U.S. patent application number 13/594214 was filed with the patent office on 2013-04-25 for brachytherapy devices and related methods having microencapsulated brachytherapy materials.
The applicant listed for this patent is Seth A. Hoedl, Bruce Kitzman. Invention is credited to Seth A. Hoedl, Bruce Kitzman.
Application Number | 20130102832 13/594214 |
Document ID | / |
Family ID | 47746914 |
Filed Date | 2013-04-25 |
United States Patent
Application |
20130102832 |
Kind Code |
A1 |
Hoedl; Seth A. ; et
al. |
April 25, 2013 |
BRACHYTHERAPY DEVICES AND RELATED METHODS HAVING MICROENCAPSULATED
BRACHYTHERAPY MATERIALS
Abstract
A brachytherapy device includes a bioabsorbable support and a
plurality of microcapsules on the support. Each of the plurality of
the microcapsules includes a plurality of microspheres and a
bioabsorbable microcapsule wall that encloses the plurality of
microspheres. The plurality of microspheres includes
radiation-emitting microspheres comprising a radioactive material,
radio-opaque microspheres comprising a radio-opaque material or a
combination thereof.
Inventors: |
Hoedl; Seth A.; (Somerville,
MA) ; Kitzman; Bruce; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hoedl; Seth A.
Kitzman; Bruce |
Somerville
Durham |
MA
NC |
US
US |
|
|
Family ID: |
47746914 |
Appl. No.: |
13/594214 |
Filed: |
August 24, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61527391 |
Aug 25, 2011 |
|
|
|
Current U.S.
Class: |
600/8 |
Current CPC
Class: |
A61N 5/1001 20130101;
A61N 2005/1024 20130101; A61N 2005/1023 20130101 |
Class at
Publication: |
600/8 |
International
Class: |
A61N 5/10 20060101
A61N005/10 |
Claims
1. A low-dose-rate (LDR) brachytherapy device comprising: a
bioabsorbable support; a plurality of microcapsules on the support,
each of the plurality of a microcapsules comprising a plurality of
microspheres and a bioabsorbable microcapsule wall that encloses
the plurality of microspheres, wherein the plurality of
microspheres comprises radiation-emitting microspheres comprising a
radioactive material, radio-opaque microspheres comprising a
radio-opaque material or a combination thereof.
2. The device of claim 1, wherein the plurality of microspheres
have a diameter of about 1 to 20 microns.
3. The device of claim 2, wherein the plurality of microspheres are
sized and configured so as to be subject to phagocytosis by
macrophages in a subject after bioabsorption of the bioabsorbable
support and the bioabsorbable microcapsule wall.
4. The device of claim 3, wherein the bioabsorbable support and the
microcapsule wall have a decay time that is greater than about two
and a half times a half life of the radioactive material.
5. The device of claim 1, wherein some of the plurality of
microspheres comprise a radioactive core and an outer wall.
6. The device of claim 5, wherein the radioactive core comprises a
radioactive material and a biocompatible polymer and/or
ceramic.
7. The device of claim 1, wherein some of the plurality of
microspheres comprise a porous material and a radio-isotope
deposited therein.
8. The device of claim 5, wherein the outer wall comprises glass or
acrylic.
9. The device of claim 1, wherein the microcapsule wall comprises a
poly-lactide, poly-glycolide, polycaprolactone,
poly-trimethylene-carbonate, polyanhdride, co-polymers formed
thereof, and/or combinations thereof.
10. The device of claim 1, wherein the bioabsorbable support
comprises a poly-lactide, poly-glycolide, polycaprolactone,
poly-trimethylene-carbonate, polyanhdride, co-polymers formed
thereof, and/or combinations thereof.
11. The device of claim 1, wherein the bioabsorbable support is
configured to seal the microcapsules therein after
implantation.
12. The device of claim 11, wherein a size and/or thickness of the
bioabsorbable support and/or microcapsule walls is configured to
release the microspheres after a predetermined time.
13. The device of claim 12, wherein the predetermined time is
greater than two and a half times a half life of the radioactive
material.
14. The device of claim 12, wherein the predetermined time is about
three months.
15. The device of claim 1, wherein the bioabsorbable support
comprises a seed casing that is configured to seal the plurality of
microcapsules therein prior to bioabsorption of the support.
16. The device of claim 1, wherein the bioabsorbable support
comprises a substantially linear support having a plurality of
wells therein that is configured to seal the plurality of
microcapsules in respective ones of the plurality of wells prior to
bioabsorption of the support.
17. The device of claim 1, wherein the bioabsorbable support
comprises a substantially planar support that is configured to seal
the plurality of microcapsules therein prior to bioabsorption of
the support.
18. A microcapsule comprising: a microcapsule outer wall; a
plurality of microspheres enclosed by the microcapsule outer wall,
wherein the plurality of microspheres comprises radiation-emitting
microspheres comprising a radioactive material, radio-opaque
microspheres comprising a radio-opaque material or a combination
thereof.
19. The microcapsule of claim 18, wherein the plurality of
microspheres have a diameter of about 1 to 20 microns.
20. The microcapsule of claim 19, wherein the plurality of
microspheres are sized and configured so as to be subject to
phagocytosis by macrophages in a subject after bioabsorption of the
bioabsorbable support and the bioabsorbable microcapsule wall.
21. The microcapsule of claim 18, wherein some of the plurality of
microspheres comprises a radioactive core and an outer wall.
22. The microcapsule of claim 21, wherein the radioactive core
comprises a radioactive material and a biocompatible polymer and/or
ceramic.
23. The microcapsule of claim 18, wherein some of the plurality of
microspheres comprise a porous material and a radio-isotope
deposited therein.
24. The microcapsule of claim 21, wherein the outer wall comprises
glass or acrylic.
25. The microcapsule of claim 18, wherein the microcapsule wall
comprises a poly-lactide, poly-glycolide, polycaprolactone,
poly-trimethylene-carbonate, polyanhdride, co-polymers formed
thereof, and/or combinations thereof.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 61/527,391, filed Aug. 25, 2012, the
disclosure of which is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to brachytherapy, and more
particularly, to brachytherapy devices having microencapsulated
radioactive materials.
BACKGROUND
[0003] Low-dose rate brachytherapy may provide a viable alternative
to external beam radiation and high-dose rate brachytherapy.
Although low-dose brachytherapy is most often used for prostate
cancer, low-dose brachytherapy is being considered increasingly
with respect to other cancers, such as breast cancer.
[0004] Although there are encouraging results to suggest that
low-dose rate brachytherapy seeds currently used in prostate cancer
can eradicate early stage breast cancer, because these seeds were
designed to treat prostate instead of breast cancer, there are
several clinical issues that may prohibit broad adoption. For
example, some medical physicists have expressed concern that the
radiation dose delivered to the tissue will be uncertain due to
changes in the lumpectomy cavity and seed migration. In addition,
there is a great concern that radio-opaque markers in the seeds,
used to identify the location of the seeds in post-implant CT
scans, will confuse subsequent mammograms by either looking like a
local recurrence or hiding a local recurrence in the "shadow" of
the radio-opaque marker. In addition, some women may prefer to not
have permanent, metal implants in a breast.
SUMMARY OF EMBODIMENTS OF THE INVENTION
[0005] In some embodiments, a brachytherapy device includes a
bioabsorbable support and a plurality of microcapsules on the
support. Each of the plurality of microcapsules includes a
plurality of microspheres and a bioabsorbable microcapsule wall
that encloses the plurality of microspheres. The plurality of
microspheres includes radiation-emitting microspheres comprising a
radioactive material, radio-opaque microspheres comprising a
radio-opaque material or a combination thereof.
[0006] In some embodiments, the plurality of microspheres have a
diameter of about 1 to 20 microns. The plurality of microspheres
may be sized and configured so as to be subject to phagocytosis by
macrophages in a subject after bioabsorption of the bioabsorbable
support and the bioabsorbable microcapsule wall. In some
embodiments, the bioabsorbable support and the microcapsule wall
have a decay time that is greater than about two and a half times a
half life of the radioactive material. Some of the plurality of
microspheres may include a radioactive core and an outer wall. The
radioactive core may include a radioactive material and a
biocompatible polymer and/or ceramic. The radioactive core may
include a porous material and a radio-isotope deposited therein.
The outer wall may include glass or acrylic.
[0007] In some embodiments, the microcapsule wall includes a
poly-lactide, poly-glycolide, polycaprolactone,
poly-trimethylene-carbonate, polyanhdride, co-polymers formed
thereof, and/or combinations thereof
[0008] In some embodiments, the bioabsorbable support includes a
poly-lactide, poly-glycolide, polycaprolactone,
poly-trimethylene-carbonate, polyanhdride, co-polymers formed
thereof, and/or combinations thereof
[0009] In some embodiments, the bioabsorbable support is configured
to seal the microcapsules therein after implantation.
[0010] In some embodiments, a size and/or thickness of the
bioabsorbable support and/or microcapsule walls is configured to
release the microspheres after a predetermined time. The
predetermined time may be greater than two and a half times a half
life of the radioactive material. The predetermined time may be
about three months.
[0011] In some embodiments, the bioabsorbable support comprises a
seed casing that is configured to seal the plurality of
microcapsules therein prior to bioabsorption of the support.
[0012] In some embodiments, the bioabsorbable support comprises a
substantially linear support having a plurality of wells therein
that is configured to seal the plurality of microcapsules in
respective ones of the plurality of wells prior to bioabsorption of
the support.
[0013] In some embodiments, the bioabsorbable support comprises a
substantially planar support that is configured to seal the
plurality of microcapsules therein prior to bioabsorption of the
support.
[0014] In some embodiments, a microcapsule includes a microcapsule
outer wall, and a plurality of microspheres enclosed by the
microcapsule outer wall, wherein the plurality of microspheres
comprises radiation-emitting microspheres comprising a radioactive
material, radio-opaque microspheres comprising a radio-opaque
material or a combination thereof.
[0015] In some embodiments, the plurality of microspheres have a
diameter of about 1 to 20 microns. The plurality of microspheres
may be sized and configured so as to be subject to phagocytosis by
macrophages in a subject after bioabsorption of the bioabsorbable
support and the bioabsorbable microcapsule wall.
[0016] In some embodiments, some of the plurality of microspheres
comprises a radioactive core and an outer wall. The radioactive
core may include a radioactive material and a biocompatible polymer
and/or ceramic. The radioactive core may include a porous material
and a radio-isotope deposited therein. The outer wall may include
glass or acrylic. The microcapsule wall may include a poly-lactide,
poly-glycolide, polycaprolactone, poly-trimethylene-carbonate,
polyanhdride, co-polymers formed thereof, and/or combinations
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The accompanying drawings, which are incorporated in and
constitute a part of the specification, illustrate embodiments of
the invention and, together with the description, serve to explain
principles of the invention.
[0018] FIG. 1 is a cross-sectional schematic diagram of a
low-dose-rate (LDR) brachytherapy device according to some
embodiments of the present invention.
[0019] FIG. 2 is a cross-sectional schematic diagram of a
bioabsorbable microcapsule including radioactive microspheres
according to some embodiments of the present invention.
[0020] FIG. 3 is a cross-sectional schematic diagram of a
bioabsorbable microcapsule including radio-opaque microspheres
according to some embodiments of the present invention.
[0021] FIG. 4 is a cross-sectional schematic diagram of a
bioabsorbable microcapsule including radioactive microspheres and
radio-opaque microspheres according to some embodiments of the
present invention.
[0022] FIG. 5 is a cross-sectional schematic diagram of a
radioactive microsphere according to some embodiments of the
present invention.
[0023] FIG. 6 is a cross-sectional schematic diagram of a
radio-opaque microsphere according to some embodiments of the
present invention.
[0024] FIG. 7 is a cross-sectional schematic diagram of a
brachytherapy seed having a radioactive core comprising
microcapsules according to some embodiments of the present
invention.
[0025] FIG. 8 is a cross-sectional schematic diagram of a generally
linear brachytherapy device having a radioactive core comprising
microcapsules according to some embodiments of the present
invention.
[0026] FIG. 9 is a top view schematic diagram of a generally planar
brachytherapy device having a radioactive core comprising
microcapsules according to some embodiments of the present
invention.
[0027] FIG. 10 is a cross-sectional side view of the brachytherapy
device of FIG. 9.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0028] The present invention now will be described hereinafter with
reference to the accompanying drawings and examples, in which
embodiments of the invention are shown. This invention may,
however, be embodied in many different forms and should not be
construed as limited to the embodiments set forth herein. Rather,
these embodiments are provided so that this disclosure will be
thorough and complete, and will fully convey the scope of the
invention to those skilled in the art.
[0029] Like numbers refer to like elements throughout. In the
figures, the thickness of certain lines, layers, components,
elements or features may be exaggerated for clarity.
[0030] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
the invention. As used herein, the singular forms "a," "an" and
"the" are intended to include the plural forms as well, unless the
context clearly indicates otherwise. It will be further understood
that the terms "comprises" and/or "comprising," when used in this
specification, specify the presence of stated features, steps,
operations, elements, and/or components, but do not preclude the
presence or addition of one or more other features, steps,
operations, elements, components, and/or groups thereof. As used
herein, the term "and/or" includes any and all combinations of one
or more of the associated listed items. As used herein, phrases
such as "between X and Y" and "between about X and Y" should be
interpreted to include X and Y. As used herein, phrases such as
"between about X and Y" mean "between about X and about Y." As used
herein, phrases such as "from about X to Y" mean "from about X to
about Y."
[0031] Unless otherwise defined, all terms (including 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. It will be further understood that terms, such
as those defined in commonly used dictionaries, should be
interpreted as having a meaning that is consistent with their
meaning in the context of the specification and relevant art and
should not be interpreted in an idealized or overly formal sense
unless expressly so defined herein. Well-known functions or
constructions may not be described in detail for brevity and/or
clarity.
[0032] It will be understood that when an element is referred to as
being "on," "attached" to, "connected" to, "coupled" with,
"contacting," etc., another element, it can be directly on,
attached to, connected to, coupled with or contacting the other
element or intervening elements may also be present. In contrast,
when an element is referred to as being, for example, "directly
on," "directly attached" to, "directly connected" to, "directly
coupled" with or "directly contacting" another element, there are
no intervening elements present. It will also be appreciated by
those of skill in the art that references to a structure or feature
that is disposed "adjacent" another feature may have portions that
overlap or underlie the adjacent feature.
[0033] Spatially relative terms, such as "under," "below," "lower,"
"over," "upper" and the like, may be used herein for ease of
description to describe one element or feature's relationship to
another element(s) or feature(s) as illustrated in the figures. It
will be understood that the spatially relative terms are intended
to encompass different orientations of the device in use or
operation in addition to the orientation depicted in the figures.
For example, if the device in the figures is inverted, elements
described as "under" or "beneath" other elements or features would
then be oriented "over" the other elements or features. Thus, the
exemplary term "under" can encompass both an orientation of "over"
and "under." The device may be otherwise oriented (rotated 90
degrees or at other orientations) and the spatially relative
descriptors used herein interpreted accordingly. Similarly, the
terms "upwardly," "downwardly," "vertical," "horizontal" and the
like are used herein for the purpose of explanation only unless
specifically indicated otherwise.
[0034] It will be understood that, although the terms "first,"
"second," etc. may be used herein to describe various elements,
these elements should not be limited by these terms. These terms
are only used to distinguish one element from another. Thus, a
"first" element discussed below could also be termed a "second"
element without departing from the teachings of the present
invention. The sequence of operations (or steps) is not limited to
the order presented in the claims or figures unless specifically
indicated otherwise.
[0035] "Biocompatible" as used herein refers to a material and any
metabolites or degradation products thereof that are generally
non-toxic to the recipient and do not cause any significant adverse
effects to the subject. The criteria for defining significant
adverse effects may be based on criteria used by regulatory
agencies such as the U.S. Food and Drug Administration.
[0036] "Biodegradable" or "bioabsorbable" refers to a material that
will degrade or erode under physiologic conditions to smaller units
or chemical species that are capable of being metabolized,
eliminated, absorbed or excreted by the subject.
[0037] Although embodiments are described herein as relating to
breast cancer and implantation in breast tissue, it should be
understood that other types of cancer may be treated using the
methods and devices described herein, including lung cancer,
bladder cancer, colon cancer, kidney or renal cancer, pancreatic
cancer, prostate cancer thyroid cancer, head and neck cancers and
soft tissue sarcomas.
[0038] Embodiments according to the present invention will now be
described with respect to FIGS. 1-10.
[0039] An exemplary device 10 in which a substrate or scaffold
support 20 includes a plurality of wells 22 is shown in FIG. 1. The
wells 22 may include either a radioactive material 30 or a
radio-opaque marker material 40 or a combination thereof As
illustrated in FIGS. 2-3, the radioactive material 30 may be
provided by a plurality of radiation treatment microcapsules 50
(FIG. 2) and the radio-opaque marker material 40 may be provided by
a plurality of radio-opaque microcapsules 50 (FIG. 3). The
radiation treatment microcapsules 50 include a bioabsorbable
microcapsule body or wall 52 that has radioactive microspheres 54
embedded therein. The radio-opaque microcapsules 60 include a
bioabsorbable microcapsule body or wall 62 that has radio-opaque
microspheres 64 embedded therein. Although the device 10 of FIG. 1
is illustrated with respect to wells 22 that include either a
radioactive material 30 or a radio-opaque marker material 40, it
should be understood that the wells 22 may include both radiation
treatment microcapsules 50 and radio-opaque microcapsules 60.
Moreover, as illustrated in FIG. 4, a microcapsule 70 is shown that
includes both radioactive microspheres 54 and radio-opaque
microspheres 64. Therefore, microcapsules according to some
embodiments may include either radioactive or radio-opaque
microspheres or a combination thereof
[0040] In this configuration, LDR brachytherapy devices according
to some embodiments may addresses concerns such as future imaging
(e.g., mammography) and cosmetic concerns of LDR brachytherapy,
including the potential toxicity of the radio-isotope or its decay
products to healthy tissue as they are released from the
bioabsorbable device. The microcapsules 50, 60, 70 (FIGS. 2-4) and
various components of the support 20 (FIG. 1) may be biocompatible
and biodegradable and/or bioabsorbable; however, the radioactive
microspheres 54 and radio-opaque microspheres 64 may be
biocompatible, but not biodegradable or bioabsorbable. Thus, the
biodegradable/bioabsorbable components of the device 10 may be
selected such that they degrade or absorb into the body after a
substantial amount of radioactive decay has occurred. After the
biodegradable components degrade/absorb into the body, the
microspheres 54, 64 disperse within the body. In some embodiments,
the radioactive microspheres 54 and the biodegradable components of
the device 10 may be selected so that the time that the
biodegradable/bioabsorbable components take to degrade and release
the radioactive microspheres 54 is sufficient to allow significant
decay of the radioactive material in the microspheres 54. Stated
otherwise, the biodegradable components of the device 10 permit the
radioactive microspheres 54 to be fixed in a desired location
during radiation treatment, but once the radioactive material has
decayed such that its therapeutic value is decreased and its
potential to deliver radiation to healthy tissue is reduced, the
biodegradable components of the device 10 degrade and/or are
absorbed into the body and the microspheres 54, 64 are released. In
some embodiments, devices described herein will not directly expose
a patient to the radioactive components after it is bioabsorbed or
biodegraded. As illustrated in FIGS. 5-6, the microspheres 54, 64
may include a respective microsphere core 54A, 64A and an outer
microsphere wall 54B, 64B. The walls 54B, 64B may be biocompatible
and may provide a barrier between the respective cores 54A, 64A and
tissue in the body.
[0041] In some embodiments, the size of the microspheres 54, 64 is
selected so that macrophages in the patient's body can engulf the
microspheres in the process of phagocytosis.
[0042] Although embodiments according to the present invention are
described with respect to the linear or string-shaped device 10 of
FIG. 1, it should be understood that the microcapsules according to
some embodiments may be provided as part of LDR brachytherapy
devices having any suitable shape and configuration, including
conventional brachytherapy seed shapes, planar sheets,
uni-directional devices having a radiation shielding material and
the like. Examples of LDR brachytherapy devices that may be
suitable for use with the microcapsules described herein, for
example, with respect to FIGS. 2-4 may be found, e.g., in U.S. Pat.
No. 7,686,756 and U.S. Publication No. 20090275793, the disclosures
of which are hereby incorporated by reference in their entirety.
For example, as shown in FIG. 7, a brachytherapy device 110
according to embodiments of the present invention includes a sealed
housing or casing 112 and a radioactive material 114. The
radioactive material 114 may include one or more of the
microcapsules 50, 60, 70. The sealed casing 112 may be a
biocompatible and/or bioabsorbable material. According to some
embodiments, the type of bioabsorbable material in the casing 112
may be evaluated to ensure that the radioactive material 114 is
sealed for a sufficient period of time, such as until the
radioactive material 114 decays to a safe level, such as less than
10%, less than 5% or even less than 1% of the original
radioactivity.
[0043] Although the device 110 is illustrated as a "point source"
or "seed" shape, any suitable shape of device or encapsulation of
the radioactive material may be used. For example, as shown in FIG.
8, a device 120 includes a plurality of globules of radioactive
material 122 encapsulated in a sealed casing 124. The radioactive
material 122 may include one or more of the microcapsules 50, 60,
70. The linear device 20 may be suitable for implantation, e.g., in
breast or prostate tissue. As illustrated in FIGS. 9-10, a planar
device 130 includes a radioactive material 132 in a planar sealed
casing 134. The radioactive material 132 may include one or more of
the microcapsules 50, 60, 70. The sealed casing 134 may include two
planar members 134A and 134B with the radioactive material 132
positioned therebetween.
[0044] Any suitable bioabsorbable or biodegradable material may be
used, such as copolymers and homopolymers of glycolic acid (GA) and
L-lactic acid (LA) or combinations thereof, including copolymers
having a blend of these two base materials (e.g., Vicyrl
(Polyglactin 910), for instance, is formed with a 90:10 GA-to-LA
blend). Another example is a mixture of 18:82 GA-to-LA blend to
achieve longer-term stability in the body. Atrisorb.RTM. (Zila,
Inc., Fort Collins, Colo., USA), Resolute (W. L. Gore and
Associates, Inc., Neward, Del., USA), or Lactosorb.RTM. (Biomet
Microfixation, Jacksonville, Fla., USA) may also be used.
[0045] In some embodiments, palladium-103 may be used in the
radioactive microspheres 54 of the microcapsules 50 and 70;
however, any suitable radioactive material may be used, including
palladium-103, iodine-125, cesium-131 and phosphorus-32. Although
palladium-103 and its daughter isotope rhodium are both in their
elemental forms harmless, both palladium chloride and rhodium
trichloride are toxic with intravenous rat LD50s of 3 mg/kg and 215
mg/kg respectively. Typically, palladium-103 is supplied in the
chloride form. Thus, a bioabsorbable device that liberates the
radio-isotope directly into the patient would likely face
significant regulatory hurdles to ensure its long term safety.
According to some embodiments, the outer surface of the
microspheres is made of a leak-tight biocompatible material, such
as glass or acrylic that may reduce or prevent chemical contact
with the patient after bioabsorption of the microcapsule.
[0046] In particular embodiments, the flexible scaffold or support
20 of FIG. 1 has an outer diameter of about 0.8 mm and a length of
up to 60 mm, and may be molded out of a flexible, bioabsorbable
material, such as a poly-lactide/poly-glycolide co-polymer. These
dimensions may be used so that the device may be applied with an 18
gauge brachytherapy needle. However, other suitable sizes may be
used. Generally regularly spaced wells 22 in this support 20
contain radioactive and/or radio-opaque material. The radioactive
material may be palladium-103, and the radio-opaque material could
be a gold, iodine, or barium, including compounds and combinations
thereof Both the radioactive and radio-opaque materials are each
contained within biocompatible microspheres as described
herein.
[0047] The microspheres 54, 64 may have diameters between 1 and 20
microns. As illustrated in FIGS. 5-6, the microspheres 54, 64 may
include a respective microsphere core 54A, 64A and an outer
microsphere wall 54B, 64B. The outer microsphere walls 54B, 64B may
be formed, e,g., of a leak-tight material such as glass or an
acrylic, such as polymethylmethacrylate (PMMA). The radioactive
core 54A may be formed of a radioactive material, such as
palladium-103, alone or infused in a porous base (e.g., a porous
polymer or glass material) or mixed with a polymer. The
radio-opaque core 64A may be formed of any suitable radio-opaque
material, such as gold, iodine or barium, including compounds and
combinations thereof. Although the microspheres 54, 64 are
illustrated in FIGS. 5-6 as having respective microsphere cores
54A, 64A and outer walls 54B, 64B, it should be understood that any
suitable configuration may be used. For example, in some
embodiments, the outer walls 54B, 64B are omitted and the
microspheres may be formed of a generally homogeneous material,
such as a radioactive material alone, infused in a porous base, or
mixed with another material, such as a polymer.
[0048] To minimize the risk of aerosolizing the radioactive
microspheres 54 or the radio-opaque microspheres 64 during
manufacture, which may pose safety risks, these microspheres 54, 64
may in turn be contained in the bioabsorbable microcapsules 50, 60,
70, which may have a diameter of approximately 100 microns or more.
These microcapsules may in turn be sealed into the wells 22 in the
support 20 with a bioabsorbable material or well sealant.
[0049] The bioabsorption of devices according to some embodiments
may proceed as follows. After three months (e.g., five half-lives
of the palladium-103), a device using palladium-103 would have
delivered 97% of the radiation dose. At that time, the
bioabsorbable materials, e.g., including the scaffold support, the
well sealant, and the microcapsule wall and other bioabsorbable
materials, may begin to significantly decay in the patient's body.
In some embodiments, the size and/or thickness of the scaffold
support and other bioabsorbable materials may be selected so as to
approximate a predetermined decay time, such as a decay time that
is greater than two and a half times the half life of the
radioactive material or five times or greater than the half life of
the radioactive material. The decay process may liberate the
microspheres 54, 64.
[0050] Without wishing to be bound by any particular theory, the
size of these microspheres 54, 64 may be chosen so as to increase
dispersement of the microspheres 54, 64 upon release. For example,
macrophages in the patient's body may engulf the microspheres in
the process of phagocytosis. Phagocytosis is the cellular process
of engulfing solid particles by the cell membrane to form an
internal phagosome by phagocytes and protists. In the immune
system, phagocytosis is a mechanism used to remove pathogens and
cell debris. Bacteria, dead tissue cells, and small mineral
particles are all examples of objects that may be phagocytosed. For
example, the microspheres 54, 64 may be about 1-20 microns, which
may be a suitable size to be subject to phagocytosis. The
microspheres 54, 64 may be sufficiently large so that the
macrophages cannot transport the microspheres to the patient's
lymph nodes where they may collect and appear confusingly similar
to a cancer occurrence or recurrence with a CT or fluoroscopy scan.
Instead, due to the size of the microsphere, the macrophages may
disperse, but then fix in place, the microspheres 54, 64. The walls
54A, 64A of these microspheres 54, 64 may permanently contain both
the decay products of the radioactive material core 54A and the
radio-opaque material core 64A, respectively, for example, with a
suitable material such as glass or acrylic, which may reduce or
prevent direct contact with body tissue. As noted above, in some
embodiments, the walls 54A, 64A may be omitted. Thus, the device
may no longer be felt as a permanent implant by the patient and it
may be appear to dissolve on a CT scan or other imaging scan
because the radio-opaque markers in the microspheres 64 will have
dispersed such that their visibility is reduced or eliminated.
Exposure of healthy tissue to the potentially toxic components of
the radioactive materials in the microspheres 54 may also be
reduced or eliminated because sufficient radiation decay occurs
prior to the release of the microspheres 54, 64 outside of the
desired treatment area.
[0051] After a CT or MRI scan of the diseased tissue, such as a
breast following a lumpectomy, health professionals, such as
medical physicists in consultation with radiation oncologists, may
plan the placement and location of the devices described herein so
that a dose is delivered to the diseased tissue while sparing the
adjacent healthy tissue. The number and lengths of the devices may
be determined for the desired or optimal treatment plan, and
therefore, devices according to some embodiments may be
customizable for each patient. For example, for breast cancer, it
is anticipated that between five to ten linear or string-shaped
scaffold devices with lengths between about 1 and 6 cm may be
needed to treat a malignancy. As in the case of seeds, the devices
according to embodiments of the present invention may be applied in
an outpatient setting with minimal anesthesia and the patient may
likely leave the hospital the same day. A follow-up CT scan after
implantation may be used to confirm device placement and perform
quality control.
[0052] According to some embodiments of the present invention, a
low-dose rate (LDR) brachytherapy device may reduce or minimize
some of the practical problems with permanent seed implants with
cancers such as breast cancer while maintaining the LDR technique's
efficacy, lower side effect profile, and high convenience when
compared to high dose brachytherapy or radiation beam treatment. In
particular embodiments, a device of sufficient size to deliver a
uniform or substantially uniform radiation dose and stay fixed in
place in tissue, such as breast tissue, may have reduced dosimetry
uncertainties than traditional seeds. Devices according to some
embodiments may be made of flexible polymers and may be more
comfortable for the patient than traditional seeds when implanted
in soft tissue, such as breast tissue. A bioabsorbable device may
reduce the concerns about subsequent mammograms, and cosmetic
concerns about permanent implants in soft tissue, such as breast
tissue. Moreover, devices according to the present invention may be
customized for each individual patient.
[0053] In some embodiments, a bioabsorbable or biodegradable
support or scaffold (such as the support 20 in FIG. 1, the casing
124 in FIG. 8, and the casing 134 in FIGS. 9-10) is fabricated from
a bioabsorbable material such as a poly-lactide, poly-glycolide,
polycaprolactone, poly-trimethylene-carbonate, polyanhdride,
co-polymers formed thereof, combinations thereof, or any other
suitable bioabsorbable or biodegradable material. The bioabsorbable
material may be chosen so that it has a decay time in the human
body that is long enough to allow sufficient decay of the
radioisotope, e.g., longer than at least two half-lives of the
radioisotope. The support can be formed by either injection
molding, solvent casting, laser or mechanical machining or any
other suitable method.
[0054] The microspheres containing a therapeutic radioisotope can
be fabricated in a variety of ways. In some embodiments, the
radioisotope is mixed with a biocompatible polymer, such as PMMA.
The mixture may be achieved by dissolving both the radioisotope and
the polymer in an appropriate solvent, or may be achieved by mixing
the radioisotope into the polymer when the polymer is heated into a
molten state. The radioisotope/polymer mixture may then be
fabricated into microspheres through a variety of techniques (see,
e.g., U.S. Patent Publication No. 2012/0121510) including solvent
evaporation (see, e.g., U.S. Pat. Nos. 5,407,609; 5,650,173 and
5,654,008), phase inversion (see U.S. Pat. No. 6,235,224), or
spraying methods (see U.S. Pat. No. 5,667,806), or other suitable
techniques.
[0055] In some embodiments, the radioisotope may be mixed with a
biocompatible ceramic, such as Schott.TM. 8625 glass, available
from Schott, North America, Inc., Elmsford, N.Y., U.S.A.), in the
molten phase. The glass/radioisotope mixture may then be formed
into microspheres through various techniques including spraying
methods (see U.S. Pat. No. 3,279,905). The biocompatible polymer or
biocompatible ceramic microspheres may be further processed to the
appropriate size, e.g., through a mechanical milling action (see
U.S. Pat. No. 5,011,677).
[0056] In some embodiments, the microspheres may include three
components: a porous inner core, the radioisotope, and a
biocompatible shell. The porous inner core may be made of a porous
polymer, such as polyethylene (see U.S. Pat. No. 3,865,674), a
porous glass (see U.S. Pat. No. 3,513,106) or other suitable porous
material. The porous material may be mechanically milled to the
appropriate size. The radioisotope may be deposited as a liquid
into the porous cores through a precision deposition process (See
U.S. Pat. No. 7,686,756). The radioisotope could be converted from
a soluble form into an insoluble form by various techniques,
including exposing the soluble form to a plasma, by chemical
precipitation and/or by exposing the soluble form to heat. Methods
and devices for forming non-soluble radioactive materials are
disclosed in U.S. patent application Ser. No. 12/434,131, filed May
1, 2009 and published as U.S. Publication No. 2009/0275793 on Nov.
5, 2009, the disclosure of which is incorporated herein by
reference in its entirety. Once converted to an insoluble form, the
core and radioisotope may be encapsulated in a biocompatible
material using a spray-drying process, interfacial polymerization
process (see U.S. Pat. No. 5,277,979) a pan-coating process or any
other suitable method.
[0057] The microspheres containing a radio-opaque material may be
fabricated as described above with respect to the microspheres that
contain a therapeutic radioisotope except that a radio-opaque
material, such as a gold or barium containing compound, replaces
the radioisotope.
[0058] The microcapsules containing the microspheres (which in turn
contain a therapeutic radioisotope or a radio-opaque material) may
be fabricated, for example, by mixing the microspheres with a
bioabsorbable material, such as poly-lactide, poly-glycolide,
polycaprolactone, poly-trimethylene-carbonate or co-polymers formed
thereof with a suitable solvent that does not dissolve the material
or shell wall of the microspheres. The bioabsorbable shell may have
a decay time in the human body that is sufficiently long to encase
the radioisotope during its therapeutically useful lifetime and to
release the radioisotope after significant decay has occurred,
e.g., longer than at least two half-lives of the therapeutic
radioisotope or more. This mixture may then be formed into
microcapsules of specific size through any of the methods discussed
above.
[0059] In some embodiments, the microcapsules are suspended in an
emulsion containing a bioabsorbable material dissolved in an
appropriate solvent such as toluene or xylene. The emulsion is then
deposited in appropriate wells or otherwise affixed or embedded in
the bioabsorbable or biodegradable scaffold or support. An emulsion
containing the radioactive microcapsules may be deposited in some
wells, the emulsion containing the radio-opaque microcapsules may
be deposited in other wells or the radioactive microcapsules and
radio-opaque microcapsules may be combined in a single emulsion.
The solvent may then be allowed to evaporate leaving the
microcapsules secured into the scaffold. Alternatively, the
microcapsules may be mixed into a bioabsorbable or biodegradable
material that is heated into a liquid state. In this heated state,
the mixture containing radioactive microcapsules may be deposited
in some wells, and the mixture containing radio-opaque
microcapsules would be deposited in other wells, or a single
mixture including both radioactive and radio-opaque microcapsules
may be deposited. The heated mixture may be allowed to cool,
thereby securing the microcapsules into the scaffold or
support.
[0060] Although embodiments according to the present invention have
been discussed with respect to breast and lung cancer, it should be
understood that other tumor types may also benefit from a
bioabsorbable brachytherapy device. It should be understood that
other types of cancer may be treated using the methods and devices
described herein, including bladder cancer, colon cancer, kidney or
renal cancer, pancreatic cancer, prostate cancer thyroid cancer,
head and neck cancers and soft tissue sarcomas. Moreover, in some
embodiments, shielding materials may be strategically placed in
brachytherapy devices described herein to provide generally
uni-directional radiation and to protect healthy tissue adjacent
cancer tissue. Moreover, in some embodiments, chemotherapy drugs or
other therapeutic agents may be incorporated into the brachytherapy
device and delivered to the tissue, e.g., when a portion of the
device is bioabsorbed by the body.
[0061] The foregoing is illustrative of the present invention and
is not to be construed as limiting thereof. Although a few
exemplary embodiments of this invention have been described, those
skilled in the art will readily appreciate that many modifications
are possible in the exemplary embodiments without materially
departing from the novel teachings and advantages of this
invention. Accordingly, all such modifications are intended to be
included within the scope of this invention as defined in the
claims. Therefore, it is to be understood that the foregoing is
illustrative of the present invention and is not to be construed as
limited to the specific embodiments disclosed, and that
modifications to the disclosed embodiments, as well as other
embodiments, are intended to be included within the scope of the
appended claims. The invention is defined by the following claims,
with equivalents of the claims to be included therein.
* * * * *