U.S. patent application number 10/056882 was filed with the patent office on 2002-06-27 for tissue marking using biocompatible microparticles.
This patent application is currently assigned to Carbon Medical Technologies, Inc.. Invention is credited to Klein, Dean A..
Application Number | 20020082517 10/056882 |
Document ID | / |
Family ID | 24562182 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082517 |
Kind Code |
A1 |
Klein, Dean A. |
June 27, 2002 |
Tissue marking using biocompatible microparticles
Abstract
Described are methods of tissue marking using microparticles
that have carbon surfaces, and that contain a contrast agent.
Preferred microparticles include a permanently radiopaque particle
substrate and a pyrolytic carbon surface.
Inventors: |
Klein, Dean A.; (North Oaks,
MN) |
Correspondence
Address: |
FAEGRE & BENSON LLP
2200 Wells Fargo Center
90 South Seventh Street
Minneapolis
MN
55402-3901
US
|
Assignee: |
Carbon Medical Technologies,
Inc.
|
Family ID: |
24562182 |
Appl. No.: |
10/056882 |
Filed: |
January 25, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10056882 |
Jan 25, 2002 |
|
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09638964 |
Aug 15, 2000 |
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Current U.S.
Class: |
600/564 ;
600/431 |
Current CPC
Class: |
A61K 49/0419
20130101 |
Class at
Publication: |
600/564 ;
600/431 |
International
Class: |
A61B 010/00 |
Claims
What is claimed:
1. A method for tissue marking comprising delivering detectable
microparticles to a tissue site and detecting the
microparticles.
2. The method of claim 1 wherein the microparticles comprise a
radiopaque material.
3. The method of claim 2 wherein the radiopaque material is
permanently radiopaque.
4. The method of claim 3 wherein the radiopaque material is a metal
or a metal oxide.
5. The method of claim 4 wherein the radiopaque material is
titanium, aluminum oxide, zirconium oxide, or a mixture
thereof.
6. The method of claim 1 wherein the microparticles consist of one
or more radiopaque materials.
7. The method of claim 1 wherein the microparticle comprises a
detectable coating.
8. The method of claim 1 wherein the microparticle comprises a
substrate and a coating, and the coating comprises a radiopaque
additive.
9. The method of claim 1 wherein the microparticles comprise a
radiopaque substrate and a carbon coating.
10. The method of claim 9 wherein the carbon coating comprises
pyrolytic carbon.
11. The method of claim 9 wherein the carbon comprises low
temperature isotropic pyrolytic carbon.
12. The method of claim 9 wherein the carbon comprises ultra low
temperature isotropic pyrolytic carbon.
13. The method of claim 9 wherein the radiopaque substrate
comprises a metal or a metal oxide.
14. The method of claim 9 wherein the radiopaque substrate
comprises titanium, aluminum oxide, zirconium oxide, or a mixture
thereof.
15. The method of claim 9 wherein the radiopaque substrate is
permanently radiopaque.
16. The method of claim 1 wherein the average, transverse
cross-sectional dimension of the microparticles is between about
100 and about 1000 micrometers.
17. The method of claim 1 wherein the average, transverse
cross-sectional dimension of the microparticles is between about
251 and about 300 micrometers.
18. The method of claim 1 wherein the microparticles are carried in
a biocompatible carrier to carry and deliver the
microparticles.
19. The method of claim 1 wherein the method comprises tissue
marking the site of a breast biopsy.
20. The method of claim 1 wherein the method comprises tissue
marking the site of a prostate biopsy.
21. The method of claim 1 wherein the method comprises tissue
marking the site of a tissue removal.
22. The method of claim 1 wherein the method comprises tissue
marking the site of a polyp removal from a rectum or a colon.
23. The method of claim 1 wherein the method comprises injecting
the microparticles using a hypodermic needle.
24. The method of claim 1 wherein the method comprises inserting a
hypodermic needle through the sheath of a mammotone to a tissue
site, and injecting the microparticles using the hypodermic
needle.
25. The method of claim 1 wherein the method comprises detecting
the microparticles using radiography or fluoroscopy.
26. A method of tissue marking comprising injecting detectable
microparticles to a tissue site through a hypodermic needle, and
detecting the microparticles.
27. The method of claim 26 wherein the method comprises detecting
the microparticles using radiography or fluoroscopy.
28. A method for marking a biopsy, the method comprising:
performing a biopsy; and marking the site of the biopsy using
detectable microparticles injected through a hypodermic needle.
29. The method of claim 28 wherein the microparticles are injected
using a hypodermic needle and syringe, wherein the needle is
inserted through a sheath of a biopsy probe.
30. The method of claim 29 wherein the microparticles are delivered
through the biopsy probe before the biopsy sheath is moved away
from the site of the biopsy.
31. A method for marking a site of tissue removal, the method
comprising: performing a tissue removal procedure; and marking the
site of the tissue removal using detectable microparticles injected
through a hypodermic needle.
32. The method of claim 31 wherein the microparticles are injected
using a hypodermic needle, through a mucosa.
Description
BACKGROUND
[0001] Tissue marking generally is a method of marking a position
in a body, such as a specific position on tissue or an organ, to
allow re-visiting of the position at a later time to check for
progress or developments of an ailment or a treatment, or to allow
re-treatment at the same site. As an example, tissue marking can be
used during biopsy or other tissue-removal procedures to accurately
mark the site of the tissue-removal or biopsy, to allow a
treatment-giver to later return to the same site if desired, e.g.,
to monitor the status of the tissue in question, or to do another
biopsy.
[0002] Such tissue marking can be useful in procedures relating to
colon or rectum biopsies or tissue removal, prostrate biopsies, or
breast biopsies.
[0003] Specifically with respect to breast biopsies, it is not
uncommon in modern breast biopsies, e.g., using a mammotone breast
biopsy system sold under the trademark name BIOPSYS, from Ethicon
Endo-Surgery, Inc., for all evidence of a lesion to be removed
during biopsy. Removing all trace of the tissue also removes
identifying features from the site, and makes it difficult to
return to the same location later, to re-check the site. This
dilemma, created by a removal of a potentially malignant breast
mass or cluster of microcalcifications during core biopsy, can be
ameliorated by placing radiographically visible markers immediately
after the biopsy. The marker, e.g., a radiopaque material, can be
used to help locate the biopsy site in case malignancy is
determined, thereby enabling return to the same site and optionally
a subsequent treatment such as surgical excision, even if the
mammographic findings associated with the original lesions were
removed completely.
[0004] One localization method involves placing a metallic clip
(e.g., sold under the trade name Micromark.TM., from Biopsys
Medical) through an 11-or14-gauge probe of a motorized, vacuum
core-cutting biopsy device, and attaching the clip to the site of a
biopsy, to mark the location of the biopsy. Such clips measure
approximately 3 mm across, and are permanent and radiopaque. The
use of marking clips has been described in the following articles:
Burbank, Fred, MD, Farcier, Nancy, MD, "Tissue Marking Clip for
Stereotactic Breast Biopsy: Initial Placement Accuracy, Long-term
Stability, and Usefulness as a Guide for Wire Localization,"
Radiology 1997; 205:407-415; Liberman, Laura, MD, Dershaw, David,
MD, Morris, Elizabeth A., MD, Abramson, Andrea F., MD, Thorton,
Cynthia M., RT (R)(M), Rosen Paul Peter, MD, "Clip Placement After
Stereotactic Vacuum-Assisted Breast Biopsy," Radiology, 1997;
205:417-422.
[0005] Another example of an application for tissue marking is in
prostate biopsies. It is recognized that initial biopsies may not
be fully determinative in the prostate. See, e.g., Jonathan I., MD,
"Are You Getting Maximum Diagnostic and Prognostic Information from
your Prostate Needle Biopsy?" Contemporary Urology, 106, April
1999. Tissue marking can ensure that the tissue of
non-determinative initial biopsies can be monitored for progressive
disease, and that if necessary a follow-up biopsy can be performed
at the site of the initial biopsy.
[0006] Other methods of tissue marking or "localization" are
described in articles of the technical literature: see e.g.,
Fajardo, Laurie L., MD, Bird, Richard E., MD, Herman, Cheryl R.,
MD, DeAngalis, Gia A., MD, "Placement of Endovascular Embolization
Microcoils to Localize the Site of Breast Lesions Removal at
Sterotactic Core Biopsy," Radiology, 1998, 206: 275-278. Still
another method of localizing breast lesions is described at
Goldberg, Ronald P., MD, Hall, Ferris M., M.D., and Simon, Morris,
MD. "Preoperative Localization of Non-Palpable Breast Lesions Using
a Wire Marker and Perforated Mammographic Grid," Radiology 146:
833-835, March 1983; see also U.S. Pat. Nos. 4,341,220 and
5,665,092.
SUMMARY OF THE INVENTION
[0007] The invention provides a method of tissue marking. The
method includes the use of detectable, preferably radiopaque
particles delivered to a tissue site for later detection. The
particles can preferably be delivered into the body to a desired
site by injection using a hypodermic needle and syringe, or another
similar instrument, or percutaneously, with the assistance of a
biopsy probe. Microparticles can preferably be of an average size
in the range from about 100 to 1000 microns, more preferably from
about 200 to 500 microns, and most preferably from about 251 to
about 300 microns, in transverse, cross-sectional dimension. The
microparticles can preferably be permanently radiopaque, and may
optionally comprise a carbon coating.
[0008] An optional carbon surface may include, for example,
pyrolytic carbon, e.g., isotropic carbon such as low temperature
isotropic carbon, vitreous carbon, or any other useful form of
carbon. The carbon can be coated onto a particle substrate as a
thin coating or film, thereby creating a particle having a highly
biocompatible carbon surface. While not required, pyrolytic carbon
can be preferred.
[0009] The particle substrate can be but is not necessarily
biocompatible, and should be capable of withstanding the conditions
of the process for coating a carbon surface onto the substrate,
which might include elevated temperatures. In particularly
preferred embodiments, particle substrates can be radiopaque, most
preferably permanently radiopaque. Exemplary radiopaque materials
can include metals and metal oxides such as zirconium oxide and
aluminum oxide, gold, titanium, silver, stainless steel, oxides and
alloys thereof, etc.
[0010] The microparticles can be delivered using a fluid carrier,
which can be any biologically compatible material capable of
delivering the microparticles to a desired tissue site, such as a
biologically compatible suspension, solution, or other form of a
fluid or gel. Examples of materials useful in biologically
compatible carriers include saline, dextrans, glycerol,
polyethylene glycol, corn oil or safflower, other polysaccharides
or biocompatible polymers, methyl cellulose, glucan, agarose, etc.,
either singly or in combination.
[0011] The use of microparticles in tissue marking methods,
preferably by injecting through a hypodermic needle and syringe or
a like instrument, has advantages over other tissue marking
methods. For instance, delivery of microparticles using a needle
and syringe allows very precise delivery of microparticle markers
to a desired tissue site; this is particularly true if a biopsy
probe used to perform a biopsy is used to assist delivery of
microparticles for tissue marking, without first moving the biopsy
sheath. Additionally, microparticles can be used in tissue
locations where other types of tissue markers are not or cannot be
used. For example, some tissue locations such as the colon or
rectum do not lend themselves to the use of marking clips, yet it
is possible to deliver microparticles to these locations for
effective marking. And, embodiments of useful microparticles having
a carbon-coated surface are very biocompatible. As another
advantage, preferred embodiments of the microparticles can be
permanently radiopaque, e.g., by virtue of a permanently radiopaque
particle substrate. The location of permanently radiopaque
particles can be monitored, by known methods, for as long as the
radiopaque microparticles remain in a body.
[0012] An aspect of the invention relates to a method for tissue
marking. The method includes delivering detectable microparticles
to a tissue site and detecting the microparticles.
[0013] Another aspect of the invention relates to a method of
tissue marking. The method includes injecting detectable
microparticles to a tissue site through a hypodermic needle, and
detecting the microparticles.
[0014] Yet another aspect of the invention relates to a method for
marking a biopsy. The method includes performing a biopsy and
marking the site of the biopsy using detectable microparticles
injected through a hypodermic needle.
[0015] Yet another aspect of the invention relates to a method for
marking a site of tissue removal. The method includes performing a
tissue removal procedure and marking the site of the tissue removal
using detectable microparticles injected through a hypodermic
needle.
[0016] For purposes of the present disclosure, the following terms
shall be given the following meanings.
[0017] The term "biocompatible," refers to materials which, in the
amount employed, are non-toxic and substantially non-immunogenic
when used internally in a patient, and which are substantially
insoluble in blood. Suitable biocompatible materials include
ceramics, metals and metal oxides such as titanium, gold, silver,
stainless steel, oxides thereof, aluminum oxide, zirconium oxide,
etc., carbon such as pyrolytic carbon or low temperature or ultra
low temperature isotropic carbon.
[0018] The term "detectable" refers to materials capable of being
detected during or after injection into a mammalian subject, by
methods generally used for monitoring and detecting such materials,
e.g. magnetic resonance, X-ray, ultrasound, magnetotomography,
electrical impedance imaging, light imaging (e.g. confocal
microscopy and fluorescence imaging) and nuclear imaging (e.g.
scintigraphy, SPECT and PET). Examples include contrast-enhancing
agents such as radiopaque materials. Contrast-enhancing agents may
be either water soluble or water insoluble. Examples of water
soluble radiopaque materials include metrizamide, iopamidol,
iothalamate sodium, iodomide sodium, and meglumine. Examples of
water insoluble radiopaque materials include metals and metal
oxides such as gold, titanium, silver, stainless steel, oxides
thereof, aluminum oxide, zirconium oxide, etc.
DETAILED DESCRIPTION
[0019] The invention provides methods of marking tissue for any
reason, such as to mark the site of the removal of a tissue, e.g.,
the removal of a polyp from a colon or rectum; to mark the site of
a biopsy, including a breast biopsy, a prostate biopsy, a colon
biopsy, a rectum biopsy; or to mark the site of any other medical
procedure or removal of tissue or biopsy at another tissue
location. The tissue may be marked for any reason, for example to
return to the same tissue site to monitor the progress of a medical
condition or a treatment, or to perform a subsequent biopsy at the
same site. Or, the tissue may be marked to provide a target for
radiation treatment, i.e., detectable microparticles can be
delivered to a tissue site to act as a target at which or near a
beam of radiation can be precisely directed.
[0020] The invention, generally stated, involves marking a tissue
site using detectable microparticles, preferably that are also
biocompatible. The microparticles contain some detectable component
(some well-known detectable components are referred to as a
"contrast-enhancing agent") that causes the microparticles to be
detectable, e.g., allows the microparticles to be tracked,
monitored, or otherwise detected by known methods, including
radiography or fluoroscopy. The detectable component, e.g.,
contrast-enhancing agent, can be any material capable of enhancing
contrast in a desired imaging modality (e.g. magnetic resonance,
X-ray, ultrasound, magnetotomography, electrical impedance imaging,
light imaging (e.g. confocal microscopy and fluorescence imaging)
and nuclear imaging (e.g. scintigraphy, SPECT and PET)).
Contrast-enhancing agents are well known in the medical arts, with
any of a variety of such contrast-enhancing agents being suitable
for use according to the methods of the invention
[0021] A detectable component is preferably capable of being
substantially immobilized within a microparticle, and may be
incorporated into a microparticle for use in tissue marking in any
of a variety of ways, e.g., as part of a particle substrate, as a
surface coating or an additive to a surface coating such as a
carbon coating, or elsewhere. In one sense, a detectable component
can be added to a material that is not detectable, e.g., not
radiopaque. The detectable component may be provided in any
location or portion of a microparticle, by known methods. Preferred
detectable materials, and their compositions with respect to
microparticles, are described below.
[0022] According to a preferred mode of the invention, the
microparticles comprise a permanently radiopaque material which can
be permanently detected within a body following delivery to a
tissue site. Permanent radiopacity is unlike contrast-enhancing
agents or radiopaque materials which biodegrade or otherwise lose
their effectiveness (detectability, e.g., radiopacity) over a
period of time, e.g., days or weeks, such as 7 to 14 days. (See,
e.g., PCT/GB98/02621). An advantage of permanent radiopaque
materials is that they can be detected for as long as they remain
in a body, whereas non-permanent radiopaque materials or other
types of contrast-enhancing agents are detectable for only a
limited time. See generally, Assignee's copending U.S. patent
application Ser. No. 09/602,323, entitled Embolization Using Carbon
Coated Microparticles, and filed on Jun. 23, 2000, the full
disclosure of which is incorporated herein by reference.
[0023] Some examples of radiopaque materials include paramagnetic
materials (e.g. persistent free radicals) and compounds, salts, and
complexes of paramagnetic metal species (for example transition
metal or lanthanide ions); heavy atom (i.e. atomic number of 37 or
more) compounds, salts, or complexes (e.g. heavy metal compounds,
iodinated compounds, etc.); radionuclide-containing compounds,
salts, or complexes (e.g. salts, compounds or complexes of
radioactive metal isotopes or radiodinated organic compounds); and
superparamagentic materials (e.g. metal oxide or mixed oxide
particles, particularly iron oxides). Preferred paramagnetic metals
include Gd (III), Dy (III), Fe (II), Fe (III), Mn (III) and Ho
(III), and paramagnetic Ni, Co and Eu species. Preferred heavy
metals include Pb, Ba, Ag, Au, W, Cu, Bi and lanthanides such as
Gd, etc.
[0024] The amount of detectable material included in a
microparticle used for tissue marking should be sufficient to allow
detection of the microparticle as desired. The amount used in any
particular application or microparticle may depend on various
factors such as the size of the microparticles, the total amount of
microparticles delivered, the type of contrast-enhancing agent,
etc. According to some embodiments of the invention, microparticles
can be made up of 100 percent radiopaque material. Alternatively,
for radiopaque particles that are coated with a carbon surface,
e.g., as described below, the microparticles can have any relative
amounts of radiopaque particle substrate to carbon coating that
will allow the microparticles to be used as detectable tissue
markers, for example from about 50 to 100 percent by weight
radiopaque particle substrate based on the total weight of the
particle substrate and the carbon coating. Optionally, some, i.e.,
only a portion, but not all microparticles used in a particular
tissue marking procedure (tissue marking composition, as described
below) can include a detectable component.
[0025] In one preferred embodiment of the invention, the
microparticles are completely made up of permanently radiopaque
material, preferably in a form that is biologically compatible, and
are delivered directly to a tissue site as such.
[0026] In another embodiment, microparticles for tissue marking
according to the invention can have a surface that comprises
carbon. The carbon-containing particle surface may be in the form
of a carbon-containing coating or carbon-containing film of any
type of carbon, e.g., pyrolytic carbon (such as low temperature
isotropic or LTI carbon), another type of isotropic carbon, or
vitreous carbon, preferably in a form that is biocompatible.
Various forms of carbon are described in the article "Material
Properties and Applications of Pyrolite.RTM. Carbon," by Al Beavan,
as published in Materials Engineering, February 1990, incorporated
herein by reference. Examples of carbon coated particles are
described, e.g., in U.S. Pat. No. 5,792,478, the full disclosure of
which is incorporated herein by reference.
[0027] The atomic structure of both pyrolytic, e.g., LTI carbon,
and vitreous carbon is similar to graphite, a common form of
carbon, but the alignment between hexagonal planes of atoms is not
as well ordered as in graphite. Pyrolytic carbon is characterized
by a more chaotic atomic structure with warped hexagonal planes,
missing atoms, and generally a more turbostatic appearance. This
results in better bonding between layer planes. See Beavan.
[0028] The carbon-coated microparticles can preferably be
constructed as a particle substrate having a carbon surface, e.g.,
a particle substrate having a layer of carbon coated thereon. While
the substrate need not be biocompatible due to its being coated
with a preferably biocompatible layer comprising carbon, it can be
preferred that the particle substrate also be biocompatible.
[0029] Such carbon-coated microparticles may be prepared using any
of a variety of coating processes to deposit carbon onto a particle
substrate. A particle substrate can be selected for compatibility
with the coating process, meaning that it should be capable of
withstanding temperatures used in a given process for coating
carbon onto a particle substrate. Relatively hard metallic or
ceramic materials capable of withstanding high temperature
conditions of a coating process can generally be preferred
materials for a particle substrate. Metals, metal oxides, and
alloys, including but not limited to medical grade stainless steel,
silver, gold, titanium and titanium alloys, and oxide derivatives
of stainless steel or titanium or titanium alloys, are also
acceptable materials for the particle substrate, with aluminum
oxide, and zirconium oxide being especially suitable. Carbon itself
in any of its various forms, e.g., pyrolytic carbon, non-pyrolytic
carbon, isotropic carbon, graphite, or vitreous carbon, may be
useful as a particle substrate material. Thus, the microparticles
may include a carbon coating deposited on a carbon particle
substrate, and may be substantially or entirely made of carbon. In
one embodiment of the invention, both the particle substrate and
the carbon coating may comprise pyrolytic carbon.
[0030] Particle substrates intended to be coated with carbon,
whatever their composition, should be of sufficient diameter,
shape, and uniformity that they can be coated with carbon, as
described, to produce carbon-coated particles of a size, quality,
and nature as described herein. Preferably, the particle
substrates, prior to coating, can be selected and processed, e.g.,
milled, extruded, sifted, cleaned, filtered, or otherwise formed,
etc., to provide a desired combination of particle size, shape, and
quality, to result in coated particles of a desired size, shape,
and quality.
[0031] Pyrolytic carbon can be produced and coated onto a substrate
surface by known methods, e.g., as described in the Beavan article,
and in U.S. Pat. No. 5,792,478, cited above. Generally,
hydrocarbons and alloying gases are decomposed to prepare a
pyrolytic carbon coating on a particle substrate. The particle
substrates are included with the hydrocarbons and alloying gases in
a fluidized or floating bed at a temperature sufficient to cause
deposition of pyrolyzed carbon onto the substrate surface, e.g.,
from about 1200 to 1500C (see Beavan, p.2). Inert gas flow is used
to float the bed of particle substrates, optionally including an
inert mixing media. The hydrocarbon pyrolysis results in a high
carbon, low hydrogen content carbon material being deposited as a
solid material onto the particle substrates.
[0032] Alternatively, a carbon coating (sometimes referred to as
"ultra-low-temperature isotropic carbon") may be applied to a
particle substrate using any one of other various coating processes
for depositing carbon, e.g., a vacuum vapor deposition process.
Such a method uses ion beams generated from any of a variety of
known processes, such as the disassociation of CO.sub.2, reactive
dissociation in vacuum of a hydrocarbon as a result of a glow
discharge, sublimation of a solid graphite source, or cathode
sputtering of a graphite source. Gold has been found to be an
especially suitable substrate material for vacuum vapor deposited
carbon. Other substrates, including but not limited to nickel,
silver, stainless steel, or titanium are also quite acceptable as a
substrate material for this type of coating process.
[0033] The high strength, resistance to breakdown or corrosion, and
durability of a carbon surface ensures effective, long term
functioning of microparticles in tissue marking applications. The
established biocompatibility of carbons such as pyrolytic and
vitreous carbon makes the described particles particularly suitable
for tissue marking applications. The microparticle substrates may
be completely encased by a carbon surface. This results in a smooth
coated particle with no substrate exposure on the surface of the
particle. Preferred carbon coatings can be in the range of
fractions of thousandths of an inch, e.g., about one half of a
thousands of an inch (0.0005 inches), on average, covering the
surface of the particle substrate.
[0034] The microparticles, whether coated or uncoated, are
preferably generally rounded particles that have a smooth surface.
The smooth surface enhances passage of the microparticles through a
hypodermic needle. Microparticles are preferably subjected to a
cleaning and sieving process to remove contaminants and to separate
out particles of a size less than or greater than a desired size
range. The particles may preferably range in size from 100 microns
to 1,000 microns in average, transverse cross-sectional dimension,
preferably in the range from about 200 to 500 microns, and a
particularly preferred size range for use in tissue marking
applications can be between about 251 and about 300 microns. To
achieve this most preferred such size range, microparticles may be
processed, e.g., segregated to a selected size range, for example
using a sieving process such that the minimum microparticle
dimension will pass through a U.S. No. 50 Screen Mesh (300 micron
grid size opening) but will not pass through a U.S. No. 60 Screen
Mesh (250 micron grid size). That minimum dimension will be the
transverse, cross-sectional dimension on oblong or elongated
particles, with that dimension coinciding with the particle
diameter on generally spherical particles.
[0035] Microparticles can be delivered to a tissue site using any
instrument or apparatus that can be used to inject an amount of
microparticles, preferably contained or suspended in a carrier,
through the skin, mucosa, or through an incision in the skin, to a
desired tissue site. Preferred instruments include instruments such
as hypodermic needles or other similar needle-like apparatuses,
such as any small bore instrument, cannula, etc. (All of these
types of instruments will be referred to collectively herein, for
convenience, using the term "hypodermic needle" or "needle.") The
particular instrument used for delivery is not critical, provided
that its components are compatible with the tissue marking
composition (described below) (i.e., the apparatus components will
not readily degrade in the tissue marking composition, and vice
versa).
[0036] According to one specific example of a method of delivering
microparticles for tissue marking, microparticles can be delivered
using a hypodermic needle and a syringe, by inserting the
hypodermic needle into a desired tissue site, followed by delivery
of the microparticles to the tissue site.
[0037] Optionally, any of a variety of surgical or non-invasive or
minimally-invasive surgical instruments can also be used to assist
in delivery. For example, following removal of a polyp from a colon
or a rectum, by known surgical methods, a hypodermic needle can be
inserted through the mucosa, at the site of the polyp, to deliver
microparticles. As another example, relating to breast biopsies, a
mammotone inserted through a small incision in the skin can be
maintained in the operative position, and a needle can be inserted
through its sheath, to precisely deliver microparticles to the site
of biopsy.
[0038] Once a needle is in place (e.g., during or soon after a
biopsy or tissue removal has been performed) microparticles can be
slowly injected through the needle to the desired tissue site. The
microparticles are of a size that can be effectively deposited
through a hypodermic needle or like instrument, and that will
substantially remain at the tissue site where delivered. If the
particles are too small, they can be engulfed by the body's white
cells (phagocytes) and carried to distant organs or be carried away
in the microvasculature and travel until they reach a site of
sufficient constriction to prevent further movement. On the other
hand, particles should not be so large that they cannot be
effectively delivered using a hypodermic needle or the like. For
the method of the present invention, a particularly preferred,
average microparticle size can be from about 100 to 1000 microns,
e.g., 200 to 500 microns, preferably from about 251 to 300 microns,
because sizes can allow injection through small bore instruments
and are large enough to avoid migration of the microparticles from
the injection site. See generally, Malizia, Anthony A., Jr.,
Reiman, Herbert M., Meyers, Robert P., Sande, Jonathan R., Barham,
Steven S., Benson, Ralph C., Jr., Dewanjee, Mrinal K., and Utz,
William J., "Migration and Granulomatous Reaction After
Periurethral Injection of Polytef (Teflon)," JAMA, Jun. 22/29, 1984
volume 251, No. 24.
[0039] The use of microparticles in tissue marking methods,
preferably injected by use of a needle and syringe or a like
instrument, has advantages over the use of other tissue marking
methods. For instance, delivery of microparticles using a needle
and syringe allows very precise delivery of microparticles to a
desired tissue site. This is particularly true if the biopsy probe
used to perform a biopsy is immediately subsequently used to
delivery the microparticles, without first moving the probe sheath.
Other advantages are that microparticles can be used where other
types of tissue markers either cannot be used, or are not used.
Specifically, tissue-marking clips are not used in the colon or
rectum, whereas microparticles can be injected to these tissues.
Additionally, tissue marking clips can sometimes be inadvertently
attached to tissue that will move and cause movement of the clip,
such as a ligament. The injection of microparticles avoids such
problems.
[0040] The amount of microparticles introduced in a tissue marking
procedure can be any amount sufficient to mark a location to be
detected at a later time. The amount delivered can vary depending
on factors such as the size of the microparticles the amount of
detectable component in the microparticles factors relating to the
patient, etc. Such factors will be within the skill of an artisan
of ordinary skill in the medical or tissue marking arts, and such
an artisan will be able to understand what is a useful amount of
microparticles for delivery to body tissue sites.
[0041] According to the invention, the microparticles can be
contained and used for delivery in a tissue marking composition
comprising an injectable combination of microparticles in a
biocompatible carrier. The carrier can be any biocompatible fluid
capable of delivering the microparticles to a desired tissue site.
A carrier may include, for example, a biologically compatible
suspension, solution, or other form of a fluid or gel. Examples of
materials useful in biologically compatible carriers include
saline, dextrans, glycerol, polyethylene glycol, corn oil or
safflower oil, other polysaccharides or biocompatible polymers,
methyl cellulose, glucan, agarose, etc., either singly or in
combination.
[0042] The carrier can preferably be an aqueous suspension or
solution, other fluid, or gel of polymeric chains of B-D glucose,
commonly referred to as .beta.-glucan. The glucose units are linked
to each other at the 1-3, 1-4, or 1-6 positions and form polymeric
chains ranging to several thousand daltons in weight.
[0043] .beta.-glucan is a naturally occurring constituent of cell
walls in essentially all living systems including plants, yeast,
bacteria, and mammalian systems. Its effects and modulating actions
on living systems have been studied extensively (see Abel, G., and
Czop, J.K., "Stimulation of Human Monocyte B-glucan Receptors by
Glucan Particles Induces Production of TNF-.differential. and
1L-B," Int. J. Immunopharmacol., 14(8):1363-1373, 1992 and
references included therein). .beta.-glucan, when administered in
experimental studies, elicits and augments host defense mechanisms
including the steps required to promote healing by first intent,
thereby stimulating the reparative processes in the host system.
.beta.-glucan is removed from tissue sites through macrophagic
phagocytosis or by enzymatic destruction by serous enzymes. The
destruction or removal of .beta.-glucan, as well as its available
viscosity and lubricous nature, make it a useful carrier for the
microparticles in tissue marking applications.
[0044] Aqueous solutions, suspension, fluids, or gels of
.beta.-glucan can be produced that have favorable physical
characteristics as a carrier for microparticles in tissue marking
applications. The viscosity can vary from a thin liquid to a firm,
self-supporting gel. Irrespective of viscosity, the .beta.-glucan
has excellent lubricity, thereby creating a particle-carrier
composition which is easily administered by delivery to a
predetermined body site through a small bore needle. A preferred
.beta.-glucan composition is .beta.-D-glucan containing
4-0-linked-.beta.-D-glycopyranosyl units and
3-0-linked-.beta.-D-glycopyr- anosyl units. The carrier can be of
sufficient viscosity to assure that the microparticles remain
suspended therein, for a sufficient time duration to accomplish the
injection procedure.
[0045] Another example of a preferred carrier material is methyl
cellulose or another linear unbranched polysaccharide. Further
examples of appropriate carrier materials include agarose,
hyaluronic acid, polyvinyl pyrrolidone or a hydrogel derivative
thereof, dextran or a hydrogel derivative thereof, glycerol,
polyethylene glycol, succinylated collagen, liquid collagen,
oil-based emulsions such as corn or safflower, or other
polysaccharides or biocompatible organic polymers either singly or
in combination with one or more of the above-referenced
solutions.
[0046] The amount of microparticles to carrier in a tissue marking
composition can be any amount that will provide a tissue marking
composition that is flowable and injectable, and that will allow a
desired amount of microparticles to be delivered to a tissue site.
Preferred amounts of microparticles in a tissue marking composition
can be in the range from about 20 to 60 percent by volume, more
preferably from about 25 to 40 percent by volume.
[0047] In use, the tissue marking composition can typically be
injected in a fluid state, e.g., as a slurry, suspension, or
emulsion, through a needle, into a body tissue site. When deposited
into a body tissue, the carrier will be carried away into the body,
e.g., through the blood stream, and disperse or be destroyed. It is
necessary that at least some of the microparticles, preferably most
or substantially all of the microparticles, are substantially
immobile upon deliver to a tissue site for marking. Microparticles
used for tissue marking according to the invention are sufficiently
immobile to be used for tissue marking applications; if the
microparticles tend to move at all after delivery to a tissue site,
the microparticles generally will do so only up the path of the
needle used to inject them.
[0048] While subsequent portions of the description include
language relating specifically to tissue marking in breast biopsy
applications, all types of tissue marking applications are
considered to be within the contemplation of the present invention.
Examples include other types of biopsy applications such as colon,
rectum, or prostate biopsies, and non-biopsy applications including
tissue marking for other types of medical procedures such as tissue
removal, e.g., the removal of polyps from the rectum or colon. Or,
the tissue may be marked to provide a target for radiation
treatment, i.e., detectable microparticles can be delivered to a
tissue site to act as a target at which a beam of radiation can be
precisely directed. One of ordinary skill in the medical or biopsy
arts will understand and appreciate how detectable microparticles
can be used in these and other tissue marking or biopsy processes
e.g., by guiding a delivery apparatus to a desired body tissue and
delivering an amount of the microparticles to the site, for
detection at that site at a later time.
[0049] Factors that might be considered, controlled, or adjusted
for in applying the process to a particular tissue marking
application might include consideration of the composition of the
microparticles; the amount of microparticles to be delivered to the
body site; factors relating to the method of delivery including the
particular equipment (e.g., needle or biopsy probe) used for
delivery, and the method and route used to place the dispensing end
of the delivery device at the desired body site; etc. All of these
factors will be appreciated by one of ordinary skill in the tissue
marking or medical arts, and can be readily dealt with to apply the
described methods to a wide variety of tissue marking
procedures.
[0050] Biopsy is a method by which a tissue sample is removed from
a site of a body to diagnose the tissue as healthy or diseased,
e.g., carcinogenic. Biopsies are performed on tissues of many
different body organs, including prostate and breast tissues. The
means used to perform the biopsy can include any equipment and
techniques generally known or useful in biopsy procedures.
[0051] Breast biopsies can be performed using stereotactic,
vacuum-assisted breast biopsy techniques and equipment therefore.
Such techniques and equipment involve the use of minimally invasive
instruments and techniques such as automated surgical biopsy
devices. These methods and devices relate to percutaneous
procedures that include inserting a needle-like instrument through
a very small incision in the breast to access the tissue mass of
interest and obtain a tissue sample for later examination and
analysis. See, e.g., U.S. Pat. No. 6,086,544, incorporated herein
by reference. It is not uncommon in modern breast biopsies, e.g.,
using a mammotone breast biopsy system sold under the trade name
BIOPSYS, from Ethicon Endo-Surgery, Inc., for all evidence of a
lesion to be removed during the biopsy.
[0052] According to the invention, detectable microparticles can be
used to mark the site of a biopsy, e.g., a breast biopsy. The
microparticles can be used to locate the biopsy site in case
malignancy is determined, thereby enabling a return to the site and
subsequent surgical treatment, e.g., excision, even if the
mammographic findings associated with the original lesions were
removed completely.
[0053] The detectable microparticles can be delivered to the site
of the breast biopsy using any sort of a needle delivery system.
According to a preferred method of the invention, microparticles
can be delivered using the same biopsy equipment, e.g., the same
biopsy sheath, as used to perform the biopsy, so as to achieve very
precise marking of the biopsied site.
[0054] A rabbit research study was conducted to evaluate potential
applications of radiopaque pyrolytic carbon coated zirconium oxide
beads.
[0055] The following is a summary of the study results:
[0056] Study Objective
[0057] The objective of the research study was to determine the
qualitative and quantitive persistence of the radiopaque pyrolytic
carbon coated beads.
[0058] Model Description
[0059] Rabbits were selected as the most appropriate species for
this study for the following reasons: Auricular injection has
frequently been used to quantify the persistence of materials. The
cartilage in the ear provides a substrate over which the material
can be inserted and subsequently measured. Migration from the
insertion site proximally can be readily observed. Rabbits also
provide a "non-growing" model. Therefore the effects of growth are
not a study factor. The relative constancy of the landmarks in a
smaller animal allows bony landmarks for dissection at
necropsy.
[0060] The study called for injection of the carbon coated beads
into rabbits in the following locations:
[0061] Ear subcutaneous tissue
[0062] Stomach/esophagus sub-mucosa
[0063] Large intestine/colon sub-mucosa
[0064] The rabbit's large intestine lining was found to be too thin
for the injection needle and so the efforts in this location were
abandoned; only the ear and stomach/esophagus locations were
possible.
[0065] A total of 5 rabbits had injections (0.5-1.0 ml) in both
ears and 2 rabbits had a total of 7 injections (0.25 ml each) in
the intestine/stomach location.
[0066] Measurements
[0067] Persistence in location was measured by radiography and
necropsy. Flat film radiographs were taken pre-and post-procedure
to document persistence and non-migration. Radiographs were taken
at sacrifice to document non-migration (stomach/esophagus).
[0068] Results
[0069] Ear
[0070] Procedure
[0071] Volumes between 0.5-10 ml of beads were injected in both
ears of 5 rabbits. The beads were injected subcutaneously between
the skin and the auricular cartilage on the convex surface of the
ear using disposable 16-gauge needles. All ears were examined after
injection and a x-ray of the ear was taken for record purposes.
[0072] 1 Week Post-procedure
[0073] There were no evidence of swelling, inflammation or edema
associated with the injection site or the injections.
[0074] 2 Weeks Post-procedure
[0075] Minor reddish and swelling around each injected bulk was
observed.
[0076] 3 Weeks Post-procedure
[0077] All injection sites were easily visible with little evidence
of redness or swelling.
[0078] 5 Weeks Post-procedure
[0079] At 5 weeks post-procedure, rabbits #1 and #2 were
necropsied.
[0080] The ears as well as the internal organs were examined
grossly. Upon dissection of the periauricular tissue on the skull
and anterior and posterior to the base of the ear, no beads were
observed in the tissues.
[0081] The ears were examined for migration of beads from the site
of injection. The examinations were accomplished by
tran-illuminating the tissues with bright light. No particles were
observed beyond the boundaries of the lesions.
[0082] Stomach/Esophagus
[0083] Procedure
[0084] Using the gastric model, multiple sub-serosal injections
were made along the greater curvature of the stomach. Approximately
0.25 ml of material was injected at each of 4 sites in one rabbit
and 3 sites in another rabbit. The injections were made using a
1-ml syringe of material and a 16-gauge needle.
[0085] 2 Weeks Post-Procedure
[0086] Observations were consistent with that of the ear data.
[0087] 8 Week Post-Procedure
[0088] At 8 weeks post-procedure, following radiography, both
rabbits were necropsied. The following summarizes the results:
[0089] There was no apparent loss of beads or migration of beads
from the injection site.
[0090] No gross migration of particles on the surface of the
stomach or on the surface of the abdominal structures was
noted.
[0091] The injection sites appeared well healed with no evidence of
erythema or swelling noted in or about the injection sites.
[0092] Gross examination of the abdominal structures did not
demonstrate any gross abnormalities.
[0093] Summary Of Study
[0094] Radiopaque carbon coated beads were injected subcutaneously
between the skin and the auricular cartilage on the convex surface
of ears, and subs-serosally along the greater curvature of the
stomach in rabbits. Weekly examination demonstrated minimal
inflammatory response to the injected area. At 5 weeks (ear) and 8
weeks (stomach/esophagus) post-procedure the radiopaque beads
appeared stable in place.
* * * * *