Permanent, removable tissue markings

• US 20030167964A1
• Filed: 03/14/2003
• Published: 09/11/2003
• Est. Priority Date: 11/20/1998
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Freedom-2, Inc.
• Inventors: Anderson, Richard R., Drill, Craig A., Mlynarczyk, Susanna K.
• Granted Patent: US 6,800,122 B2
• Time in Patent Office: Days
• US Class Current: 106/31.03
• CPC Class Codes: A61K 2800/412 Microsized, i.e. having sizes between 0.1 and 100 microns
• CPC Class Codes: A61K 2800/438 Thermochromatic; Photochromic; Phototropic
• CPC Class Codes: A61K 2800/56 Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
• CPC Class Codes: A61K 2800/624 by macromolecular compounds
• CPC Class Codes: A61K 8/0241 Containing particulates characterized by their shape and/or structure see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes
• CPC Class Codes: A61Q 1/025 Semi-permanent tattoos, stencils, e.g. "permanent make-up"
• CPC Class Codes: A61Q 19/04 for chemically tanning the skin topical sun or radiation screening or tanning preparations A61Q17/04
• CPC Class Codes: C09D 11/00 Inks
• CPC Class Codes: C09D 11/02 Printing inks C09D11/30 takes precedence
• CPC Class Codes: C09D 11/037 characterised by the pigment
• CPC Class Codes: C09D 11/50 Sympathetic, colour changing or similar inks
• CPC Class Codes: Y10S 430/145 Infrared
• CPC Class Codes: Y10S 430/165 Thermal imaging composition
• CPC Class Codes: Y10T 428/2991 Coated
• CPC Class Codes: Y10T 428/2993 Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]

Abstract

The present invention provides microparticles that create permanent tissue markings, such as tattoos, designed in advance for change and/or removal on demand, as well as methods for implanting the microparticles in tissue and changing and/or removing the resulting markings. Colored microparticles are constructed with specific electromagnetic absorption and/or structural properties that facilitate changing and/or removing tissue markings made using the microparticles by applying specific energy (such as electromagnetic radiation from a laser or flash-lamp) to the tissue marking site.

Claims

1. A method of applying to a tissue a detectable marking that can be changed or removed, or both, on demand, the method comprising:

obtaining colored microparticles each comprising a chromophore and having a specific property that is designed in advance to enable the microparticles to be altered when exposed to a specific energy; and

implanting into the tissue a sufficient number of the colored microparticles to form a detectable tissue marking, wherein the tissue marking is permanent until the specific energy is applied to alter the microparticles to change or remove, or both, the detectable marking.

2. The method of claim 1, wherein the chromophore provides the specific property.

3. The method of claim 1, wherein the microparticles further comprise a material that provides the specific property.

4. The method of claim 1, wherein the specific property is the absorption of the specific energy.

5. The method of claim 1, wherein the specific property is photochemical reactivity when the microparticles are exposed to the specific energy.

6. The method of claim 1, wherein the specific property is thermochemical reactivity when the microparticles are exposed to the specific energy.

7. The method of claim 1, wherein the specific energy is electromagnetic radiation.

8. The method of claim 1, wherein the specific energy is applied once to change or remove, or both, the detectable marking.

9. A method of claim 1, wherein

(a) the colored microparticles each comprise

(i) an indispersible, biologically inert coating,

(ii) a core enveloped within the coating, wherein the core comprises the chromophore which is detectable through the coating and is dispersible in the tissue upon release from the microparticle, and, optionally

(iii) an absorption component that absorbs the specific energy and that is located in the coating or the core, or both;

and

(b) the specific property is the absorption of the specific energy to rupture the microparticle, releasing the chromophore which disperses in the tissue, thereby changing or removing, or both, the detectable marking, wherein the coating, the core, or the optional absorption component, or any combination thereof, provide the specific property.

10. The method of claim 9, wherein the dispersible chromophore is dissolved when released into the tissue.

11. The method of claim 9, wherein the dispersible chromophore is metabolized when released into the tissue.

12. The method of claim 9, wherein the chromophore is insoluble and has a size and configuration such that it is physically relocated from the detectable marking by biological processes when released into the tissue.

13. The method of claim 1, wherein the chromophore is selected from the group consisting of rifampin, β

-carotene, tetracycline, indocyanine green, Evan'"'"'s blue, methylene blue, FD&

C Blue No. 1 (Brilliant Blue FCF), FD&

C Green No. 3 (Fast Green FCF), FD&

C Red No. 3 (Erythrosine), FD&

C Red No. 40, FD&

C Yellow No. 5 (Tartrazine), and FD&

C Yellow No. 6 (Sunset Yellow FCF).

14. The method of claim 1, wherein the chromophore is a colored substance approved by the United States Food and Drug Administration for use in humans.

15. The method of claim 1, wherein the chromophore can be detected by the naked eye under normal lighting conditions.

16. The method of claim 1, wherein the chromophore can be detected when exposed to ultraviolet, near-ultraviolet, infrared, or near-infrared radiation.

17. The method of claim 9, wherein the coating, the chromophore, or the optional absorption component, or any combination thereof, absorbs specific electromagnetic radiation.

18. The method of claim 1, wherein the specific energy is near-infrared or infrared radiation.

19. The method of claim 9, wherein the coating comprises a metal oxide, silica, glass, fluorocarbon resin, organic polymer, wax, or a combination thereof.

20. The method of claim 9, wherein the coating is substantially visibly transparent and absorbs near-infrared radiation.

21. The method of claim 9, wherein the absorption component is selected from the group consisting of Schott filter glass, graphite, carbon, a metal oxide, an acrylate polymer, or a urethane polymer.

22. The method of claim 9, wherein the coating comprises an absorption component that absorbs near-infrared radiation.

23. The method of claim 20, wherein the coating is comprised of a material that absorbs the near-infrared radiation.

24. The method of claim 9, wherein the coating comprises pores of a size sufficient to allow the dispersible chromophore to leach out of the microparticle.

25. The method of claim 9, wherein multiple cores are enveloped within the coating of a single microparticle.

26. The method of claim 1, wherein the tissue is selected from the group consisting of skin, iris, sclera, dentin, fingernails, toenails, tissue beneath fingernails, tissue beneath toenails, tissue inside the mouth, or tissue lining internal body passages.

27. The method of claim 1, wherein

(a) the colored microparticles each comprise

(i) an indispersible, biologically inert coating,

(ii) a core enveloped within the coating, wherein the core comprises the chromophore which is detectable through the coating and is altered upon exposure of the microparticle to the specific energy, and optionally

(iii) an absorption component that absorbs the specific energy and that is located in the coating or the core, or both;

and

(b) the specific property is the ability of the chromophore to be altered upon exposure of the microparticle to the specific energy, thereby changing or removing, or both, the detectable marking, wherein the coating, the core, or the optional absorption component, or any combination thereof, provide the specific property.

28. The method of claim 27, wherein the chromophore is altered by losing its color upon exposure of the microparticle to the specific energy.

29. The method of claim 27, wherein the chromophore is altered by changing from an initial color to a different color upon exposure of the microparticle to the specific energy.

30. The method of claim 27, wherein the core of each microparticle further comprises a sub-microparticle that comprises a bleaching agent that is released from the sub-microparticle upon exposure of the microparticle to the specific energy, thereby bleaching the chromophore.

31. The method of claim 30, wherein the bleaching agent comprises a peroxide, hypochlorite, excited oxygen species, or free radical.

32. The method of claim 30, wherein the chromophore is pH-sensitive, and the bleaching agent is an acid, a base, or a buffer capable of effecting a pH transition within the core that bleaches the chromophore.

33. The method of claim 27, wherein the specific energy is infrared or near-infrared radiation.

34. The method of claim 27, wherein the chromophore is photobleachable, and the specific energy is absorbed by the chromophore to render it substantially invisible.

35. The method of claim 34, wherein the photobleachable chromophore is selected from the group consisting of Rose Bengal, rhodamine compounds, coumarin compounds, dye-paired ion compounds, cationic dye-borate anion complexes, and bis(diiminosuccino-nitrilo)metal complexes.

36. The method of claim 27, wherein the chromophore is thermolabile, and exposure of the microparticle to the specific energy heats and alters the chromophore.

37. The method of claim 27, wherein the absorption component is selected from the group consisting of Schott filter glass, graphite, carbon, a metal oxide, an acrylate polymer, and a urethane polymer.

38. A method of changing or removing, or both, a detectable marking created by implanting into tissue a sufficient number of colored microparticles each comprising a chromophore and having a specific property that is designed in advance to enable the microparticles to be altered when exposed to a specific energy, the method comprising:

exposing the detectable marking to the specific energy for a time sufficient to alter the microparticles, thereby changing or removing, or both, the detectable tissue marking.

39. The method of claim 38, wherein the microparticles are altered to become substantially undetectable, thereby removing the tissue marking.

40. The method of claim 39, wherein the microparticles become substantially undetectable by rupturing and releasing the chromophore.

41. The method of claim 39, wherein the microparticles become substantially undetectable by a loss of color of the chromophore.

42. The method of claim 38, wherein the microparticles are altered by changing from an initial color to a different color, thereby changing the color of the tissue marking.

43. The method of claim 38, wherein the specific energy is electromagnetic radiation.

44. The method of claim 38, wherein

(a) the colored microparticles each comprise

(i) an indispersible, biologically inert coating,

(ii) a core enveloped within the coating, wherein the core comprises the chromophore which is detectable through the coating and is dispersible in the tissue upon release from the microparticle, and, optionally

(iii) an absorption component that absorbs the specific energy and that is located in the coating or the core, or both;

and

(b) the specific property is the absorption of the specific energy to rupture the microparticle, releasing the chromophore which disperses in the tissue, thereby changing or removing, or both, the detectable marking, wherein the coating, the core, or the optional absorption component, or any combination thereof, provide the specific property.

45. The method of claim 38, wherein the specific energy is infrared or near-infrared radiation.

46. The method of claim 38, wherein the specific energy is applied at a wavelength, at an intensity, or for a duration, or any combination thereof, insufficient to completely remove or change the detectable marking, thereby partially removing or changing, or both, the detectable marking.

47. The method of claim 38, wherein

(a) the colored microparticles each comprise

(i) an indispersible, biologically inert coating,

(ii) a core enveloped within the coating, wherein the core comprises the chromophore which is detectable through the coating and is altered upon exposure of the microparticle to the specific energy, and optionally

(iii) an absorption component that absorbs the specific energy and that is located in the coating or the core, or both;

and

(b) the specific property is the ability of the chromophore to be altered upon exposure of the microparticle to the specific energy, thereby changing or removing, or both, the detectable marking, wherein the coating, the core, or the optional absorption component, or any combination thereof, provide the specific property.

48. The method of claim 47, wherein the core of each microparticle further comprises a sub-microparticle that comprises a bleaching agent that is released from the sub-microparticle upon exposure of the microparticle to the specific energy, thereby bleaching the chromophore.

49. The method of claim 48, wherein the bleaching agent comprises a peroxide, hypochlorite, excited oxygen species, or free radical.

50. The method of claim 48, wherein the chromophore is pH-sensitive, and the bleaching agent is an acid, a base, or a buffer capable of effecting a pH transition that bleaches the chromophore.

51. The method of claim 47, wherein the specific energy is infrared or near-infrared radiation.

52. The method of claim 47, wherein the chromophore is photobleachable, and the specific energy is absorbed by the chromophore to render it substantially invisible.

53. The method of claim 38, wherein the specific energy is near-ultraviolet or high-intensity visible radiation.

54. The method of claim 38, wherein the chromophore is thermolabile, and exposure of the microparticle to the specific energy heats and alters the chromophore.

55. The method of claim 47, wherein the specific energy is applied at a wavelength, at an intensity, or for a duration, or any combination thereof, insufficient to completely remove or change the detectable marking, thereby partially removing or changing, or both, the detectable marking.

56. A colored microparticle comprising

(i) an indispersible, biologically inert coating comprising from about 10 to about 95 percent of the volume of the microparticle,

(ii) a core enveloped within the coating, wherein the core comprises a chromophore that is detectable through the coating and is dispersible in living tissue upon release from the microparticle, and, optionally

(iii) an absorption component that absorbs a specific energy and that is located in the coating or the core, or both;

wherein the coating, the core, or the optional absorption component, or any combination thereof, is designed in advance to absorb the specific energy to rupture the microparticle, releasing the chromophore which disperses in the living tissue.

57. The colored microparticle of claim 56, wherein the microparticle has a radius of from 50 nanometers to 100 microns.

58. The colored microparticle of claim 56, wherein the coating comprises a metal oxide, silica, glass, fluorocarbon resin, organic polymer, wax, or any combination thereof.

59. The colored microparticle of claim 56, wherein the specific energy is infrared or near-infrared radiation.

60. The colored microparticle of claim 56, wherein the absorption component forms a plug sealing a hole in the coating, wherein the plug is destroyed upon exposure to the specific energy to open the hole in the coating.

61. The colored microparticle of claim 56, wherein one or more absorption components are located within the coating, and when exposed to the specific energy cause the coating to break open.

62. The colored microparticle of claim 56, wherein the microparticle is sterilized.

63. A tissue marking ink comprising the colored microparticle of claim 56 and a liquid carrier.

64. The ink of claim 63, wherein the carrier comprises alcohol, water, or glycerin, or any combination thereof.

65. A colored microparticle comprising

(i) an indispersible, biologically inert coating comprising from about 10 to about 95 percent of the volume of the microparticle,

(ii) a core enveloped within the coating, wherein the core comprises a chromophore that is detectable through the coating and is altered upon exposure of the microparticle to a specific energy, and optionally

(iii) an absorption component that absorbs the specific energy and that is located in the coating or the core, or both;

wherein the coating, the core, or the optional absorption component, or any combination thereof, is designed in advance to absorb the specific energy to alter the chromophore.

66. The colored microparticle of claim 65, wherein the microparticle has a radius of from 50 nanometers to 100 microns.

67. The colored microparticle of claim 65, wherein the coating comprises a metal oxide, silica, glass, fluorocarbon resin, organic polymer, or any combination thereof.

68. The colored microparticle of claim 65, wherein the specific energy is infrared or near-infrared radiation.

69. The colored microparticle of claim 65, wherein the specific energy is ultraviolet or high-intensity visible radiation.

70. The colored microparticle of claim 65, wherein the microparticle is sterilized.

71. The colored microparticle of claim 65, further comprising a sub-microparticle that comprises a bleaching agent that is released from the sub-microparticle upon exposure of the microparticle to the specific energy, thereby bleaching the chromophore.

72. The colored microparticle of claim 71, wherein the bleaching agent comprises a peroxide, hypochlorite, excited oxygen species, or free radical.

73. The colored microparticle of claim 71, wherein the chromophore is pH-sensitive, and the bleaching agent is an acid, a base, or a buffer capable of effecting a pH transition that bleaches the chromophore.

74. The colored microparticle of claim 65, wherein the chromophore is photobleachable, and exposure of the microparticle to the specific energy renders the chromophore substantially invisible.

75. The colored microparticle of claim 65, wherein the chromophore is thermolabile, and exposure of the microparticle to the specific energy renders the chromophore substantially undetectable.

76. A tissue marking ink comprising the colored microparticle of claim 65 and a liquid carrier.

77. The ink of claim 76, wherein the carrier comprises alcohol, water, or glycerin, or any combination thereof.