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US Patent 

MICRONEEDLE TATTOO PATCHES AND USE THEREOF

Abstract

Microneedle patches have been developed that can be used to deliver therapeutic, prophylactic, diagnostic agents and/or dyes to the skin. The microneedles encapsulate the agent(s) to be delivered. These are formed of a biodegradable polymer that dissolves upon insertion into skin or tissue, so that the microneedles break off from the substrate forming the patch, remaining in the skin/tissue at the site of insertion. The patches are used to create a tattoo or to deliver therapeutic, prophylactic or diagnostic agent in combination with a tattoo. In one embodiment, the microneedle patch contains both vaccine and dye pigments to administer vaccine and record such administration in one application of the microneedle patch.


Inventors:Jaklenec; Ana; (Lexington, MA) ; McHugh; Kevin J.; (Watertown, MA) ; Langer; Robert S.; (Newton, MA)
Applicant:
NameCityStateCountryType

Massachusetts Institute of Technology

Cambridge

MA

US

Family ID:63080551
Appl. No.:16/036712
Filed:July 16, 2018

Related U.S. Patent Documents







Application NumberFiling DatePatent Number

62533081Jul 16, 2017



Current U.S. Class:1/1
Current CPC Class: A61M 2202/30 20130101; A61K 9/0021 20130101; A61Q 1/02 20130101; A61M 2037/0053 20130101; A61B 2090/3979 20160201; A01K 11/005 20130101; A61K 49/0069 20130101; A61B 50/30 20160201; A61B 5/6867 20130101; A61K 8/0216 20130101; A61M 2037/0046 20130101; A61K 49/18 20130101; A61M 37/0015 20130101; A61M 2037/0061 20130101; A61B 2090/3941 20160201; A61B 2090/395 20160201; A61M 37/0076 20130101; A61B 5/0071 20130101; A61B 90/94 20160201; A61B 2090/3987 20160201; A61B 17/205 20130101; A61B 2090/3933 20160201; A61M 2037/0023 20130101; A61B 2090/397 20160201; A61B 90/90 20160201
International Class: A61M 37/00 20060101 A61M037/00; A61B 5/00 20060101 A61B005/00; A61B 90/90 20060101 A61B090/90; A61B 50/30 20060101 A61B050/30; A61K 9/00 20060101 A61K009/00; A61K 49/00 20060101 A61K049/00; A61K 8/02 20060101 A61K008/02; A61Q 1/02 20060101 A61Q001/02; A61K 49/18 20060101 A61K049/18

Claims



1. A microneedle array structure comprising a flexible base element and a plurality of biodegradable microneedles each having a first end and a second sharpened end for penetration of skin, the microneedles extending outwardly from the base element at the first end of the microneedles, The microneedles comprising therapeutic, prophylactic and/or diagnostic agent and/or dye, wherein the microneedles are released from the base element within 15 minutes of administration into the skin.

2. The microneedle array structure of claim 1 wherein the therapeutic, prophylactic or diagnostic agent and/or dye is microencapsulated prior to incorporation into the microneedles.

3. The microneedle array structure of claim 1 wherein the microneedles are formed of biodegradable polymer or a sugar composition.

4. The microneedle array structure of claim 1 wherein the dye is selected from the group consisting of inorganic nanocrystals, lanthanide-based dyes, other fluorophores, and non-fluorescent imaging agents.

5. The microneedle array structure of claim 1 wherein the dye is carbon or a tattoo ink, or a cosmetic ink.

6. The microneedle array structure of any of claim 1 wherein the dye is a near infrared imaging agent with an excitation wavelength and an emission wavelength in the near infrared range.

7. The microneedle array structure of claim 6 wherein the dye is selected from the group of inorganic nanocrystals selected from copper-based quantum dots or silver-based quantum dots.

8. The microneedle array structure of claim 1 wherein the microneedles contain dye and form a pattern for identification of the individual, medical treatment, date, location, or combination thereof.

9. The microneedle array structure of claim 1 wherein the microneedles contain therapeutic, prophylactic or diagnostic agent.

10. The microneedle array structure of claim 9 wherein the agent is a vaccine.

11. The microneedle array structure of claim 1 comprising dye not visible in visible light but visualized in infrared light, ultraviolet light or by fluoroscopy.

12. The microneedle array structure of claim 1 wherein the arrays are sequentially numbered.

13. The microneedle array structure of claim 1 in a kit comprising an imaging device comprising a source for emitting a wavelength and optionally an optical filter for detection.

14. The microneedle array structure of claim 1 wherein the agents to be delivered are preferentially located in the tip of the microneedle which remains in the body after the needle dissolves sufficiently for the flexible base to fall off.

15. The microneedle array structure of claim 1 wherein the microneedles comprise a conical structure, preferably being a combination of conical and cylindrical structures.

16. A method of providing identification and/or tattooing and/or delivery of a therapeutic, prophylactic or diagnostic agent comprising applying to the skin of an individual the microneedle array structure of claim 1.

17. The method of claim 16 wherein the individual is an animal.

18. The method of claim 16 wherein the microneedle array structure administers a vaccine and identifies the vaccine and date and/or geographic location of the vaccination.

19. The method of claim 16 wherein the individual is in need of cosmetic tattooing.

20. The method of claim 16 wherein the individual is a military person.
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Ser. No. 62/533,081, filed on Jul. 16, 2017, which is incorporated herein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] None.

FIELD OF THE INVENTION

[0003] The invention relates generally to disposable one-time use microneedle tattoo patches, which may have applications in creating records simultaneously with drug delivery, to make tattoos not visible to the eye, and in agricultural applications.

BACKGROUND OF THE INVENTION

[0004] Tattoos are generally divided into two groups--permanent and temporary. People have tattooed patterns and symbols on their skin for thousands of years, typically using a sharp object to disrupt the skin surface, and then rubbing into the wound dyes, pigments, and charcoal. These remain trapped in the skin as it heals.

[0005] In agriculture, permanent tattoos and brands (burn scars) have been used to indicate ownership. In the U.S., regulatory agencies require animals to be individually marked to share origin, to help control disease. These may be in the form of tattoos, typically made by clamping needle letters and numbers, into the inside of the ear, or more recently, using RFID tags or microchip implants. The latter are expensive, however, and may migrate. In people, elaborate tattoo machines have been developed to create colorful, detailed designs, using a mechanized needle connected to one or more dye reservoirs.

[0006] There are a number of temporary tattoos. One of the oldest was the application of ocher to the skin, more recently patterns created by plant dyes such as henna. Currently tattoos can be applied to the skin using temporary decorative skin decals that wear away in relatively short amounts of time, typically between hours and weeks. Temporary tattoo market relies on the tattoo be either on an image printed on a skin adherent material, or skin stain. For example, one type of sticker-based tattoo contains a printed image on a release sheet that is placed on a backing sheet, where the image is transferred to the skin when the backing sheet is removed. This leaves tattoo patterns on the skin that wear off in a little over a week. Airbrush tattoo is another type of temporary tattoos that is created by spraying dye pigment over a tattoo stencil placed over the skin. The dye pigment stain lasts for couple of months.

[0007] There is no currently available means of applying a permanent tattoo that is not invasive and painful. There is no currently available device for making a permanent tattoo that is disposable, individualizable, and relatively painless and non-invasive. There is no currently available device to apply a therapeutic, prophylactic or diagnostic agent in combination with a tattoo to identify the agent, the date, and/or the individual to whom it is administered. There is no device that one can use to form a tattoo which is invisible in regular light.

[0008] Therefore, it is an objective of the present invention to provide such a device.

[0009] It is another objective of the present to provide method of making and using such a device to allow painless, facile, and quick application of the dyes to the skin.

SUMMARY OF THE INVENTION

[0010] Microneedle patches have been developed. These can be used to deliver therapeutic, prophylactic, diagnostic and/or dyes (including dyes, pigments, fluorophores, etc., collectively referred to herein as "dyes") agents to the skin. The microneedles encapsulate the agent(s) to be delivered. These are formed of a biodegradable polymer that dissolves upon insertion into skin or tissue, so that the microneedles break off from the substrate forming the patch, remaining in the skin/tissue at the site of insertion. The polymer continues to degrade, leaving the agent(s) at the site of insertion.

[0011] In a preferred embodiment, the patches are used to create a tattoo. In another, the patch is used to deliver therapeutic, prophylactic or diagnostic agent in combination with a tattoo. In one embodiment, the tattoo is invisible in normal light, being visible in the infrared, fluorescent or ultraviolet light. The diameter and length of the microneedles, the agent to be imaged, and the particle size and location in the microneedles, as well as the composition, are selected to be compatible with the agent to be delivered, as well as to deliver a sufficient amount of agent at the desired site to be effective, to minimize pain, and to release from the patch in a desired time frame, preferably five minutes or less.

[0012] Active agents may be encapsulated in the microneedles for delivery through the skin of a subject. In one embodiment, vaccine is delivered through the microneedle patch. In another embodiment, the microneedle patch contains both vaccine and dye pigments to administer vaccine and record such administration in one application of the microneedle patch.

[0013] Exemplary dyes include inorganic nanocrystals, lanthanide-based dyes, other fluorophores, and non-fluorescent imaging agents. Preferably the dye is a near infrared imaging agent with an excitation wavelength and an emission wavelength in the near infrared range. A preferred type of inorganic nanocrystals is quantum dots, e.g., copper-based quantum dots or silver-based quantum dots.

[0014] Dyes are generally encapsulated in polymeric particles prior to embedding in the microneedle structure. Particles protect or diminish the photobleaching of an encapsulated dye, providing a protective environment for increasing the photostability of dyes against changes in the pH or an oxidative environment. In preferred embodiments, slow degrading microparticles are used to encapsulate dyes at a high loading efficiency with minimal leakage.

[0015] The arrangement of microneedles (size, spacing distance, quantity, density, etc.) as well as the type of dyes therein, may correspond to unique information such as a vaccination record, date, or identification of a subject. The microneedles dissolve or are degraded within 3, 4, 5, 6, 7, 8, 9, 10, or 15 minutes upon contact with skin, delivering the dye-encapsulated particles in the skin (preferably the dermis), leaving the dyes as markings/tattoos that last at least five years. These tattoos are especially useful as medical decals as a "on-patient" record of medical history: e.g., sub dermal immunization record (individual vaccination history), blood type or allergens.

[0016] A microneedle pattern, a combination of imaging dyes, or both may be used to encode multiple pieces of information in one microneedle patch. The concept is to use this to aid healthcare workers who have to act on very little patient information. Ideally the marking would not be visible to the naked eye but could be visualized using a device as simple as a cell phone from which the it or uv filters have been removed.

[0017] The patches have many advantages. They are easily mass produced, stored and shipped. They are easily applied without conventional needles and relatively painless. No bio-hazardous sharps are generated through the application of biodegradable microneedles.

[0018] The patches have applications in the defense industry, as a well to mark soldiers without using invasive means such as a chip, or means such as a "dog tag" which may be lost, providing an alternative means of identification or medical record, optionally while at the same time administering vaccines.

[0019] The patches may also be used to apply dyes for cosmetic purposes, such as lip enhancement, eyebrow darkening, or delivery of an agent such as botulinum toxin or growth factor to alleviate wrinkles.

[0020] The patches also have applications in the animal industry, providing a clean, relatively easy and painless way to permanently identify animals. The patches can be made so that the marking include a group identify (such as the USDA farm identification number) as well as individual identify.

[0021] The microneedles can be prepared by first creating a master mold using a material such as poly dimethyl siloxane (PDMS), based on the geometries created with CAD; followed by solidifying the solution/suspension containing biodegradable materials along with dye (fluorescent/non-fluorescent) or particles encapsulating dyes, therapeutic, prophylactic or diagnostic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIGS. 1A and 1B are schematics showing the workflow of tattoo implantation in the skin and an imaging process with dye (FIG. 1A) or fluorophore (FIG. 1B).

[0023] FIGS. 2A-2C are line graphs showing the absorbance spectra of IRDC3 (FIG. 2A), copper quantum dots (FIG. 2B), and silver quantum dots (FIG. 2C), respectively, with the absorbance spectra of melanin in the background.

[0024] FIGS. 3A-3C are line graphs showing the emission spectra of IRDC3 (FIG. 3A), copper quantum dots (FIG. 3B), and silver quantum dots (FIG. 3C), respectively, with the absorbance spectra of melanin in the background.

[0025] FIGS. 4A-4C are dot graphs showing the percentage of remaining fluorescence intensity of IRDC3 (FIG. 4A), silver quantum dots encapsulated in poly(methyl methacrylate) particles (FIG. 4B), and copper quantum dots encapsulated in poly(methyl methacrylate) particles (FIG. 4C), respectively, over days of photobleaching ex vivo.

[0026] FIG. 5 is a spectra of absorbance over wavelength (nm) for water, Hb, HbO.sub.2, and melanin.

[0027] FIG. 6 is a line graph showing the signal-to-noise ratios of lanthanide dye, IRDC2 when excited at 635 nm.

[0028] FIG. 7 is a line graph showing the signal-to-noise ratios of lanthanide dye, IRDC3 when excited at 808 nm.

[0029] FIG. 8A shows a schematic depicting the potential reduction of quantum yields of dyes due to absorbance of wavelengths by melanin and/or deeper tissue. When an excitation light shines on the skin, it may be absorbed by melanin and/or the deeper tissue before reaching the fluorophore. The excited fluorophore emits at a wavelength that may be absorbed by the tissue and/or melanin before emitting off the skin.

[0030] FIGS. 8B and 8C are graphs of the intensity per gram of dye (8B) and intensity per gram of particles (8C).

[0031] FIGS. 9A-9C are line graphs showing the percent of fluorescent intensities over time (minutes) of dyes that were exposed to light from a compact fluorescent (CFL) bulb (FIG. 9A), were submerged in 3 micromolar hydrogen peroxide (FIG. 9B), and were submerged in a pH5 environment (FIG. 9C), respectively.

[0032] FIG. 10 is a cross-sectional schematic of the polymeric particles containing imaging agents.

[0033] FIG. 11 is a graph of intensity versus filter wavelength (nm).

[0034] FIG. 12A shows the optimal microneedle shape and dimensions.

[0035] FIGS. 12B and 12C are graphs showing optimal microneedle dimensions for pig ear (12B) and SynDerm (12C).

DETAILED DESCRIPTION OF THE INVENTION

[0036] Unlike decorative tattoos, markings on the skin to encode medical history or medical information is challenging primarily due to the lack of appropriate inks or dyes for years long photostability and the device to administer or image them off the skin. There is no existing technology in the market that will store medical history with the aid of microneedle-based tattoo, although radio frequency identification (RFID) technology based implantable electronic chips are used under the skin.

[0037] Topical delivery of therapeutic active agents (or imaging agents) is a very useful method for achieving systemic or localized pharmacological effects. The main challenge in transcutaneous drug delivery is providing sufficient drug penetration across the skin. The skin consists of multiple layers starting with a stratum corneum layer about (for humans) 20 microns in thickness (comprising dead cells), a viable epidermal tissue layer about 70 microns in thickness, and a dermal tissue layer about two mm in thickness.

[0038] Current topical drug delivery methods are generally based upon the use of penetration enhancing methods, which often cause skin irritation, and the use of occlusive patches that hydrate the stratum corneum to reduce its barrier properties. Allowing large fractions of topically applied drug to penetrate through skin is still highly challenging with very poor efficiency.

[0039] I. Reagents and Device

[0040] A. Microneedle Patch

[0041] 1. Biodegradable Microneedles

[0042] Methods of making microneedles are well known. These are typically formed using casting into a mold, but may also be created using other available methods.

[0043] The material forming the microneedles is critical. It must be biodegradable and it must degrade sufficiently within a few minutes of insertion into the skin for the microneedle to break loose from the substrate and stay at the site of administration. It must then continue to degrade to release the agent and/or dye at the site of administration. In the preferred embodiment, the patch is pressed upon the skin for five minutes and the agent and/or dye deposited sub-dermally upon the dissolution of the microneedles.

[0044] In one embodiment, microneedles are fabricated from a combination of polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP). In another embodiment, microneedles are fabricated from a sugar-based material such that they are dissolvable at the site of administration.

[0045] Alternative materials for forming the degradable portion of the microneedles include hydroxy acids such as lactic acid and glycolic acid polyglycolide, polylactide-co-glycolide, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone). Most of these need to include additives to increase the rate of dissolution upon administration.

[0046] Optionally, the microneedle may contain other materials, including metals, ceramics, semiconductors, organics, polymers, and composites. Preferred materials of construction include pharmaceutical grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, alloys of these or other metals, silicon, silicon dioxide, and polymers.

[0047] The type of biodegradable materials (e.g., polymers) to form microneedle and/or their concentration(s) in forming microneedle are selected to provide sufficient dissolution rates in vivo or upon contacting the skin. Exemplary dissolution rates include within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 15 minutes of application to the skin, at least the tip of microneedles or the portion having embedded therein dyes or dyes encapsulated in microparticles dissolves in the skin such that the embedded dyes or microparticles encapsulating the dyes are released or deposited into the skin.

[0048] Microneedles typically penetrate deep into the dermis to prevent the dye-containing particles from shedding with skin. For example, microneedles may have a cylindrical body of a height between 0.5 mm and 6 mm, preferably between 1 mm and 4 mm, more preferably between 1.5 mm and 2 mm. Microneedles may have a tip that is conical shaped or beveled, where the tip is of a height or length between 0.1 mm and 1.2 mm, preferably between 0.2 mm and 0.8 mm, more preferably between 0.3 mm and 0.4 mm. A lower insertion force is needed for applying sharp microneedles. These geometries allow sharpness (radius of curvature) of the microneedles that are superior to traditional microneedles that are 19 G or 25 G.

[0049] In one embodiment, microneedles have a height of 1,500 .mu.m and a base of 300 .mu.m thick.

[0050] The microneedles may be arranged into an array of m.times.n microneedles within an area (e.g., 1 cm.sup.2, 10 cm.sup.2, or 50 cm.sup.2) where m and n are independently integers between 2 and 100 or greater. Laser cutting may guide the distribution of the microneedles. The array may outline a square, rectangle, diamond, or round shape. The spacing or the smallest distance between two adjacent microneedles in an array may be the same for any two microneedles, or may be different resulting in an array with a denser section of microneedles and a less dense section.

[0051] The microneedles are generally edged, preferably a substantially sharp edge to assist in penetrating the stratum corneum and epidermis and into the dermis. The edged microneedles generally have a tip that is a conical shape or beveled.

[0052] 2. Patch Substrate

[0053] The patches consist of a flexible substrate having microneedles formed thereon, the microneedles containing therapeutic, prophylactic, or diagnostic agent and/or dyes encapsulated or dispersed therein, preferably first encapsulated in microparticles.

[0054] The substrate, or base element, includes a substrate to which the microneedles are attached or integrally formed. The base element may be a patch with elongated microneedles. The patch may be formed from the same material as that for the microneedles, or different. The base element can be constructed from a variety of materials, including metals, ceramics, semiconductors, organics, polymers, and composites. The base element is generally thick enough for maneuvering; or it may be thin enough to be a sticky film for application on the skin to remain contact with the skin during the period in which the degradable microneedles dissolve in the dermis to release the dyes or particles encapsulating the dyes.

[0055] The microneedles can be oriented perpendicular or at an angle to the base element. Preferably, the microneedles are oriented perpendicular to the substrate so that a larger density of microneedles per unit area of substrate can be provided. An array of microneedles can include a mixture of microneedle orientations, heights, or other parameters.

[0056] In a preferred embodiment of the device, the base element and/or microneedles, as well as other components, are formed from flexible materials to allow the device to fit the contours of the biological barrier, such as the skin, to which the device is applied. A flexible device will facilitate more consistent penetration during use, since penetration can be limited by deviations in the attachment surface. For example, the surface of human skin is not flat due to dermatoglyphics (i.e. tiny wrinkles) and hair.

[0057] In some embodiments, the microneedle array is constructed in the form of a microneedle "patch" that is attached to the skin at the time the dye is to be transferred from the microneedles to the skin (preferably the dermis).

[0058] 3. Agents to be Encapsulated in Microneedles

[0059] There are two categories of agents to be delivered: therapeutic, prophylactic and diagnostic agents (referred to herein as "agents") and dyes, pigments, metals, fluorophores, inks (referred to herein as "dyes").

[0060] a. Dyes

[0061] A dye for marking the skin is prepared from a material that may transmit through pigmented skin, be resistant to photobleaching, be safe to the subject to which the microneedle is applied, have a relatively high quantum yield, be amenable to be loaded in particles at a high loading amount, have a low background noise, and/or be stable to variations in temperature, pH, or oxidation in the in vivo environment, for at least one year, 2 years, 3 years, 4 years, 5 years, or longer.

[0062] In some embodiments, as shown in FIG. 10, the dyes are encapsulated in polymeric particles such as poly(methyl methacrylate) (PMMA) particles or polystyrene particles, which improves the safety profile, for example, resulting in reduced toxicity compared to delivering the dye directly in the microneedles without the PMMA particles, measurable by lowered level of apoptosis of cells by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% following application of the microneedles in the skin.

[0063] Signal-to-noise (S/N) ratio in imaging an imaging agent from within the skin may be generally described by the formula:

S/N=[(1-Tissue Absorbance).times.Particle Loading.times.Quantum Yield.times.(1-Photobleaching and environmental degradation rate)]/Background noise.

[0064] Preferably the dyes for marking the skin have a S/N ratio of at least about 5, preferably at least about 15, and may be between about 50 and 150.

[0065] Preferably the marking would not be visible to the naked eye.

[0066] Inorganic Nanocrystals

[0067] Semi-conducting nanocrystals have customizable wavelengths have high quantum yields. An exemplary semi-conducting nanocrystal is near infra-red (NIR) emitting, fluorescent inorganic crystal. NIR emitting crystals emit in the range between about 900 nm and about 1,000 nm and the fluorescence is to the naked eye. These inorganic crystals provide markings under the skin, where the markings are invisible to the naked eye and may be illuminated for visualization with appropriate imaging device.

[0068] In some embodiments, the NIR emitting inorganic dye is semiconducting nanocrystals of copper or silver, which may be encapsulated in a poly methyl methacrylate (PMMA) microparticle for embedding in the microneedles.

[0069] In some embodiments, the dye is a semi-permanent or permanent, in which the dye pigment under skin has a strong photostability. For example, the dye pigment is not degraded or is only degraded for less than 50%, 40%, or 30% under skin after exposure to ambient sun light and ambient environment over the course of 6 months, 1 year, 2 years, 3 years, 5 years, or 10 years or longer. Photostability of a pigment is generally evaluated using high solar irradiance (7.times. intensity of sea level sun light) after the dye pigment is deposited under melanin pigmented human cadaver skin.

[0070] Quantum Dots

[0071] One embodiment of a suitable fluorophore is a quantum dot. Quantum dots are very small semiconductor particles, generally only several nanometres in size, so small that their optical and electronic properties differ from those of larger particles. Generally, larger quantum dots (radius of 5-6 nm, for example) emit longer wavelengths resulting in emission colors such as orange or red. Smaller quantum dots (radius of 2-3 nm, for example) emit shorter wavelengths resulting in colors like blue and green, although the specific colors and sizes vary depending on the exact composition of the QD.

[0072] Quantum dots are suitable for use as the dye in the microneedles due to their customizable wavelengths, low tissue absorption, high quantum yields, and less toxicity than lanthanide-containing dyes. In some embodiments, the quantum dots are surface modified (or stabilized) with hydrophobic organic ligands to increase hydrophobicity, thus compatibility with certain hydrophobic polymers for high loading amount in polymeric particles shown in FIG. 10. In some embodiments, quantum dots that are cadmium free mitigate potential toxicity to the skin.

[0073] Quantum dots as dyes for the microneedles can be produced from an inorganic material, generally inorganic conductive or semiconductive material including group II-VI, group III-V, group IV-VI and group IV semiconductors. Suitable semiconductor materials include, but are not limited to, Si, Ge, Sn, Se, Te, B, C (including diamond), P, BN, BP, BAs, AIN, AlP, AlAs, AlSb, GaN, GaP, GaAs, GaSb, InN, InP, InAs, InSb, AIN, AlP, AlAs, AlSb, GaN, GaP, GaAs, GaSb, ZnO, ZnS, ZnSe, ZnTe, CdS, CdSe, CdSeZn, CdTe, HgS, HgSe, HgTe, BeS, BeSe, BeTe, MgS, MgSe, GeS, GeSe, GeTe, SnS, SnSe, SnTe, PbO, PbS, PbSe, PbTe, CuF, CuCl, CuBr, CuI, Si.sub.3N.sub.4, Ge.sub.3N.sub.4, Al.sub.2O.sub.3, (Al, Ga, In).sub.2 (S, Se, Te).sub.3, Al.sub.2CO, and appropriate combinations of two or more such semiconductors.

[0074] Synthesis of Dyes

[0075] Quantum dots or inorganic nanostructures as dyes for inclusion in microneedles are generally described in U.S. Pat. No. 6,225,198, U.S. Patent Application Publication No. 2002/0066401, U.S. Pat. No. 6,207,229, U.S. Pat. No. 6,322,901, U.S. Pat. No. 6,949,206, U.S. Pat. No. 7,572,393, U.S. Pat. No. 7,267,865, U.S. Pat. No. 7,374,807, U.S. patent application 20080118755, and U.S. Pat. No. 6,861,155.

[0076] Exemplary quantum dots for inclusion in the microneedle include low toxicity, high quantum-yield copper-based quantum dots such as copper-indium-selenide with an overlay/film of zinc sulfide (ZnS), optionally doped with aluminum, i.e., CuInSe2/ZnS:Al; as well as silver-based quantum dots such as near-infrared emissive quantum dots having a core of silver-indium-selenide and a shell of ZnS, optionally doped with aluminum, i.e., AgInSe2/ZnS:Al.

[0077] Other Fluorophores

[0078] Another type of dye suitable for marking in the skin is fluorophores. A fluorophore is a fluorescent chemical compound that can re-emit light upon light excitation. Preferably, fluorophores that are not visible to the naked eye under ambient sun exposure are used as the dye for the microneedles.

[0079] In some embodiments, lanthanide-based dyes, IRDC3 or IRDC2, are used as the dye for inclusion in the microneedles.

[0080] Non-Fluorescent Dyes

[0081] Other exemplary dyes for inclusion in microneedle include non-fluorescent molecules such as paramagnetic molecules, magnetic molecules, and radionuclides.

[0082] Tattoo Inks and Dyes

[0083] Carbon (soot or ash) is often used for black. Other elements used as pigments include antimony, arsenic, beryllium, calcium, copper, lithium, selenium, and sulphur. Tattoo ink manufacturers typically blend the heavy metal pigments and/or use lightening agents (such as lead or titanium) to reduce production costs. Some pigments include inorganic materials such as ocher.

[0084] Natural materials such as henna may also be used.

[0085] b. Active Agents

[0086] The microneedles are also suitable for delivery of active agents (e.g., therapeutic, prophylactic or diagnostic agents) in addition to or separately from the delivery of the dyes or ink molecules.

[0087] In some embodiments, the active agents are encapsulated in, absorbed in, covalently bonded to, or modified onto the surface of, the same microparticles encapsulating the dyes. In other embodiments, the active agents are encapsulated in, absorbed in, covalently bonded to, or modified onto the surface of different particles from those delivering the dyes or ink molecules.

[0088] In some embodiments, the active agents are encapsulated in, absorbed in, covalently bonded to the microneedle, which upon the dissolution of the microneedle release into the skin.

[0089] Exemplary active agents can be proteins or peptides, sugars or polysaccharides, lipids, nucleotide molecules, or combinations thereof, or synthetic organic and inorganic compounds such as a low molecular weight compound having a molecular weight of less than 2000 D, more preferable less than 1000 D.

[0090] A preferred active agent is a vaccine antigen. Other agents include insulin, anti-infectives, hormones, growth regulators, and drugs for pain control. Typically the agent is administered in a dosage effective for local treatment.

[0091] The microneedle array is also useful for delivering specific compounds or actives into the skin, such as cosmetic compounds or nutrients, or various skin structure modifiers that can be delivered subcutaneously without having to visit a cosmetic surgery clinic. In addition, color cosmetics could also be delivered subcutaneously to provide long-term benefits for the skin, and even makeup or lipstick-type coloring compounds can be delivered by use of the microneedle patches. The color cosmetics are delivered into the epidermis or the dermis, where they remain in place for at least one or two months, or even longer (e.g., years). Since the epidermis is renewable, agents that are delivered there would eventually wear out; and then will be expunged from the body. This allows a person to change their "look" according to changes in fashion and style, which typically change every season.

[0092] 4. Microparticles for Encapsulation of the Dyes and/or Active Agents

[0093] In preferred embodiments, microparticles are used to encapsulate the dye and/or agent and provide an environment in which the dye and/or agent is chemically stabilized or provided with physical protection, e.g., reduced or minimal photobleaching or other negative impact in the biological environment.

[0094] In certain embodiments, the microparticles are slow degrading particles such that encapsulated dyes are protected for 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years or greater.

[0095] In some embodiments, the microparticles may reduce the oxidation of encapsulated dyes by at least 50%, 60%, 70%, 80%, 90%, or more. For example, encapsulation of IRDC3 in particles reduces the oxidizing effect of 3 micromolar hydrogen peroxide by 98%.

[0096] In some embodiments, microparticles are also used to shield the skin from toxicity associated with the dye or with high concentration of the dye. Microparticles generally do not interfere with the illumination or the emission or the dye signal through the skin.

[0097] Microparticles or nanoparticles for encapsulating dyes are generally prepared with bio-inert materials. The size of microparticles is selected to allow a high loading of the dye or the active agents and to support long residence time in the skin.

[0098] Exemplary polymers include, but are not limited to, polymers prepared from lactones such as poly(caprolactone) (PCL), polyhydroxy acids and copolymers thereof such as poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co-PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO-co-D,L-lactide), and blends thereof, polyalkyl cyanoacralate, polyurethanes, polyamino acids such as poly-L-lysine (PLL), poly(valeric acid), and poly-L-glutamic acid, hydroxypropyl methacrylate (HPMA), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, ethylene vinyl acetate polymer (EVA), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such as polyvinyl acetate), polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), celluloses including derivatized celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, and carboxymethylcellulose, polymers of acrylic acids, such aspoly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobut 1 acrylate), poly(octadecyl acrylate) (jointly referred to herein as "poly aery lie acids"), polydioxanone and its copolymers, polyhydroxyalkanoates, polypropylene fumarate, polyoxymethylene, poloxamers, poly (butyric acid), trimethylene carbonate, and polyphosphazenes.

[0099] B. Imaging

[0100] The tattoos may be visible or may be "hidden" so that they are visualized only ben exposure to IR or UV or other special lights.

[0101] The tattoos may be used to create any image and/or for identification or unique signature

[0102] Arrays of microneedle may be designed to indicate the identification of specific vaccination or other specific medical information. For example, the number of microneedles, their organization/orientation, their spacing distance, and/or the specific type of dye(s) incorporated in the microneedles may individually or in combination correlate to a specific information to be stored under skin, i.e., a signature.

[0103] The type of dyes may be selected to indicate the identification of specific vaccination or other specific medical information. For example, dyes or ink molecules having different excitation/illumination wavelengths and/or having different emission wavelengths may be applied through different microneedles to correspond to different vaccinations, medicine administrations, or other medical procedures.

[0104] Patches containing microneedles can be actuated manually with a human finger, or electrically using an electrochemical gas generator.

[0105] For imaging of the dye or tattoo on the skin, a device is used to illuminate or visualize, and optionally captures and stores, the information of illuminated dye or tattoo. For example, a portable device or a cellular phone with some imaging capabilities may be modified to visualize the marking on the skin.

[0106] Standard devices may be used, or modified to include a source for excitation, an emission filter, a power supply (e.g., battery), and/or integration with the case of a device, as well as an appropriate user interface for initiating the imaging, storing the information from the markings, and/or identifying the information from the markings.

[0107] For example, a cell phone can be modified for visualization of images not visible under standard light. Generally a laser diode and batter are integrated into a phone case to produce light with the correct excitation wavelength for a dye. For imaging an NIR dye, the stock IR filter on the phone camera is removed; and a long- or band-pass filter is added on top of the camera lens to filter out unwanted light.

[0108] In one embodiment, a smart phone (e.g., GOOGLE, NEXUS) can be modified by adding an external low powered NIR laser diode (808 nm) and an adjustable collimator. In one embodiment, a band pass filter is placed over camera piece so that camera only registers emission wavelengths from 900-1000 nm, suitable for imaging NIR emitting, inorganic nanocrystals. In a preferred embodiment, the phone is modified to use a 780 nm LED with an 800 nm short-pass filter. In another embodiment, an 850 nm long-pass color glass filer was used in series with the dielectric filter to reduce background signal. Dielectric filters are generally sharper and have a more complete cutoff. The two filters reduce the increased background signal. For imaging NIR emitting, inorganic nanocrystals, the IR cut off filter was removed from the smart phone camera module. An external circuit that powers the laser diode has a power button so that laser can be powered on from the outside.

[0109] Suitable software is typically installed in the device (e.g., cellular phone) to process the detected images and identify the markings onboard the phone to eliminate potential user error. The software may include grayscaling, binarization, and noise reduction algorithms to optimize the signal for detection. In some embodiments of processing images of IRDC3, a near infrared dye, the software generates a square around the detected fluorophores.

[0110] II. Method of Preparation

[0111] A. Fabrication

[0112] 1. Fabrication of Microneedles

[0113] Microneedles typically are long enough and sharp enough to penetrate deep into the dermis. These long and sharp microneedles may be difficult to achieve using traditional microfabrication techniques. A different fabrication process is used involving a mold.

[0114] First the geometries of microneedles are created in a computer-assisted drawing (CAD) software. Microneedle master mold can be prepared from two-photon polymerization, based on the geometries created with CAdD, and the fabricated needle design is transferred to a poly dimethyl siloxane (PDMS) solution, which hardens to form a complementary mold of the needles. A solution of the biodegradable solution mix along with dye (fluorescent/non-fluorescent) pigment is added to the PDMS mold, centrifuged and vacuumed for a sufficient time (e.g., overnight) to remove any trapped air bubbles. The resulting microneedle patch is peeled from the PDMS mold.

[0115] Alternatively, an array of microneedles are manufactured by a micromolding method, a microembossing method, or a microinjection method. For example, microfabrication processes that may be used in making the microneedles include lithography; etching techniques, such as wet chemical, dry, and photoresist removal; thermal oxidation of silicon; electroplating and electroless plating; diffusion processes, such as boron, phosphorus, arsenic, and antimony diffusion; ion implantation; film deposition, such as evaporation (filament, electron beam, flash, and shadowing and step coverage), sputtering, chemical vapor deposition (CVD), epitaxy (vapor phase, liquid phase, and molecular beam), electroplating, screen printing, lamination, stereolithography, laser machining, and laser ablation (including projection ablation). See generally Jaeger, Introduction to Microelectronic Fabrication (Addison-Wesley Publishing Co., Reading Mass. 1988); Runyan, et al., Semiconductor Integrated Circuit Processing Technology (Addison-Wesley Publishing Co., Reading Mass. 1990); Proceedings of the IEEE Micro Electro Mechanical Systems Conference 1987-1998; Rai-Choudhury, ed., Handbook of Microlithography, Micromachining & Microfabrication (SPIE Optical Engineering Press, Bellingham, Wash. 1997).

[0116] 2. Encapsulation of dyes or agents in particles

[0117] Dyes or agents may be encapsulated in particles via one or more techniques to allow a high loading amount between about 5% and 80% (wt/wt), between about 10% and 50% (wt/wt), or about 10%, 20%, 30%, 40%, or 50% wt/wt.

[0118] Therapeutic, prophylactic or diagnostic agents may be encapsulated in the same microparticles encapsulating the dyes or in different particles. Such particles encapsulating the therapeutic or prophylactic agents are capable of controlled release of the therapeutic or prophylactic agents into the skin.

[0119] Suitable techniques for making polymeric particles for encapsulation of dyes and agents include, but are not limited to, emulsion, solvent evaporation, solvent removal, spray drying, phase inversion, low temperature casting, and nanoprecipitation. The imaging agent, the therapeutic or prophylactic agents, and pharmaceutically acceptable excipients can be incorporated into the particles during particle formation.

[0120] In one embodiment, NIR dyes are milled to hundreds of nanometers before encapsulation. They may be encapsulated in PMMA particles using a double-emulsion technique. In some embodiments, the particles are prepared with non-degradable materials to encapsulate a dye in order to assay a separate release-based (e.g., leaching of dyes from particles) loss in signal from other factors such as photo-bleaching.

[0121] Emulsion or Solvent Evaporation

[0122] In this method, the polymer(s) are dissolved in a volatile organic solvent, such as methylene chloride. The organic solution containing the polymer is then suspended in an aqueous solution that contains an emulsifier, e.g., a surfactant agent such as poly(vinyl alcohol) typically under probe sonication for a period of time (e.g., 2 minutes) to form an emulsion. The dyes and/or active agents may be dissolved in the organic solvent with the polymer or in the aqueous solution, depending on its hydrophilicity/hydrophobicity. The emulsion is added to another large volume of the emulsifier with magnetic stirring to evaporate the organic solvent. The resulting emulsion is stirred until most of the organic solvent evaporated, leaving solid nanoparticles. The resulting particles are washed with water and dried overnight in a lyophilizer. Particles with different sizes and morphologies can be obtained by this method.

[0123] Solvent Removal

[0124] In this method, the polymer, the dyes and/or active agents, and other components of the particles are dispersed or dissolved in a suitable solvent. This mixture is then suspended by stirring in an organic oil (such as silicon oil) to form an emulsion. Solid particles form from the emulsion, which can subsequently be isolated from the supernatant.

[0125] Spray Drying

[0126] In this method, the polymer, the dyes and/or the active agents, and other components of the particles are dispersed or dissolved in a suitable solvent. The solution is pumped through a micronizing nozzle driven by a flow of compressed gas, and the resulting aerosol is suspended in a heated cyclone of air, allowing the solvent to evaporate from the microdroplets, forming particles.

[0127] Phase Inversion

[0128] In this method, the polymer, the dyes and/or the active agents, and other components of the particles are dispersed or dissolved in a "good" solvent, and the solution is poured into a strong non solvent for the polymeric components to spontaneously produce, under favorable conditions, nanoparticles or microparticles.

[0129] Low Temperature Casting

[0130] Methods for very low temperature casting of particles are described in U.S. Pat. No. 5,019,400 to Gombotz et al. In this method, the polymer the dyes and/or the active agents, and other components of the particles are dispersed or dissolved is a solvent. The mixture is then atomized into a vessel containing a liquid non-solvent at a temperature below the freezing point of the solution which freezes the polymer, the dyes and/or the active agents, and other components of the particles carrier as tiny droplets. As the droplets and non-solvent for the components are warmed, the solvent in the droplets thaws and is extracted into the non-solvent, hardening the particles.

[0131] 3. Prepare Microneedles with Embedded Particles Encapsulating Dyes and/or Active Agents

[0132] Particles encapsulating dyes and/or active agents may be blended or mixed with the polymer solution/suspension in a mold in forming the solidified microneedles with such particles embedded therein.

[0133] B. Sterilization and Packaging

[0134] The microneedles and substrate or base element to which the microneedles are attached to or integrally formed are generally sterilized and packaged for storage and shipping. Formed microneedles and the base element may be sterilized via gamma irradiation, UV sterilization, or other techniques that do not interfere or damage the physical structure and the electro-optical properties of encapsulated dyes.

[0135] III. Methods of Use

[0136] FIGS. 1A and 1B are schematics showing the workflow of tattoo implantation in the skin and an imaging process with dye (FIG. 1A) or fluorophore (FIG. 1B).

[0137] The arrangement of microneedles (size, spacing distance, quantity, density, etc.) as well as the type of dyes therein, may correspond to unique information such as a vaccination record, date, or identification of a subject. The microneedles dissolve or are degraded within 3, 4, 5, 6, 7, 8, 9, 10, or 15 minutes upon contact with skin, delivering the dye-encapsulated particles in the skin (preferably the dermis), leaving the dyes as markings/tattoos that last at least five years. These tattoos are especially useful as medical decals as an "on-patient" record of medical history: e.g., sub dermal immunization record (individual vaccination history), blood type or allergens.

[0138] A microneedle pattern, a combination of imaging dyes, or both may be used to encode multiple pieces of information in one microneedle patch. The concept is to use this to aid healthcare workers who have to act on very little patient information. Ideally the marking would not be visible to the naked eye but could be visualized using a device as simple as a cell phone from which the it or uv filters have been removed.

[0139] The patches have many advantages. They are easily mass produced, stored and shipped. They are easily applied without conventional needles and relatively painless. No bio-hazardous sharps are generated through the application of biodegradable microneedles.

[0140] The patches have applications in the defense industry, as a well to mark soldiers without using invasive means such as a chip, or means such as a "dog tag" which may be lost, providing an alternative means of identification or medical record, optionally while at the same time administering vaccines.

[0141] The patches may also be used to apply dyes for cosmetic purposes, such as lip enhancement, eyebrow darkening, or delivery of an agent such as botulinum toxin or growth factor to alleviate wrinkles. An advantage of the patch is that it can be trimmed or shaped just before use to personalize the tattoo to the individual and site of application.

[0142] The patches also have applications in the animal industry, providing a clean, relatively easy and painless way to permanently identify animals. The patches can be made so that the marking include a group identify (such as the USDA farm identification number) as well as individual identify.

[0143] In one embodiment, the microneedle patch is used to generate a sub-dermal marking system that can be used to track a child's vaccination history.

[0144] The skin tattoo system including a microneedle patch and optionally an imaging device does not involve an invasive procedure. It is generally applied with a low requirement of medical skills or medical resources. It can be applied at clinic, school, farm or in the field.

[0145] The microneedle patch is not reused, avoiding cross-contamination. The needles dissolve a first application to the skin, leaving no microneedles or dyes for any subsequent use.

[0146] A. Applying: Self or Medical Professional

[0147] The patch is pressed upon the skin for five minutes dye pigment would be deposited sub-dermally upon the dissolution of the microneedles.

[0148] B. Data Storing, Transfer, and Reading

[0149] Generally, medical information is readily available by imaging the skin tattoo to access the impregnated information, and does not require a patient database. Alternatively, patient information including his/her medical history is stored and downloadable from a database with data collected and interpreted from the tattoo markings on patient.

EXAMPLES

Example 1. Photostability of Fluorophore Dyes: a Lanthanide Based Inorganic Dye, a Copper-Based Quantum Dot, and a Silver-Based Quantum Dot

[0150] Methods

[0151] Preparation of Dyes and Encapsulation in Microparticles

[0152] A lanthanide based inorganic dye material, IRDC3, was obtained. A copper-based quantum dot (copper QD) was synthesized containing a core-shell structure where the core contains copper-indium-selenide and a shell contains a zinc sulfide coating/film/overlay doped with aluminum, denoted as CuInSe2/ZnS:Al. The quantum yield of this copper-based quantum dot was between 40% and 50%. It was shown to be 7,000 times less toxic than CdTe QDs in vitro, and was used safely at 258 .mu.g/kg in mice (target 3.36 .mu.g/human) (Ding K, et al., Biomaterials 2014; 35:1608-17).

[0153] A silver-based quantum dot (silver QD) was synthesized containing a core-shell structure where the core contains silver-indium-selenide and a shell contains a zinc sulfide film doped with aluminum, denoted as AgInSe.sub.2/ZnS:Al (Silver QD). The quantum yield of this silver-based quantum dot was up to 50%.

[0154] Results

[0155] These QDs were confirmed having a nanosized dimension under transmission electron microscopy (TEM). IRDC3 was examined under scanning electron microscopy (SEM).

[0156] Poly(methyl methacrylate) (PMMA) microparticles were prepared to encapsulate these fluorophores, resulting in encapsulated silver QD in PMMA particles at a loading of 60%; encapsulated copper QD in PMMA particles at a loading of 60%; and IRDC3 in PMMA particles at a loading of 1%.

[0157] 1. Emission wavelengths did not overlap with melanin absorbance wavelengths.

[0158] FIGS. 2A-2D show the absorbance spectra of IRDC3, copper QD, and silver QD, respectively. The absorbance spectrum of melanin is also shown in each spectrum.

[0159] FIGS. 3A-3C show the emission spectra of IRDC3, copper QD, and silver QD, respectively. The absorbance spectrum of melanin is also shown in each spectrum. The emission spectra of IRDC3, copper QD, and silver QD have little to no overlap with the absorbance spectrum of melanin, indicating that these three dyes were appropriate dye materials for delivery into the skin because their signals would not be absorbed by melanin, therefore detectable.

[0160] 2. IRDC3 showed superior in vitro photostability to QDs.

[0161] Methods

[0162] Fluorophore suspensions were dropcast on slides. Samples were exposed to light simulating the solar spectrum at 7.times. intensity and imaged longitudinally over a simulated 84 days to observe photobleaching. Imaging was performed with 500 mW 808 nm laser expanded 15x.times., band-pass 850-1100 nm emission filter, and a near-infra red camera.

[0163] Results

[0164] Dropcast IRDC3 intensity did not decrease during the simulated 84-day exposure period. Dropcast QDs performed poorly, likely due their broad excitation spectrum.

TABLE-US-00001 TABLE 1 Fluorescence intensity after 84-day photobleaching NIR Pigment Remaining Fluorescent Intensity (%) IRDC3 100.1 .+-. 2.2 IRDC3 in PMMA 80.7 .+-. 7.6 Ag QD in PMMA 15.3 .+-. 1.5 Cu QD in PMMA 6.9 .+-. 4.5

[0165] 3. Copper QD showed superior ex vivo photostability to silver QD or IRDC3.

[0166] Methods

[0167] Fluorophores were tattooed into pigmented human abdominal skin obtained from a cadaver and imaged longitudinally. The signal from IRDC3 encapsulated in PMMA was so low that it had to be imaged separately from the other samples.

  "Tests using human cadaver skin showed that the quantum-dot patterns could be detected by smartphone cameras after up to five years of simulated sun exposure." https://news.mit.edu/2019/storing-vaccine-history-skin-1218
 Secret UV tattoos have been around for years. Purchase a UV flashlight to detect a UV ID tattoo number.
 Follow the Money Bill Gates funding for MIT Digital Certificate tattoo ID Immunization UV Patch.  https://news.mit.edu/2017/mit-undertakes-grand-challenge-innovation-global-vaccine-manufacturing-0222

RICE UNIVERSITY
"When the needles dissolve in about two minutes, they deliver the vaccine and leave the pattern of tags just under the skin, where they become something like a bar-code tattoo." https://bioengineering.rice.edu/news/quantum-dot-tattoos-hold-vaccination-record

A Invisible UV Digital Identification Tattoo Micro Needle Array Patch for COVID-19 Immunization?


UNITED STATES PATENT and TRADEMARK OFFICE

Official link below for the Massachusetts Institute of Technology Patent on the Digital UV Tattoo Immunization Patch.

http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220190015650%22.PGNR.&OS=DN/20190015650&RS=DN/2019001565

Quotes directly from the US PATENT;

" The patches have applications in the defense industry, as a well to mark soldiers without using invasive means such as a chip, or means such as a "dog tag" which may be lost, providing an alternative means of identification or medical record, optionally while at the same time administering vaccines. "

" The arrangement of microneedles (size, spacing distance, quantity, density, etc.) as well as the type of dyes therein, may correspond to unique information such as a vaccination record, date, or identification of a subject. "

"the NIR emitting inorganic dye is semiconducting nanocrystals of copper or silver,"

" Optionally, the microneedle may contain other materials, including metals, ceramics, semiconductors "

" the dye is a semi-permanent or permanent "

 Quotes from the US PATENT relating to black and brown human skin;

The quote is about Melanin (skin color). Melanin in this instance is a reference to a human of darker skin completion. A scientific way of saying black or brown human skin. The patent holders took extra care to confirm that the UV tattoo would be easily scanned on black and brown complexion humans.

" Photostability of a pigment is generally evaluated using high solar irradiance (7x intensity of sea level sun light) after the dye pigment is deposited under melanin pigmented human cadaver skin "

" Fluorophores were tattooed into pigmented human abdominal skin obtained from a cadaver and imaged longitudinally. "

Google Patent link https://patents.google.com/patent/WO2019018301A1/


Chinese Patent filed on 05/01/2020 The Link is here  CN 111093629 






Massachusetts Institute of Technology Patent on the Digital UV Tattoo Immunization Patch follow the money. Research and development was funded by the Bill and Melinda Gates Foundation. https://news.mit.edu/2017/mit-undertakes-grand-challenge-innovation-global-vaccine-manufacturing-0222

I know this all seems so far fetched and unreal but I assure you this tech is here now. Like some twisted episode of the " Black Mirror " TV series on NetFlix this tech has already been deployed in third world nations and is being pushed for use as the COVID-19 vaccine delivery method.
" Some are calling on technology companies to develop a "digital vaccine" to provide necessary data, "

 Please go to this link and consider signing the petition against this invasive and unprecedented digital UV Tattoo invasion of your privacy and your Basic Human Rights. Do not donate any money just sign the petition. Fear is the only emotion that stops action but Courage spurs action into change!. Let the world know that it is time to stand up and stop Human Beings from becoming like cattle, pets, or property via a digital mark such as a microchip, a brand, or a tattoo with a international digital Identification number. At this petition website look under the more updates link to find more information and facts about the Technology .

change.org/Right2Deny

 These covert UV Micro Needle Tattoo Patchs would be invisible in normal lighting conditions.
  Secret UV tattoos revealed on the TV show The Blindspot. Purchase a UV Flashlight in preparation for a possible covert UV Immunization Tattoo.
 Tech site CNET news "UN wants a universal digital ID for your data"
The goal is to ID every single human being and put that ID in a International Data base !

https://www.cnet.com/news/refugees-digital-id-tech-companies-id2020-summit-united-nations/


Please make a stand and sign this petition!


It is a Basic Human Right not be numbered like an Animal. History reflects the tragedy of a Tattoo numbering system once used on human beings during World War II by the Nazi and Adolph Hitler.



Hi-TECH Immunization micro needle tattoo patch or lo-tech Nazi Auschwitz concentration camp tattoo. Digital or Analog tattoo. The tattoo number to make you a sub human animal can be dressed up in new clothes but it is still the same thing! 

Human Rights are not a disposable option to be thrown aside at the whim of those in charge or at the whim of those who desire to make a profit ! Freedom of Life, Liberty, and pursuit of Happiness are all violated by this UV digital ID tattoo patch technology.

   No human being should be forced to take a Digital Certificate Tattoo Mark on or in their body. It is our Right to Deny this tattoo technology. A international registry linked to a digital Immunization mark could also be linked to your financial records, driver's license, passports, visa, and many other private sources. Once this starts it will encompass all aspects of your life. You will not be permitted to enter a place of business, go to work, make any transaction without this UV tattoo Immunization mark. It is also a violation of many individuals religious rights and liberties not to mention the health risks of Near-Infrared Quantum Dot Dye made of Copper, Silver, Cadmium, and other toxic compounds.

Think about this, currently your employer and any place of business already has the authority to deny you entry based on a body temperature check or the use of a mask. You walk in the entrance submit to a forehead scan and if you pass you get to enter. Is it really that much of a leap to see where this could be going. You are already going thru the motions right NOW ! Soon the forehead temp scan and mask may be replaced with the loss of all freedom, the digital tattoo ID UV immunization certificate delivered with your micro needle vaccination of COVID-19 or a future pandemic.


Please take a moment to  educate yourself about this new technology and help spread the word on this covert attempt to Tattoo Patch the world with a Digital  invisible Identification Number that will become the property of a International digital certificate data base.

change.org/Right2Deny

History is laden with atrocities committed against mankind, all perpetrated by the " Intellectually Smarter and Superior ones" who say that they have your best interest in mind !

mengele-richard_baer_rudolf_hoess_auschwitz-_album_hocker






They are euphoric with the illusion of Superior Intelligence, Arrogance, Power, Greed,  and control of the sub human masses beneath them. To such men you are no longer a human but a sub standard animal that desrves no rights.

 Holocaust tattoo

Digital or Analog tattoo ID number it is all the same. 1940s or NOW it is still the samething.


"COVID-19 Vaccine With Patch Delivery Technology Enters Preclinical Testing at UC Davis"






Australia's Front Line News"Are immunity passports and ‘vaccine tattoos’ coming?"



The COVID-19 Cipher.


"See Sheep Surrender"

C ...  (@) (@)  ...See
O ......"Ovid" is Latin for
V ....... SHEEP
I   ......
D .......
19 ..... is the number of Surrender. S is number 19 in the alphabet. "On October 19, 1781, British General Charles Cornwallis surrendered his army of some 8,000 men to General George Washington at Yorktown" This was essentially the end of the war and the military birth of the USA.

Josephus number 19 and surrender. At the siege of Masada the Roman Army prevailed capturing King Herod's mountain top fortress but the Hebrew defenders had formed a suicide pact thus denying a complete victory, only Josephus and one other defender remained who Josephus convinced to surrender. Josephus was number 19 in the suicide pact.
"Josephus’s repeated calls for surrender to the Romans have been labeled as betrayal."

Bible verse
Romans 6:19
your human infirmity leads me to employ these familiar figures--and just as you once SURRENDERED your faculties into bondage to Impurity and ever-increasing disregard of Law, so you must now SURRENDER them into bondage to Righteousness ever advancing towards perfect holiness

image-880108-94259057_3039044686161001_3961479406341324800_n-6512b.jpg
image-880109-94615549_3039044882827648_4995806830862008320_n-aab32.jpg

Nano Tech is here and this new revolutionary field of research and development has amazing medical and scientific possibilities. History shows us that we as humans have always used scientific leaps for the best and most moral of reasons! Just think of Gun Powder, Aircraft Flight, Motorized Movement, and splitting the Atom for Nuclear Energy. With every leap of science follows the weaponization of it.

  "Engineers at the Massachusetts Institute of Technology (MIT) — with support from the Gates Foundation — have developed a novel way to deliver multiple vaccinations at once."

"The vaccine uses microparticles that resemble tiny coffee cups. The microparticles are each about the size of a grain of fine sand." 

" The microparticles are injected into the bloodstream"