Title: Permanent, removable tissue markings
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.
Patent Number: 6,881,249 Issued on 04/19/2005 to Anderson, et al.
| Inventors:
|
Anderson; Richard R. (Lexington, MA);
Mlynarczyk; Susanna K. (San Francisco, CA);
Drill; Craig A. (New York, NY)
|
| Assignee:
|
The General Hospital Corporation (Boston, MA);
Freedom-2, LLC (New York, NY)
|
| Appl. No.:
|
387404 |
| Filed:
|
March 14, 2003 |
| Current U.S. Class: |
106/31.03; 106/31.15; 106/31.32; 106/31.33; 106/31.64; 106/31.65; 428/403 |
| Intern'l Class: |
C09D 011//00; B32B 009//00 |
| Field of Search: |
106/31.03,31.15,31.32,31.33,31.64,31.65
428/403
424/98,490,9.8
|
References Cited [Referenced By]
U.S. Patent Documents
| 2487557 | Nov., 1949 | Jourgensen | 106/31.
|
| 2735780 | Feb., 1956 | Le Compte et al. | 106/31.
|
| 3011899 | Dec., 1961 | Bergman | 106/31.
|
| 3272585 | Sep., 1966 | Rafferty et al. | 106/31.
|
| 3640889 | Feb., 1972 | Stewart | 106/31.
|
| 3708334 | Jan., 1973 | Firth et al. | 106/31.
|
| 3873687 | Mar., 1975 | Demko | 106/31.
|
| 4155886 | May., 1979 | DeGoler | 106/31.
|
| 4214490 | Jul., 1980 | Chizek | 106/31.
|
| 4280813 | Jul., 1981 | DeGoler | 106/31.
|
| 4493869 | Jan., 1985 | Sweeny et al. | 428/201.
|
| 4610806 | Sep., 1986 | Rosen | 106/31.
|
| 4816367 | Mar., 1989 | Sakojiri et al. | 430/138.
|
| 4861627 | Aug., 1989 | Mathiowitz et al. | 427/213.
|
| 4891043 | Jan., 1990 | Zeimer et al. | 604/20.
|
| 4897268 | Jan., 1990 | Tice et al. | 424/422.
|
| 4898734 | Feb., 1990 | Mathiowitz et al. | 424/426.
|
| 4900556 | Feb., 1990 | Wheatley et al. | 424/450.
|
| 4921757 | May., 1990 | Wheatley et al. | 428/402.
|
| 4933185 | Jun., 1990 | Wheatley et al. | 424/461.
|
| 4937119 | Jun., 1990 | Nikles et al. | 428/64.
|
| 5041292 | Aug., 1991 | Feijen | 424/484.
|
| 5049322 | Sep., 1991 | Devissaguet et al. | 264/4.
|
| 5087461 | Feb., 1992 | Levine et al. | 426/96.
|
| 5157412 | Oct., 1992 | Kleinschmidt et al. | 346/1.
|
| 5217455 | Jun., 1993 | Tan | 606/9.
|
| 5234711 | Aug., 1993 | Kamen et al. | 427/213.
|
| 5330565 | Jul., 1994 | Saitoh et al. | 523/102.
|
| 5334575 | Aug., 1994 | Noonan et al. | 503/227.
|
| 5376347 | Dec., 1994 | Ipponmatsu et al. | 423/338.
|
| 5384333 | Jan., 1995 | Davis | 514/772.
|
| 5409797 | Apr., 1995 | Hosoi et al. | 430/138.
|
| 5445611 | Aug., 1995 | Eppstein et al. | 604/49.
|
| 5601859 | Feb., 1997 | Penaluna | 426/5.
|
| 5690857 | Nov., 1997 | Osterried et al.
| |
| 6013122 | Jan., 2000 | Klitzman et al. | 106/31.
|
| 6416740 | Jul., 2002 | Unger | 424/9.
|
| 6470891 | Oct., 2002 | Carroll | 128/897.
|
| 2002/0074003 | Jun., 2002 | Carroll | 128/897.
|
| 2003/0113540 | Jun., 2003 | Anderson et al. | 428/403.
|
| 2003/0167964 | Sep., 2003 | Anderson et al. | 106/31.
|
| Foreign Patent Documents |
| 3420867 | Dec., 1985 | DE.
| |
| 2705615 | Dec., 1994 | FR.
| |
| 137175 | Oct., 1980 | JP.
| |
| 61047410 | Jul., 1986 | JP.
| |
| 98202 | Apr., 1993 | JP.
| |
| WO 93/04411 | Mar., 1993 | WO.
| |
| WO 98/48716 | Nov., 1998 | WO.
| |
Other References
Taylor et al., "Light and Electron Microscopic Analysis of Tattoos Treated
by Q-Switched Ruby Laser", The Journal of Investigative Dermatology,
97:131-136 (1991), no month available.
PCT International Search Report PCT/US99/27540, Apr. 2000.
|
Primary Examiner: Klemanski; Helene
Attorney, Agent or Firm: Fish & Richardson P.C.
Parent Case Text
This application is a division under 37 C.F.R. .sctn. 1.53(b) of
application Ser. No. 09/197,105 filed on Nov. 20, 1998 now abandoned, the
entire disclosure of which is incorporated herein by reference.
Claims
What is claimed is:
1. 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
(iii) a discrete absorption component that absorbs a specific energy and
that is located in the coating or the core, or both;
wherein the absorption component ruptures the microparticle when exposed to
the specific energy, releasing the chromophore which disperses in the
living tissue.
2. The colored microparticle of claim 1, wherein the microparticle has a
radius of from 50 nanometers to 100 microns.
3. The colored microparticle of claim 1, wherein the coating comprises a
metal oxide, silica, glass, fluorocarbon resin, organic polymer, wax, or
any combination thereof.
4. The colored microparticle of claim 1, wherein the specific energy is
infrared or near-infrared radiation.
5. The colored microparticle of claim 1, 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.
6. The colored microparticle of claim 1, wherein one or more absorption
components are located within the coating, and when exposed to the
specific energy cause the coating to break open.
7. The colored microparticle of claim 1, wherein the microparticle is
sterilized.
8. A tissue marking ink comprising the colored microparticle of claim 1 and
a liquid carrier.
9. The ink of claim 8, wherein the carrier comprises alcohol, water, or
glycerin, or any combination thereof.
10. 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
(iii) a discrete absorption component that absorbs the specific energy and
that is located in the coating or the core, or both;
wherein the absorption component alters the chromophore when exposed to the
specific energy.
11. The colored microparticle of claim 10, wherein the microparticle has a
radius of from 50 nanometers to 100 microns.
12. The colored microparticle of claim 10, wherein the coating comprises a
metal oxide, silica, glass, fluorocarbon resin, organic polymer, or any
combination thereof.
13. The colored microparticle of claim 10, wherein the specific energy is
infrared or near-infrared radiation.
14. The colored microparticle of claim 10, wherein the specific energy is
ultraviolet or high-intensity visible radiation.
15. The colored microparticle of claim 10, wherein the microparticle is
sterilized.
16. The colored microparticle of claim 10, further comprising a
sub-microparticle, wherein the sub-microparticle comprises a bleaching
agent and a discrete absorption component that causes the bleaching agent
to be released from the sub-microparticle upon exposure of the
microparticle to the specific energy, thereby bleaching the chromophore.
17. The colored microparticle of claim 16, wherein the bleaching agent
comprises a peroxide, hypochlorite, excited oxygen species, or free
radical.
18. The colored microparticle of claim 16, 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.
19. A tissue marking ink comprising the colored microparticle of claim 10
and a liquid carrier.
20. The ink of claim 19, wherein the carrier comprises alcohol, water,
glycerin, or any combination thereof.
21. A colored microparticle comprising:
(i) a biologically inert coating having a thickness of from 0.05 to 0.6
times the radius of the microparticle,
(ii) a core enveloped within the coating, wherein the core comprises a
chromophore which is detectable through the coating and is dispersible in
living tissue upon release from the microparticle,
wherein the microparticle ruptures upon exposure to a specific energy.
22. The colored microparticle of claim 21, wherein the microparticle has a
radius of from 50 nanometers to 100 microns.
23. The colored microparticle of claim 21, wherein the coating comprises a
metal oxide, silica, glass, fluorocarbon resin, organic polymer, wax, or
any combination hereof.
24. The colored microparticle of claim 21, wherein the specific energy is
infrared or near-infrared radiation.
25. The colored microparticle of claim 21, wherein the coating further
comprises an absorption component.
26. The colored microparticle of claim 25, wherein the absorption component
forms a plug sealing an opening in the coating, wherein the opening is
unsealed upon exposure to the specific energy.
27. A tissue marking ink comprising the colored microparticle of claim 21
and a liquid carrier.
28. The ink of claim 27, wherein the carrier comprises at least one of
alcohol, water, or glycerin.
29. The colored microparticle of claim 16, wherein the sub-microparticle
comprises a coating, and the discrete absorption component is located in
the bleaching agent or the coating, or both.
30. A tissue marking particle comprising a chromophore encapsulated by a
biologically inert coating, the chromophore being dispersible within
tissue, wherein the chromophore has an average particle size of less than
about 50 nm.
31. The particle of claim 30, wherein the particle absorbs a specific
energy.
32. The particle of claim 31, wherein the coating absorbs a specific
energy.
33. The particle of claim 31, wherein the chromophore absorbs specific
energy.
34. The particle of claim 33, wherein the chromophore is thermochemically
reactive and the specific energy is heat energy.
35. The particle of claim 30, wherein the chromophore is soluble in bodily
fluids within the tissue.
36. The particle of claim 30, wherein the chromophore is capable of being
metabolized in the tissue.
37. The particle of claim 30, wherein the coating is ruptured when exposed
to a specific energy.
38. The particle of claim 30, wherein the chromophore is selected from the
group consisting of rifampin, .beta.-carotene, tetracycline, indocyanine
green, Evan's blue, methylene blue, Brilliant Blue FCF, Fast Green FCF,
Erythrosine, Allura Red AC, Tartrazine, and Sunset Yellow FCF.
39. The particle of claim 31, wherein the specific energy is near-infrared
or infrared radiation.
40. The particle of claim 32, wherein the specific energy is near-infrared
or infrared radiation.
41. The particle of claim 33, wherein the specific energy is near-infrared
or infrared radiation.
42. The particle of claim 30, wherein the coating comprises at least one of
a metal oxide, silica, glass, fluorocarbon resin, organic polymer, or wax.
43. The particle of claim 30, wherein the coating is substantially visibly
transparent and absorbs near-infrared radiation at a wavelength within the
range of from 750 nm to 2000 nm.
44. The particle of claim 30, wherein the coating comprises pores of a size
sufficient to allow the dispersible chromophore to leach out of the
particle.
45. The particle of claim 30, wherein the particle further comprises a
discrete absorption component selected from the group consisting of Schott
filter glass, graphite, carbon, a metal oxide, an acrylate polymer, and a
urethane polymer.
Description
FIELD OF THE INVENTION
The invention relates to permanent tissue markings that can be changed or
removed, or both, on demand.
BACKGROUND OF THE INVENTION
Tattoos have been used in almost every culture throughout history. They
have been found on a five thousand year old human mummy, and decorated
figurines suggest their use at least fifteen thousand years ago. Tattoos
have been used for many purposes including identity, beauty, artistic and
spiritual expression, medicine, and magic.
In the United States, statistics are not kept on tattooing but the practice
has apparently been growing in popularity for the past few decades. The
majority of tattoos are apparently obtained by people under forty years of
age, including a significant proportion of teenagers. An estimated 2
million people are tattooed every year.
In the U.S. today, the uses of tattooing have expanded to include not only
the familiar artistic tattoo, but also permanent makeup, for example,
permanent eyebrows, eyeliner, lip liner, and lip color; corrective or
reconstructive pigmentation, for example, repigmentation of scar tissue or
areola reconstruction on mastectomy patients; medical markings, for
example, marking gastrointestinal surgery sites for future monitoring; and
identification markings on animals, for example, pedigree "tags" on
purebred pets.
The tattooing procedure consists of piercing the skin with needles or
similar instruments to introduce an ink that includes small particles of
pigment suspended in a liquid carrier. During the healing process, some
particles of pigment are sloughed from the skin surface and others are
transported to the lymphatic system. What one sees as the tattoo are the
remaining particles of pigment located in the dermis where they are
engulfed by phagocytic skin cells (such as fibroblasts and macrophages) or
are retained in the extracellular matrix.
To create a permanent tattoo one must implant pigments that are not
dissolved or digested by living tissue. Primitive pigments probably
consisted of graphite and other carbon substances. Modern pigments also
include inorganic metal salts and brightly colored organometallic
complexes.
Tattoo ink ingredients have never yet been regulated or fully disclosed to
the public. Ink composition and pigment sources remain trade secrets.
Allergic reactions to these unknown and/or undisclosed substances, rare
but in some cases severe, have been reported at the time of tattooing,
well after the time of tattooing, and after exposure to sunlight or laser
treatments.
The long-term health effects, including potential toxicity and/or
carcinogenicity of tattoo pigments, have not been studied and are not
known. Unfortunately, these pigments, chosen for their permanence, are
believed to remain in the body for life, concentrated in the lymph nodes,
even if the visible tattoo is "removed" from the marked area, for example,
by laser treatment.
A widely recognized problem with tattoos is that they cannot be easily
removed. One survey indicated that about half of all Americans with
tattoos at some point wish they could remove them. Dissatisfaction can
stem from undesired social disapproval; from the appearance of a tattoo
that may be poorly executed, out-of-style, or inaccurate (commonly in the
case of name-containing vow tattoos); or from changes in the wearer's
self-perception or lifestyle, which are especially likely for the
increasing number of young customers.
Tattoo "removal" methods have included overtattooing without ink,
dermabrasion, and surgical excision, all of which usually leave
unacceptable appearance and/or scarring. The use of these removal methods
was recorded as early as the first century A.D. in Rome, when soldiers
returned from barbaric regions with tattoos that were unacceptable to
society.
In fact, there had been no significant technological advances in tattoo
removal methods until the 1960s when Dr. Leon Goldman pioneered the use of
pulsed lasers. This method was improved in the 1980s by Dr. R. Rox
Anderson, and has since become widely practiced. Removal can now also be
achieved using variable-wavelength intense pulsed light sources
(flash-lamps).
Ideally, short, powerful light pulses are absorbed specifically by tattoo
pigment particles with little or no absorption by surrounding tissue,
thereby causing the particles of pigment to break apart with minimal
damage to neighboring skin structures. Skin injury is extremely local and
scarring is uncommon. Instantaneously, some particles of pigment are
apparently broken into pieces which have far less optical absorption than
the original particles, and thus are less visible. During the healing
process, many particles are physically removed from the tattoo site while
others remain in the dermis as a residual tattoo.
Despite advantages over older methods, laser or flash-lamp removal of
standard tattoos is not ideal. A treatment course requires an average of
approximately eight laser treatments at a cost of several hundred dollars
apiece. The treatments must be spaced at least one month apart and can be
painful. Because a laser must be chosen for absorption of its emission
wavelength by the particular pigment, multiple lasers are needed to treat
multicolored tattoos effectively; however, a removal practitioner's office
may not offer the optimal laser(s) to treat a specific tattoo. Certain
pigments, including many greens, remain difficult to remove, and there is
currently no commercially available tattoo removal laser which effectively
treats most yellow pigments. Intense visible light sometimes targets the
skin's natural epidermal pigment, melanin, resulting in temporary or
permanent hypo- or hyperpigmentation, especially in dark or tanned skin,
and/or hair loss in the area. In addition, some tattoo pigments undergo
color changes in response to treatment. For example, inks used for
permanent makeup often contain certain iron, titanium, or other oxides
which are irreversibly blackened upon exposure to Q-switched lasers, and
cannot always be removed by further treatments.
After the treatment course, most patients can expect that a tattoo will not
be prominently visible or recognizable, but it is unusual to be able to
restore the skin to its original pre-tattoo appearance. Because of the
numerous drawbacks, only a fraction of those people who are unhappy with
their tattoos pursue tattoo removal.
SUMMARY OF THE INVENTION
The invention provides for permanent markings (such as tattoos) in tissue
(typically living tissue, such as skin) that are designed in advance to be
easily changed and/or removed on demand. These markings are created using
indispersible microparticles that consist of or contain chromophores.
These microparticles are designed in advance with one or more specific
properties (such as electromagnetic and/or structural properties) that
allow the microparticles to be altered by exposure to a specific energy
(such as a specific electromagnetic radiation) to change and/or remove the
tissue markings.
In general, the invention features a method of applying to a tissue a
detectable marking that can be changed or removed, or both, on demand, by
obtaining colored microparticles each including 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 (for example,
electromagnetic radiation such as near-infrared (near-IR), infrared (IR),
near-ultra violet (near-UV), or high intensity visible radiation); 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. In
this method, the chromophore or an additional material can provide the
specific property, which can be, for example, the absorption of the
specific energy, photochemical reactivity, or thermochemical reactivity
when the microparticles are exposed to the specific energy. The specific
energy can be applied only once to change or remove, or both, the
detectable marking.
In certain embodiments, the colored microparticles each include (i) an
indispersible, biologically inert coating, (ii) a core enveloped within
the coating, wherein the core includes 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 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.
For example, the dispersible chromophore can be dissolved or metabolized
when released into the tissue, or the chromophore can be insoluble and
have a size and configuration such that it is physically relocated from
the detectable marking by biological processes when released into the
tissue. The chromophore can be or include rifampin, .beta.-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), or
FD&C Yellow No. 6 (Sunset Yellow FCF). The chromophore can be any colored
substance approved by the United States Food and Drug Administration for
use in humans. In certain embodiments, the chromophore can be detected by
the naked eye under normal lighting conditions or when exposed to UV,
near-UV, IR, or near-IR radiation.
In other embodiments, the coating, the chromophore, or the optional
absorption component, or any combination thereof, absorb specific
electromagnetic radiation. The coating can be made of or include a metal
oxide, silica, glass, fluorocarbon resin, organic polymer, wax, or a
combination thereof. The coating can be substantially visibly transparent
and absorb near-IR radiation, for example, at a wavelength between about
750 nm and about 2000 nm. The absorption component can be or include
Schott filter glass, graphite, carbon, a metal oxide, an acrylate polymer,
or a urethane polymer. The coating can itself absorb, or include an
absorption component that absorbs, near-IR, IR, near-UV, or high intensity
visible radiation.
In another embodiment, the coating can include pores of a size sufficient
to allow the dispersible chromophore to leach out of the microparticle,
for example, over a period of weeks or months, so that the tissue marking
disappears at a given time. This provides tissue markings that fade slowly
after microparticle implantation. These markings can also be removed at
once upon exposure to the specific energy. The microparticles can also
include multiple cores enveloped within one coating.
The invention also features a method in which the colored microparticles
each include (i) an indispersible, biologically inert coating, (ii) a core
enveloped within the coating, wherein the core includes the chromophore
which is detectable through the coating and is altered upon exposure of
the microparticle to the specific energy (such as near-infrared or
infrared radiation), and optionally (iii) an absorption component that
absorbs the specific energy and that is located in the coating or the
core, or both; and in which 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. In
this embodiment, the chromophores need not be dispersible, and the
microparticles are not necessarily ruptured.
For example, the chromophore can be altered by losing its color or by
changing from an initial color to a different color upon exposure to the
specific energy. The microparticle can further include a sub-microparticle
that includes a bleaching agent that is released from the
sub-microparticle upon exposure of the microparticle to the specific
energy, thereby bleaching the chromophore (for example, rendering it
substantially invisible). The bleaching agent can be a peroxide,
hypochlorite, excited oxygen species, or free radical. The chromophore can
be 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.
The photobleachable chromophore can be Rose Bengal, rhodamine compounds,
coumarin compounds, dye-paired ion compounds, cationic dye-borate anion
complexes, or bis(diiminosuccino-nitrilo)metal complexes. The chromophore
can also be thermolabile, and exposure of the microparticle to the
specific energy heats and alters the chromophore. In this method, the
absorption component can be Schott filter glass, graphite, carbon, a metal
oxide, an acrylate polymer, or a urethane polymer.
The methods can be used to mark a variety of tissues including skin, iris,
sclera, dentin, fingernails, toenails, tissue beneath fingernails, tissue
beneath toenails, tissue inside the mouth, and tissue lining internal body
passages. In these methods, the specific energy can be 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. The specific energy can be applied only once to effect the
rupture or alteration.
In another aspect, the invention features 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, by
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. In this method, the microparticles
are altered to become substantially undetectable, thereby removing the
tissue marking, for example, by rupturing and releasing the chromophore,
or by losing the color of the chromophore. Alternatively, the
microparticles can be altered by changing from an initial color to a
different color, thereby changing the color of the tissue marking. In this
method, the colored microparticles can be those described herein.
In yet another aspect, the invention features colored microparticles that
includes (i) an indispersible, biologically inert coating that provides
from about 10 to about 95 percent of the volume (such as 15 to 25 or 35
percent) of the microparticle (and that renders the chromophores less
dispersible or indispersible), (ii) a core enveloped within the coating,
wherein the core is or includes 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 (such as near-infrared or infrared radiation) 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.
In another aspect the invention features a colored microparticle that
includes (i) an indispersible, biologically inert coating comprising from
about 10 to about 95 percent of the volume of the microparticle (such as
40 or 50 to 80 or 90 percent), (ii) a core enveloped within the coating,
wherein the core is or includes a chromophore that is detectable through
the coating and is altered upon exposure of the microparticle to a
specific energy (such as near-infrared, infrared, ultraviolet, or
high-intensity visible radiation), 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.
These microparticles can have a radius of from 50 nanometers to 100
microns. The coating can be or include a metal oxide, silica, glass,
fluorocarbon resin, organic polymer, wax, or any combination thereof. In
certain embodiments of the rupturable microparticles, 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. Alternatively, the coating can include one or more absorption
components that when exposed to the specific energy cause the coating to
break open. The colored microparticles can be sterilized.
The colored microparticles (preferably the microparticles with a
non-rupturing outer coating) can further include a sub-microparticle (that
can have its own coating), for example, in the core, that includes a
bleaching agent (such as a peroxide, hypochlorite, excited oxygen species,
or free radical) that is released from the sub-microparticle upon exposure
of the microparticle to the specific energy, thereby bleaching the
chromophore. The chromophore can be photobleachable, and exposure of the
microparticle to the specific energy renders the chromophore substantially
invisible. The chromophore can be thermolabile, and exposure of the
microparticle to the specific energy renders the chromophore substantially
undetectable or invisible.
The invention also features tissue marking inks that include the colored
microparticles and a liquid carrier, which can include alcohol, water, or
glycerin, or any combination thereof.
Additional embodiments are possible wherein the microparticles do not
necessarily include a coating or encapsulation, and the microparticles are
designed in advance with strong absorption of specific energy which
renders the chromophores (1) dispersible from the microparticles or (2)
invisible.
A significant feature of composite microparticles, especially such as those
that are ruptured, is that a common property (such as a specific
electromagnetic absorption peak) can be included in diverse microparticles
(having multiple colors). These diverse microparticles can include a
common material (in composite constructions) or materials with similar
absorption spectra. For example, this design allows removal of multiple
colors in a tissue marking through common treatment with a specific type
of energy (such as one wavelength emitted by one existing laser).
As used herein, a "microparticle" is a particle of a relatively small size,
not necessarily in the micron size range; the term is used in reference to
particles of sizes that can be implanted to form tissue markings and thus
can be less than 50 nm to 100 microns or greater. In contrast, a
"nanoparticle" is specifically a particle in the nanometer (10.sup.-9)
size range, for example, 15 nm or 500 nm. A micro- or nanoparticle may be
of composite construction and is not necessarily a pure substance; it may
be spherical or any other shape.
As used herein, a "dispersible" substance (such as a chromophore) is (1)
dissolved by (and is soluble in) bodily fluids, for example, those within
a cell or tissue; (2) metabolized (including digested) by living tissue
and/or cells into one or more new chemical products; and/or (3) of a size
(on average no larger than about 50 nanometers, but in some cases
necessarily much smaller, for example, less than about 5 nm), made of a
material, and configured such that normal bodily processes result in its
physical relocation from tissue (from cells or from extracellular matrix).
As used herein, an "indispersible" substance (such as a coating material or
an individual microparticle) does not disintegrate, dissolve, or become
metabolized in tissue. "Indispersible" microparticles are also large
enough on average (generally greater than about 50 nm, but depending on
the material as small as 5 nm or even smaller) and have a configuration on
average such that when a plurality is implanted into tissue a sufficient
number is retained to form a detectable marking, even though some number
of the individual microparticles may be relocated from the tissue marking
site through biological processes (such as lymphatic transport).
An "inert" or "biologically inert" substance (such as the coating material
of a microparticle) generally creates no significant biochemical,
allergic, or immune response after the normal healing period when
implanted into living tissue.
A "chromophore" is broadly defined herein as a substance (solid, liquid, or
gas) that has color or imparts a color to the intact microparticles
(including when the substance itself lacks color, for example, a clear
gas, but scatters electromagnetic waves, for example, light, and thus may
appear colored, for example, white, blue, green, or yellow, depending on
its scattering properties) under some conditions, for example, all of the
time or after exposure to a certain wavelength (such as in a fluorescent
substance). For example, a chromophore can be a fluorescent,
phosphorescent, wavelength up-converting, or other substance that may
normally be substantially invisible, but that emits ultraviolet, visible,
or infrared wavelengths during and/or after exposure to wavelengths from a
particular region of the electromagnetic spectrum. A chromophore can also
be a substance that reversibly or irreversibly changes color spontaneously
or in response to any stimulus.
"Color" is broadly defined herein as a detectable (that is, visible or able
to be made visible under certain lighting conditions, or able to be
detected using a device, for example, an infrared camera) property
determined by a substance's electromagnetic absorption and/or emission
spectrum (that is, in the ultraviolet, near-ultraviolet, visible,
near-infrared, infrared, and other ranges). Black and white are colors
under this definition.
As used herein, a substance (such as a chromophore) is "invisible" when
essentially no color can be detected (such as in a tissue marking site)
apart from the normal coloration of the substance's surroundings (such as
skin or other tissue) by the naked eye under normal lighting conditions,
for example, diffuse sunlight or standard artificial lighting. A substance
is "undetectable" when it is invisible to the naked eye under normal
lighting conditions, and also invisible by the naked eye, or a device,
under any other lighting conditions (such as fluorescent, UV, or
near-infrared).
As used herein, a "permanent tissue marking" or "tissue marking" is any
mark created by the introduction of microparticles of the invention into
tissue, typically living tissue, with the intention of permanent or
long-term endurance. Markings can be any color and must be detectable, for
example, by the naked eye or by an infrared detection device, when exposed
to electromagnetic radiation in one or more regions of the spectrum, for
example, the visible or near-infrared regions. A permanent marking is
generally a marking that remains visible or otherwise detectable until it
is exposed to a specific energy. However, in certain embodiments, a
permanent marking can be a mark that is designed in advance to disappear
after a predetermined time, for example after one or several months,
and/or can be removed by exposure to a specific energy before the
predetermined time.
As used herein, a "tattoo" is a type of tissue marking wherein the tissue
is usually skin. "Standard tattoos" and the pigments used to create them
have not been designed in advance for change and/or removal.
As used herein, a "non-invasive" procedure for creating a tissue marking
implants microparticles into the tissue without the use of an implement
that enters the surface of the tissue. Forces that can be applied to
microparticles to achieve non-invasive tattooing include ballistic,
electrical (such as through iontophoresis or electroporation), magnetic,
electromagnetic, ultrasonic, chemical, and chemical gradient forces, or
any combination of these forces.
As used herein, "removal" of a tissue marking means either the physical
removal of the substance(s) that create the appearance of the marking, or
the destruction or facilitated loss of some chromophoric property that
renders the marking invisible. Thus, all, some, or none of the components
(chromophores, coating material, etc.) of the microparticles may be
physically relocated from the tissue when a tissue marking is "removed."
Tissue marking microparticles that are "designed in advance" for change
and/or removal means that the materials and/or structure of the
microparticles are selected and/or engineered, and intended, to facilitate
change and/or removal of the tissue marking. It in no way implies that a
pre-determined removal method must be used, that this or another removal
method is the best method, or that a removal method is explicitly outlined
at the time of microparticle design. Multiple removal methods may be
acceptable for removing a given marking. Adjustments made to any proposed
method may affect removal efficacy positively, negatively, or not at all.
Unless otherwise defined, all technical and scientific terms used herein
have the same meaning as commonly understood by one of ordinary skill in
the art to which this invention belongs. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present invention, suitable methods and
materials are described herein. All publications, patent applications,
patents, and other references mentioned herein are incorporated by
reference in their entirety. In case of conflict, the present
specification, including definitions, will control. In addition, the
materials, methods, and examples are illustrative only and are not
intended to be limiting.
The invention provides several advantages over standard tattoos and their
removal. Standard tattoos are made using unregulated pigments of
undisclosed nature which, once implanted, are in direct contact with
living tissue for the recipient's life, even if no longer visible at the
tissue marking site. A course of many treatments to remove a standard
tattoo is not always successful, yet it is time-consuming and expensive,
may expose the tissue to a damaging amount of radiation, requires
guesswork and experimentation on the part of the practitioner, and, in the
case of multicolored tattoos, may require multiple lasers.
Through practice of the methods disclosed herein, tissue marking removal
treatments can become essentially 100% effective. The associated costs of
removal in terms of time (such as length of treatment course) and/or money
can be reduced compared to standard tattoo removal treatment.
By using tissue markings specifically designed in advance for removal, the
invention can reduce the total dose of energy (such as laser radiation) to
which the tissue marking site must be exposed for removal. The incidence
of patient pain and complications including skin injury can be reduced
compared to treatments to remove standard tattoos, which can include more
irradiation sessions at higher fluences.
In addition, the parameters (such as fluence and pulse duration) for
removal of tissue markings of the invention can be optimized in controlled
studies. When provided to practitioners, guesswork and experimentation can
be eliminated from treatments to remove tissue markings of the invention
and treatment outcome will be predictable.
Whereas removal of standard multicolored tattoos requires treatment with
multiple laser wavelengths absorbed by different pigments, microparticles
of the invention can be constructed such that one type of energy (such as
one wavelength) can target diverse microparticles. One benefit of this
feature, if multicolored microparticles are designed in advance for
removal by a single wavelength, is that removal practitioners will need
only one device to treat all patients for removal of tissue markings of
the invention. Currently, practitioners do not always have all of the
lasers needed for optimal treatment of standard multicolored tattoos, in
part because tattoo removal devices are expensive (approximately $30,000
for a 3 Joule, Q-switched ruby laser to about $100,000 for a flash-lamp).
In addition, the invention can reduce short- and long-term health risks
associated with standard tattoo pigments. Microparticles of the invention
can be designed to be inert and non-toxic when implanted in tissue and/or
can be constructed using materials that are already accepted for long-term
use in the human body.
According to important embodiments of the invention, chromophores are
encapsulated in inert materials to provide the microparticles for tissue
marking. These chromophores have minimal direct contact with the
recipient's body; whereas, in standard tattoos, the chromophoric pigments
are directly in contact with the body in tissue cells and are thought to
be stored in the lymph nodes for life.
Furthermore, the composition of tissue marking inks made with the new
microparticles will be known and can be disclosed in advance to allow
those with recognized allergies to avoid implantation and to provide
critical information for treating reactions.
Other features and advantages of the invention are apparent from the
following detailed description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic cross-sectional view of a colored microparticle.
FIG. 2 is a schematic cross-sectional view of a colored microparticle
containing chromophore nanoparticles.
FIG. 3 is a schematic cross-sectional view of a colored microparticle
containing sub-microparticles comprising encapsulated chromophores.
FIG. 4 is a schematic cross-sectional view of a colored microparticle
containing a bleachable chromophore and a sub-microparticle comprising an
encapsulated bleaching agent.
FIG. 5 is a schematic cross-sectional view of another embodiment of a
colored microparticle.
DETAILED DESCRIPTION
Microparticles capable of providing selectively removable tissue markings
must meet several criteria. First, they must be or contain a chromophore
that is detectable and has a color that is different from the color of the
tissue. Second, the microparticles and/or their chromophoric properties
must be removed by a specific externally applied treatment. Third, the
microparticles must be indispersible, as described herein, in the tissue
under normal physiological conditions. Fourth, any component of the
microparticles which will at any time (such as during implantation or
removal or while the marking exists) come into contact with the tissue
must be substantially biologically inert, unreactive, or safely
metabolized.
It is theoretically possible to select a palette of pure materials that
meet all four criteria for use as tissue marking microparticles. A more
efficient way to design the microparticles is to prepare them as
composites of two or more materials. The combination of several materials'
properties can more easily satisfy the four criteria. For example, the
chromophore may satisfy criteria 1, 2, and 4, and a coating may satisfy
criteria 3 and 4.
Microparticles
Microparticles of the invention are generally composed of a biologically
inert coating material enveloping at least one core comprising one or more
chromophores. The microparticles have a diameter of about 50 nm to about
100 microns, but may be smaller or larger as long as the microparticles
can be implanted into a tissue to provide a tissue marking. They can be
spherical, as shown in the figures, or any other shape.
FIG. 1 shows a basic microparticle 10, which includes a coating 20
encapsulating a core containing chromophore(s) 30. As shown in
microparticle 50 of FIG. 2, the core may contain discrete chromophore
nanoparticles 32.
In certain cases, as depicted in FIG. 3, it may be useful to encapsulate a
plurality of composite sub-microparticles 70, comprising chromophore(s) 30
and substantially transparent coating 75 (which may or may not be the same
material as used in coating 20), in coating 20 to form microparticle 60.
Sub-microparticles 70 can be any size as long as they fit within the
microparticle 60.
In another embodiment, illustrated schematically in FIG. 4, bleachable
chromophore(s) 34 and composite sub-microparticle(s) 90 (comprising
bleaching agent(s) 100 and coating 95) are encapsulated in coating 20 to
form microparticle 80.
FIG. 5 depicts an optional configuration for the microparticle in FIG. 1,
where two or more cores containing chromophore(s) 30 can be present within
the coating 20 of a single microparticle 110. Analogous multi-core
versions of the microparticles in FIGS. 2 to 4 can also be constructed.
Generally, coating 20 and/or 75 or 95 is made from any substantially
transparent material(s) (that is, a material that allows the encapsulated
chromophore to be detected, for example, seen) that is indispersible (and
is therefore generally retained in tissue) and is biologically inert under
physiological conditions. The coating can have a thickness ranging from
about 0.05 r (about 86% core loading, 14% coating, by volume) to about 0.6
r (about 6.4% core loading, 93.6% coating, by volume), where r is the
microparticle radius. The coating can be from about 10 to about 95 percent
of the total volume of a microparticle.
Any substance or combination of substances that imparts color to a
microparticle and which is usually, but not necessarily in all cases,
inert and unreactive in the body, may be chosen as chromophore(s) 30, 32,
or 34, as long as it is subject to removal (or alteration) according to
one of the two general methods described in detail hereafter, or another
suitable method.
Depending on the planned removal method of the microparticles depicted in
FIGS. 1 to 5, an additional absorption component(s) 40 may or may not be
incorporated into coatings 20, 75, or 95, and/or mixed with chromophore(s)
30, chromophoric nanoparticles 32, or bleaching agent(s) 100.
The microparticles schematically depicted herein and described generally
above can be constructed in two embodiments according to the intended
removal method (except for microparticle 80 which is specific to a single
removal method). In the first embodiment, microparticles can be
constructed to contain dispersible chromophores that are removed when
microparticles are made permeable, for example, by rupture of a coating.
In the second embodiment, microparticles can contain chromophores that are
rendered invisible without rupturing the microparticles.
More specifically, according to the first embodiment, microparticles 10,
50, 60, and 110 can contain dispersible chromophore(s) 30 or 32. Tissue
markings made using these microparticles can be removed when desired using
a method wherein the tissue marking is exposed to specific electromagnetic
radiation which ruptures the microparticles. For example, the
microparticles can rupture as the result of heating, for example, when the
coating 20 and/or 75, chromophore(s) 30 or 32, or additional absorption
component(s) 40 absorb the specific radiation. In this embodiment, when
the chromophores are dispersed from the tissue marking site, the tissue
marking disappears; this can occur over the course of several minutes to
several weeks following irradiation.
Microparticles 10, 50, and 110 which contain dispersible chromophores(s) 30
and 32 can also be constructed with porous coatings such that the
chromophore(s) leaches out and is dispersed over time; if desired, these
microparticles can also be designed in advance for removal using specific
electromagnetic radiation as in the above description.
According to the second embodiment, microparticles 10, 50, 60, 80, and 110
can contain specific encapsulated chromophores 30, 32, or 34 whose
chromophoric properties can be changed to become invisible when the
microparticle is
