tattoos, respectively. Figure 4E and 4F shown.

[0120] Example 6. Preparation of tattoo microneedle patches for vaccination

[0121] The two-component microneedle patch is designed to deliver inactivated poliovirus (IPV) vaccine and manufacture tattoo markers simultaneously. Unit price batch IPV type 2 (Middle East Forces, MEF strain) is provided by Bilthoven Biologicals (Bilthoven, Netherlands). The antigen concentration measured in the batch vaccine is 834D antigen units (DU / ml) per milliliter. The reserve IPV solution is concentrated with an Amicon ultracentrifuge spin filter (Millipore Sigma) with a 100kDa molecular weight cutoff. The final antigen concentration is determined to be 3.6kDU / ml. All DU values ​​were measured using a sandwich enzyme-linked immunosorbent assay (ELISA) as described in Edens, C., Dybdahl-Sissoko, NC, Weldon, WC, Oberste, MS, and Prausnitz, MR. Inactivated polio vaccination using a microneedle patch is immunogenic in the rhesus macaque. Vaccine, 33, 4683-4690 (2015).

[0122] The IPV vaccine and tattoo ink were loaded separately into different sections of the microneedle patch to obtain a two-component microneedle patch. As described in Example 3, the tattoo ink was loaded into one side of the microneedle patch. The IPV vaccine was similarly loaded into the other side of the microneedle patch, but a different first casting solution containing 3.6 kDU / ml IPV, 7.5 (w / v) maltodextrin (Sigma) and 2.5% (w / v) xylitol (Sigma) and a different second casting solution containing 36% (w / v) maltodextrin, 12% (w / v) xylitol and 1% (w / v) PVA were used. The two second casting solutions were in contact with each other on the mold surface and dried into a single patch.

[0123] Example 7. Application of microneedle patches for vaccination and tattooing of the skin

[0124] During the application of the microneedle patch, Wistar mice (9 weeks old, female, Charles River Laboratories) were anesthetized via isoflurane inhalation. Five mice were immunized against IPV type 2 with a two-component microneedle patch that applied 8DPU IPV vaccine to the skin. The microneedle patch was pressed against the shaved mouse skin for approximately 10 seconds and left in place for approximately 15 minutes before peeling. For the control group, six mice were immunized against IPV type 2 by intramuscular injection in the thigh muscle of the hind limb. The intramuscular injection solution was prepared by reconstructing and diluting the vaccine portion of the two-component microneedle patch to deliver the same dose in 100 μl intramuscular injection solution.

[0125] Blood samples from animals were collected over a six-week period to determine polio-specific neutralizing antibody titers. All blood samples were collected via tail vein bleeding in a collection tube containing a clot activator (BD Diagnostics, Franklin Lakes, NJ). Serum was separated from the blood samples by centrifugation at 6000 x g for 1.5 minutes. Serum samples were stored in centrifuge tubes at -20 ° C until antibody titer analysis was performed. All procedures involving animals in this study were approved by the IACUC of the Georgia Institute of Technology.

[0126] Polio-specific neutralizing antibody titers in serum samples were determined by the Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (Atlanta, GA) using the methods described in Combined immunization of infants with oral and inactivated poliovirus vaccines: results of a randomized trial in The Gambia, Oman, and Thailand, WHO Collaborative Study Group on Oral and Inactivated Poliovirus Vaccines, Bulletin of the World Health Organization, 74, 253-268 (1996). Briefly, 80-100 cell culture infectious doses (CCID 50 ) were mixed with serially diluted serum samples and incubated at 35°C for 3 h, followed by the addition of Hep-2 cells. 2After 5 days of incubation at 4 °C, the plates were stained with crystal violet and cell viability was determined by optical density measurement in a spectrophotometer. Neutralization titers were then calculated by the Spearman-Karber method. The detection limit of the assay was 2.5 log 2 titer, and the detection accuracy is ±0.5log 2 Titer.

[0127] Immune responses following vaccination revealed no significant differences in neutralizing antibody responses to vaccination between the microneedle patch and intramuscular vaccination groups.

[0128] Example 8. Tattoo microneedle patch for medical tattooing

[0129] A tattoo microneedle patch was made for each of the eight different blood group codes and for a diabetes warning consisting of a "T1D" logo (i.e., type 1 diabetes) and a red cross symbol. Figures 5A-5C As shown, the microneedle mold depicts the tattoo image in the correct orientation. Figures 5D-5F As shown, the tattoo microneedle patch displays a mirror image of the tattoo so that the image is in the correct orientation when the tattoo was applied. These tattoos applied ex vivo to pig skin Figure 5G-5I Displayed in.

[0130] These medical tattoos demonstrate the feasibility of developing tattoo microneedle patches to provide information using different numbers, letters, symbols, colors, and combinations thereof to create medical tattoo patches that can be easily applied and create easily readable tattoo images.

[0131] Example 9. Photosensitive and Thermosensitive Tattoo Microneedle Patches

[0132] Since it may be useful to have tattoos that respond to environmental changes to provide different information in different environments, light-visible and UV-visible tattoo inks are combined in tattoo microneedle patches to create tattoos with differential information based on lighting conditions. Figure 6A-6B In the display, Fig. 6A The "STOP" patch is visible in sunlight, and Figure 6B The "GO" is visible under UV light. In daylight, the "STOP" mark is visible on the excised pig skin, such as Figure 6C As shown, the "GO" mark is visible in the dark under UV light, as Fig.6D It is worth noting that the "STOP" sign is not visible in the dark, but Fig. 6E As shown, both the "STOP" and "GO" markings are visible under UV lighting in daylight.

[0133] Two different inks are used to form the red cross symbol. The inner cross is made using a thermochromic ink that changes color in response to temperature changes, and the outer circle is made using a regular tattoo ink. Fig. 7A and 7C As shown in Figure 2, the thermochromic ink is invisible or barely visible in ambient conditions. However, upon heating across a threshold of 40°C in the microneedle path and once the tattoo is applied ex vivo to pig skin, the inner cross reversibly changes color, as shown in Figure 2. Figure 6B and 6D This type of thermosensitive tattoo can be used, for example, to monitor temperature in the skin during a fever or during treatments involving exposure to high temperatures. Other thermochromic inks can change to different colors or change at different temperatures, which could enable more color-changing options for thermosensitive microneedle patch tattoos.

[0134] Example 10. QR code tattoo microneedle patch

[0135] Tattoo microneedle patches can also be formed in the pattern of a QR code. A typical QR code consists of dark squares (called modules) on a white background. The grid pattern of a QR code stores digitized data, which can be text (e.g., with medical information) or an Internet link (e.g., to a database) and can be read by an imaging device such as a smartphone camera.

[0136] like Fig. 8A As shown, the target QR code has 29 x 29 modules encoding the target URL address. Figure 8B The QR code microneedle patch shown was made according to the methods disclosed herein and inserted into pig skin ex vivo.

[0137] like Figure 8C As shown, the tattoo point is not square, and is not adjacent to each other like a standard QR code module. Despite the presence of these differences and the visual and morphological characteristics of the skin, the tattoo QR code is successfully read by various well-known applications, including WeChat (version 8.0.15, Shenzhen, China, Tencent) and TikTok (version 22.8.4, Singapore, TikTok Private Limited), and other widely installed code readers (that is, downloading more than 10,000,000 code readers) from Google Play Store (Google Play Store), such as QR and barcode scanners (version 2.2.18, Hong Kong, China, Gamma Game Company (Gamma Play)) and QR scanners: barcode scanners and QR code scanners (version 2.4.5.GP, British Virgin Islands, Simple Design Company). All read attempts are tracked to the encoded URL address as expected.

[0138] Some embodiments of the present disclosure may be described in light of one or more of the following:

[0139] Embodiment 1. A microneedle patch for creating a tattoo image on the skin, the microneedle patch comprising: a backing layer; and an array of microneedles, the array of microneedles extending from the backing layer, each of the microneedles comprising a distal tip portion, the distal tip portion comprising a tattoo substance; wherein the microneedles are configured to be inserted into the skin of a subject, and wherein the microneedles are configured to release the tattoo substance in the skin, thereby creating the tattoo image in the skin, wherein the tattoo image is visible to the human eye.

[0140] Embodiment 2. The microneedle patch of embodiment 1, wherein each microneedle in the array of microneedles corresponds to a dot or pixel of the tattoo image or a portion thereof.

[0141] Embodiment 3. The microneedle patch according to embodiment 1 or 2, wherein the subject is a human.

[0142] Embodiment 4. The microneedle patch according to embodiment 1 or 2, wherein the subject is a domestic animal, such as a pet or livestock.

[0143] Embodiment 5. The microneedle patch of any one of embodiments 1 to 4, wherein at least a portion of the microneedles are configured to dissolve in vivo to release the tattoo substance.

[0144] Embodiment 6. The microneedle patch of any one of embodiments 1 to 5, wherein the microneedles are configured to separate from the backing layer after being inserted into the skin.

[0145] Embodiment 7. The microneedle patch of any one of embodiments 1 to 6, wherein the microneedles further comprise a proximal portion between the backing layer and each of the distal tip portions, wherein the proximal portion is substantially free of the tattoo substance.

[0146] Embodiment 8. The microneedle patch according to embodiment 7, wherein the proximal portion comprises a water-soluble material, such as polyvinyl pyrrolidone, polyvinyl alcohol, a sugar such as sucrose, or a combination thereof.

[0147] Embodiment 9. The microneedle patch according to any one of embodiments 1 to 8, wherein the microneedle density in the array is 50 microneedles / cm 2 Up to 20,000 microneedles / cm 2 , for example 90 microneedles / cm 2 Up to 1,000 microneedles / cm 2 or 100 microneedles / cm 2 Up to 500 microneedles / cm 2 .

[0148] Embodiment 10. A microneedle patch according to any one of embodiments 1 to 9, wherein the array of microneedles is configured to be inserted into about 0.5 cm 2 To about 10cm 2 in the tissue area.

[0149] Embodiment 11. The microneedle patch of any one of embodiments 1 to 10, wherein the tattoo image is configured to be permanent.

[0150] Embodiment 12. The microneedle patch of any one of embodiments 1 to 10, wherein the tattoo image is configured to be temporary.

[0151] Embodiment 13. The microneedle patch of any one of embodiments 1 to 12, wherein the tattoo image comprises letters, numbers, symbols, patterns and / or other encoded information that can be read from outside the body.

[0152] Embodiment 14. The microneedle patch of any one of Embodiments 1 to 13, wherein the tattoo image comprises medical / veterinary warnings and / or medical / veterinary medical information.

[0153] Embodiment 15. The microneedle patch according to any one of embodiments 1 to 14, wherein the tattoo substance comprises single-color ink, multi-color ink, color-changing ink or fluorescent ink.

[0154] Embodiment 16. The microneedle patch according to any one of embodiments 1 to 15, wherein the microneedles do not contain a drug.

[0155] Embodiment 17. The microneedle patch according to any one of embodiments 1 to 15, wherein the microneedles further comprise a drug.

[0156] Embodiment 18. A kit for creating a tattoo image, comprising: two or more microneedle patches, each patch comprising: a backing layer; and an array of microneedles extending from the backing layer; wherein each microneedle in the array of microneedles comprises a distal tip portion, the distal tip portion comprising a tattoo substance, wherein the microneedles of each of the two or more microneedle patches are configured to be inserted into the skin to form a tattoo image.

[0157] Embodiment 19. A kit according to embodiment 18, wherein the two or more microneedle patches are configured to cooperate to produce a composite tattoo, wherein the composite tattoo is produced by selectively positioning the tattoo images from each microneedle patch relative to each other, such as adjacent to each other and / or overlapping each other.

[0158] Embodiment 20. The kit of Embodiment 18 or 19, further comprising an alignment template configured to facilitate selective positioning of the two or more microneedle patches on the skin.

[0159] Embodiment 21. The kit of any one of Embodiments 18 to 20, further comprising an applicator configured to facilitate insertion of each of the two or more microneedle patches into the skin.

[0160] Embodiment 22. The kit of any one of Embodiments 18 to 21, wherein the tattoo image is visible to the human eye.

[0161] Embodiment 23. A method for applying a tattoo to skin, the method comprising: positioning a first microneedle patch on a first area of ​​human skin, wherein the first microneedle patch comprises a first array of microneedles, each microneedle in the first array of microneedles comprises a distal tip portion, and the distal tip portion comprises a tattoo substance; inserting at least the distal tip portion of each microneedle in the first array of microneedles into the human skin; and releasing the tattoo substance in the human skin to form a first tattoo image visible to the human eye.

[0162] Embodiment 24. The method according to embodiment 23 further comprises: positioning a second microneedle patch on a second area of ​​human skin, wherein the second microneedle patch comprises a second array of microneedles, each microneedle in the second array of microneedles comprises a distal tip portion, and the distal tip portion comprises a tattoo substance; inserting at least the distal tip portion of each microneedle in the second array of microneedles into the skin of the person; and releasing the tattoo substance in the skin of the person to form a second tattoo image visible to the human eye, wherein the first and second tattoo images cooperate to produce a composite tattoo, and the composite tattoo is produced by selectively positioning the first and second tattoo images relative to each other.

[0163] Embodiment 25. The method of Embodiment 24, wherein the first and second tattoo images are adjacent to each other or overlap each other.

[0164] Embodiment 26. The method of any one of embodiments 23 to 25, wherein the microneedles dissolve in vivo to release the tattoo substance.

[0165] Embodiment 27. The method of any one of embodiments 23 to 25, wherein the first and / or second microneedle patch is a microneedle patch according to any one of embodiments 1 to 17.

[0166] Embodiment 28. A method for making a tattoo microneedle patch, the method comprising: casting a first component in a mold having a cavity defining an array of microneedles, wherein the first component comprises a tattoo substance; and solidifying the first component in the mold to form the array of microneedles or at least the distal tip portion of the microneedles in the mold, wherein each microneedle in the array of microneedles corresponds to a dot or pixel of a predefined tattoo image or a portion thereof.

[0167] Embodiment 29. The method according to embodiment 28, further comprising: casting a second composition onto the distal tip portion of the microneedle to form a proximal portion of the microneedle.

[0168] Embodiment 30. The method of embodiment 29, wherein the second composition does not include tattoo material.

[0169] Embodiment 31. The method of any one of embodiments 28 to 30, further comprising: casting a backing layer onto the substrate of the microneedles.

[0170] Embodiment 32. The method of any one of Embodiments 28 to 31, wherein at least the distal tip portion of each of the microneedles is configured to dissolve after insertion into the skin of a subject.

[0171] Embodiment 33. The method of any one of Embodiments 28 to 32, wherein the predefined tattoo image or portion thereof is based on customized information provided by a user.

[0172] Embodiment 34. A method according to embodiment 33, wherein the custom information provided by the user includes a digital design in which the user has selected the characteristics and / or arrangement of each of the pixels that will correspond to each of the microneedles in the array of microneedles formed.

[0173] Embodiment 35. A method according to Embodiment 33 or 34, wherein the user selects the color of the tattoo substance and / or the presence or absence of the tattoo substance in each of the microneedles in the array of microneedles.

[0174] Embodiment 36. The method of any one of Embodiments 28 to 35, further comprising selectively removing one or more microneedles from the formed array of microneedles.

[0175] Embodiment 37. The method of any one of Embodiments 34 to 36, wherein the digital design is transmitted from the user to the manufacturer via a web application or other computer or mobile device interface.

[0176] As used herein, the term "about" indicates a value for a given amount, and may include amounts ranging within 10% of the stated value, or optionally within 5% of the value, or in some embodiments within 1% of the value.

[0177] Although the present disclosure has been described with reference to several exemplary embodiments, it will be appreciated by those skilled in the art that the present disclosure is not limited to such disclosed embodiments. In fact, the disclosed embodiments may be modified to incorporate any number of variations, alterations, substitutions, or equivalent arrangements not described herein but commensurate with the spirit and scope of the present disclosure.

Claims

1. A microneedle patch for creating a tattoo image on the skin, the microneedle patch comprising: Backing layer; as well as an array of microneedles extending from the backing layer, the microneedles each comprising a distal tip portion comprising a tattoo substance; wherein the microneedles are configured to be inserted into the skin of a subject, and wherein the microneedles are configured to release the tattoo substance in the skin, thereby creating the tattoo image in the skin, The tattoo image is visible to the human eye.

2. The microneedle patch of claim 1, wherein each microneedle in the array of microneedles corresponds to a dot or pixel of the tattoo image or a portion thereof.

3. The microneedle patch of claim 1, wherein the subject is a human.

4. The microneedle patch according to claim 1, wherein the subject is a domestic animal, such as a pet or livestock.

5. The microneedle patch of claim 1, wherein at least a portion of the microneedles are configured to dissolve in vivo to release the tattoo substance. The microneedle patch according to claim 1 , wherein the microneedles are configured to be separated from the backing layer after being inserted into the skin.

7. The microneedle patch of claim 1, wherein the microneedles further comprise a proximal portion between the backing layer and each of the distal tip portions, wherein the proximal portion is substantially free of the tattoo substance.

8. The microneedle patch of claim 7, wherein the proximal portion comprises a water-soluble material, such as polyvinyl pyrrolidone, polyvinyl alcohol, a sugar such as sucrose, or a combination thereof.

9. The microneedle patch according to claim 1, wherein the microneedle density in the array is 50 microneedles / cm 2 Up to 20,000 microneedles / cm 2 , for example 90 microneedles / cm 2 Up to 1,000 microneedles / cm 2 or 100 microneedles / cm 2 Up to 500 microneedles / cm 2 .

10. The microneedle patch of claim 1, wherein the array of microneedles is configured to be inserted to about 0.5 cm 2 To about 10cm 2 in the tissue area.

11. The microneedle patch of claim 1, wherein the tattoo image is configured to be permanent.

12. The microneedle patch of claim 1, wherein the tattoo image is configured to be temporary.

13. The microneedle patch of claim 1, wherein the tattoo image comprises letters, numbers, symbols, patterns and / or other encoded information that can be read from outside the body.

14. The microneedle patch of claim 1, wherein the tattoo image includes medical / veterinary warnings and / or medical / veterinary medical information.

15. The microneedle patch according to claim 1, wherein the tattoo substance comprises single-color ink, multi-color ink, color-changing ink or fluorescent ink.

16. The microneedle patch according to any one of claims 1 to 15, wherein the microneedles do not contain a drug.

17. The microneedle patch according to any one of claims 1 to 15, wherein the microneedles further comprise a drug.

18. A kit for creating a tattoo image, the kit comprising: Two or more microneedle patches, each patch comprising: a backing layer; and an array of microneedles extending from the backing layer; wherein each microneedle in the array of microneedles comprises a distal tip portion, the distal tip portion comprising a tattoo substance, The microneedles of each of the two or more microneedle patches are configured to be inserted into the skin to form a tattoo image.

19. The kit of claim 18, wherein the two or more microneedle patches are configured to cooperate to produce a composite tattoo, the composite tattoo being produced by selectively positioning the tattoo images from each microneedle patch relative to each other, such as adjacent to each other and / or overlapping each other.

20. The kit of claim 19, further comprising an alignment template configured to facilitate selective positioning of the two or more microneedle patches on the skin.

21. The kit of claim 18, further comprising an applicator configured to facilitate insertion of each of the two or more microneedle patches into the skin.

22. A kit according to any one of claims 18 to 21, wherein the tattoo image is visible to the human eye.

23. A method of applying a tattoo to skin, the method comprising: positioning a first microneedle patch onto a first area of ​​skin of a person, wherein the first microneedle patch comprises a first array of microneedles, each microneedle in the first array of microneedles comprises a distal tip portion, the distal tip portion comprising a tattoo substance; inserting at least the distal tip portion of each microneedle in the first array of microneedles into the skin of the person; as well as The tattoo material is released in the skin of the person to form a first tattoo image visible to the human eye.

24. The method of claim 23, further comprising: positioning a second microneedle patch on a second area of ​​the person's skin, wherein the second microneedle patch comprises a second array of microneedles, each microneedle in the second array of microneedles comprising a distal tip portion, the distal tip portion comprising a tattoo substance; inserting at least the distal tip portion of each microneedle in the second array of microneedles into the skin of the person; as well as releasing the tattoo substance in the skin of the person to form a second tattoo image visible to the human eye, Wherein the first and second tattoo images cooperate to produce a composite tattoo, the composite tattoo being produced by selectively positioning the first and second tattoo images relative to each other.

25. The method of claim 24, wherein the first and second tattoo images are adjacent to each other or overlap each other.

26. The method of any one of claims 23 to 25, wherein the microneedles dissolve in vivo to release the tattoo substance.

27. A method for making a tattoo microneedle patch, the method comprising: casting a first composition in a mold having a cavity defining an array of microneedles, wherein the first composition comprises a tattoo substance; as well as solidifying the first composition in the mold to form the array of microneedles or at least the distal tip portions of the microneedles in the mold, Each microneedle in the array of microneedles corresponds to a point or pixel of a predefined tattoo image or a portion thereof.

28. The method of claim 27, further comprising: A second composition is cast onto the distal tip portion of the microneedle to form a proximal portion of the microneedle.

29. The method of claim 28, wherein the second composition does not include a tattooing substance.

30. The method of claim 27, further comprising: A backing layer was cast onto the microneedle substrate.

31. The method of any one of claims 27 to 30, wherein at least the distal tip portion of each of the microneedles is configured to dissolve after insertion into the skin of a subject.

32. A method according to any one of claims 27 to 30, wherein the predefined tattoo image or part thereof is based on custom information provided by a user.

33. A method according to claim 32, wherein the custom information provided by the user includes a digitized design in which the user has selected the characteristics and / or arrangement of each of the pixels that will correspond to each of the microneedles in the array of microneedles formed.

34. The method of claim 33, wherein the user selects a tattoo substance color and / or the presence or absence of a tattoo substance in each of the microneedles in the array of microneedles.

35. The method of claim 32, further comprising selectively removing one or more microneedles from the formed array of microneedles.

36. The method of claim 33, wherein the digital design is transmitted from the user to the manufacturer via a web application or other computer or mobile device interface.

Images