U.S. patent application number 10/684124 was filed with the patent office on 2004-05-27 for biopsy site marker and process and apparatus for applying it.
This patent application is currently assigned to SenoRx, Inc.. Invention is credited to Burbank, Fred H., Forcier, Nancy, Jones, Michael L., Lubock, Paul.
Application Number | 20040101479 10/684124 |
Document ID | / |
Family ID | 23348485 |
Filed Date | 2004-05-27 |
United States Patent
Application |
20040101479 |
Kind Code |
A1 |
Burbank, Fred H. ; et
al. |
May 27, 2004 |
Biopsy site marker and process and apparatus for applying it
Abstract
A biopsy site marker comprises small bodies or pellets of
gelatin which enclose substantially in their interior a radio
(X-ray) opaque object. The gelatin pellets are deposited into the
biopsy site, typically a cylindrical opening in the tissue created
by the recent use of a vacuum assisted large core biopsy device, by
an applicator device that includes an elongated cylindrical body
that forms a flexible tube and a piston slidable in the tube. One
end of the tube is placed into the biopsy site. Typically, several
gelatin pellets, only some of which typically do, but all of which
may contain the radio opaque object, are deposited sequentially
into the site through the tube. The radio opaque objects contained
in the gelatin bodies are of a non-biological configuration and
readily identifiable as man-made object, so that in observation by
typical mammography equipment they do not assume the shape of a
line, whereby they are readily distinguishable from granules and
lines of calcification.
Inventors: |
Burbank, Fred H.; (San Juan
Capistrano, CA) ; Lubock, Paul; (Laguna Niguel,
CA) ; Jones, Michael L.; (Capistrano Beach, CA)
; Forcier, Nancy; (Laguna Niguel, CA) |
Correspondence
Address: |
Edward J. Lynch
DUANE MORRIS LLP
Spear Tower, Suite 2000
One Market
San Francisco
CA
94105
US
|
Assignee: |
SenoRx, Inc.
|
Family ID: |
23348485 |
Appl. No.: |
10/684124 |
Filed: |
October 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10684124 |
Oct 10, 2003 |
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10001043 |
Oct 31, 2001 |
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6662041 |
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10001043 |
Oct 31, 2001 |
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09343975 |
Jun 30, 1999 |
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6347241 |
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09343975 |
Jun 30, 1999 |
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09241936 |
Feb 2, 1999 |
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6161034 |
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Current U.S.
Class: |
424/9.42 |
Current CPC
Class: |
A61M 37/0069 20130101;
A61K 49/006 20130101; A61B 2090/3908 20160201; A61B 10/02 20130101;
A61B 2017/00004 20130101; A61B 90/39 20160201; A61B 2090/3987
20160201; A61B 2090/3933 20160201; A61B 2090/395 20160201 |
Class at
Publication: |
424/009.42 |
International
Class: |
A61K 049/04 |
Claims
What is claimed is:
1. A biopsy site marker comprising: a body of gelatin, and an X-ray
detectable body of specific predetermined non-biological
configuration embedded in said body of gelatin.
2. A biopsy site marker in accordance with claim 1 where the X-ray
detectable body is comprises metal.
3. A biopsy site marker in accordance with claim 2 where the X-ray
detectable body comprises stainless steel.
4. A biopsy site marker in accordance with claim 1 where the X-ray
detectable body comprises ceremic materials or metal oxides.
5. A biopsy site marker in accordance with claim 1 additionally
comprising a plurality of air bubbles embedded in said body of
gelatin.
6. A biopsy site marker in accordance with claim 1 wherein the
gelatin has a Bloom rating in the range between approximately 150
to 300 Bloom.
7. A biopsy site marker in accordance with claim 6 wherein the
gelatin has a Bloom rating in the range between approximately 200
to 300 Bloom.
8. A biopsy site marker in accordance with claim 1 wherein the body
of gelatin is dehydrated.
9. A biopsy site marker comprising: a body of gelatin that has a
bloom rating in the range between approximately 150 to 300 Bloom; a
plurality of air bubbles embedded in said body of gelatin, and an
X-ray detectable body of specific predetermined non-biological
configuration embedded in said body of gelatin.
10. A biopsy site marker in accordance with claim 9 wherein the
X-ray ray detectable body of specific predetermined non-biological
configuration comprises metal.
11. A biopsy site marker in accordance with claim 10 wherein the
X-ray detectable body of specific predetermined non-biological
configuration comprises stainless steel.
12. A biopsy site marker in accordance with claim 9 wherein the
body of gelatin is configured in the shape of a cylinder.
13. A biopsy site marker in accordance with claim 9 wherein the
body of gelatin is dehydrated.
14. A biopsy site marker in accordance with claim 12 wherein the
body of gelatin is dehydrated and is approximately of 1 to 3 mm in
diameter and is approximately 5 to 10 mm long.
15. A biopsy site marker in accordance with claim 14 wherein the
body of gelatin is approximately of 2 mm in diameter and is
approximately 8 mm long.
16. A biopsy site marker in accordance with claim 15 wherein the
body of gelatin has a Bloom rating in the range between
approximately 200 to 300 Bloom.
17. A biopsy site marker in accordance with claim 10 wherein the
X-ray detectable body of specific predetermined non-biological
configuration is configured substantially in the shape of a Greek
letter gamma (.gamma.).
18. A biopsy site marker in accordance with claim 17 wherein the
X-ray detectable body of the Greek letter gamma (.gamma.)
configuration consists essentially of an electrochemically etched
stainless steel body.
19. An applicator device for a biopsy site marker, the device
comprising: an elongated cylindrical body that forms a flexible
tube and includes a cylindrical cavity having an internal lumen, an
open end and a closed end and a ramp-shaped opening in proximity of
the closed end; and a piston that is moveable back and forth in the
cylindrical cavity forming the tube, the tube being adapted to be
loaded in the internal lumen with a plurality of biopsy site marker
bodies comprising dehydrated gelatin said marker bodies being
disposed between the end of the piston and the ramp-shaped opening
when the piston is extended outwardly from the cylindrical
cavity.
20. An applicator device in accordance with claim 19 wherein the
elongated cylindrical body has an internal diameter of
approximately 0.070".
21. In combination: an applicator tube having an internal lumen, an
open end and a closed end and a ramp-shaped opening in proximity of
the closed end; a flexible rod dimensioned to fit into and be
slidable in the internal lumen, and a plurality of biopsy site
markers comprising a body of dehydrated gelatin, and an X-ray
detectable body of specific predetermined non-biological
configuration embedded in said body of gelatin, said biopsy site
markers being enclosed in the internal lumen, from where they can
be pushed out with the flexible rod through the ramp-shaped opening
into a biopsy site.
22. The combination in accordance with claim 21 wherein the X-ray
detectable body of the biopsy site markers comprises metal.
23. The combination in accordance with claim 21 where the X-ray
detectable body of the biopsy site markers comprises stainless
steel.
24. The combination in accordance with claim 21 wherein the X-ray
detectable body of the biopsy site markers comprises ceramic
materials or metal amides.
25. The combination in accordance with claim 21 where the biopsy
site markers additionally comprise a plurality of air bubbles
embedded in said body of gelatin.
26. The combination in accordance with claim 21 wherein the gelatin
of the biopsy site markers has a Bloom rating in the range between
approximately 150 to 300 Bloom.
27. The combination in accordance with claim 26 wherein the gelatin
of the biopsy site markers has a Bloom rating in the range between
approximately 200 to 300 Bloom.
28. The combination in accordance with claim 21 further comprising
at least one biopsy site marker that has a body of dehydrated
gelatin, and lacks the X-ray detectable body of specific
predetermined non-biological configuration embedded in said body of
gelatin.
29. The combination in accordance with claim 28 comprising an array
of a plurality of said biopsy site markers having said X-ray
detectable body of specific predetermined non-biological
configuration and a plurality of said biopsy site markers having a
body of dehydrated gelatin and lacking the X-ray detectable body of
specific predetermined non-biological configuration, said array
being enclosed in the internal lumen.
30. The combination in accordance with claim 29 wherein said biopsy
site markers having said X-ray detectable body of specific
predetermined non-biological configuration and said biopsy site
markers having a body of dehydrated gelatin and lacking the X-ray
detectable body of specific predetermined non-biological
configuration alternate in said array.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is in the field of markers to be
employed at biopsy sites to permanently mark the site, and to
methods and apparatus for applying the permanent marker. More
particularly, the present invention relates to a marker that is
optimally adapted for marking biopsy sites in human breast tissue
with permanently placed markers that are detectable by X-ray.
[0003] 2. Brief Description of the Background Art
[0004] In modern medical practice small tissue samples, known as
biopsy specimens, are often removed from tumors, lesions, organs,
muscles and other tissues of the body. The removal of tissue
samples may be accomplished by open surgical technique, or through
the use of a specialized biopsy instruments such as a biopsy
needle. A well known state-of-the-art instrument that is often used
in connection with the practice of the present invention is known
as the "vacuum assisted large core biopsy device".
[0005] After a tissue sample has been removed, it is typically
subjected to diagnostic tests or examinations to determine
cytology, histology, presence or absence of chemical substances
that act as indicators for disease states, or the presence of
bacteria or other microbes. The above mentioned and other
diagnostic tests and examinations per se are well known in the art
and need not be described here. It is sufficient to note that the
information obtained from these diagnostic tests and/or
examinations is often of vital importance for the well-being of the
patient and is used to make or confirm diagnoses and often to
formulate treatment plans for the patient. As is known, obtaining a
tissue sample by biopsy and the subsequent examination are
frequently, almost invariably, employed in the diagnosis of cancers
and other malignant tumors, or to confirm that a suspected lesion
or tumor is not malignant, and are frequently used to devise a plan
for the appropriate surgical procedure or other course of
treatment.
[0006] Examination of tissue samples taken by biopsy, often by the
above-mentioned "vacuum assisted large core biopsy sampler" is of
particular significance in the diagnosis and treatment of breast
cancer which is the most common cancer suffered by women in the
U.S.A and elsewhere in the industrially developed world. Proper
diagnostic procedures, frequent examination by well known
techniques such as "mammography" and prompt subsequent surgical
treatment have, however, significantly reduced the mortality rate
caused by this form of cancer. For this reason, in the ensuing
discussion of the pertinent background art and in the ensuing
description the invention will be described as used for marking
biopsy sites in human and other mammalian breast, although the
invention is suitable for marking biopsy sites in other parts of
the human and other mammalian body as well.
[0007] Thus, as is known, when an abnormal mass in the breast is
found by physical examination or mammography a biopsy procedure
follows almost invariably. The nature of the biopsy procedure
depends on several factors. Generally speaking, if a solid mass or
lesion in the breast is large enough to be palpable (i.e., felt by
probing with the fingertips) then a tissue specimen can be removed
from the mass by a variety of techniques, including but not limited
to open surgical biopsy or a technique known as Fine Needle
Aspiration Biopsy (FNAB). In open surgical biopsy, an incision is
made and a quantity of tissue is removed from the mass for
subsequent histopathological examination. In the FNAB procedure, a
small sample of cells is aspirated from the mass through a needle
and the aspirated cells are then subjected to cytological
examination.
[0008] If a solid mass of the breast is small and non-palpable
(e.g., the type typically discovered through mammography), a
relatively new biopsy procedure known as "stereotactic needle
biopsy" may be used. In performing a stereotactic needle biopsy of
a breast, the patient lies on a special biopsy table with her
breast compressed between the plates of a mammography apparatus and
two separate digital x-rays are taken from two slightly different
points of view. A computer calculates the exact position of the
lesion with X and Y coordinates as well as depth of the lesion
within the breast. Thereafter, a mechanical stereotactic apparatus
is programed with the coordinates and depth information calculated
by the computer, and such apparatus is used to precisely advance
the biopsy needle into the small lesion. Usually at least five
separate biopsy specimens are obtained from locations around the
small lesion as well as one from the center of the lesion.
[0009] After the biopsy sample is taken, it may take several days
or even a week before the results of the examination of the sample
are obtained, and still longer before an appropriate treatment
decision is reached. If the decision involves surgery it is clearly
important for the surgeon to find the location in the breast from
where the tumor tissue has been taken in the biopsy procedure, so
that the entire tumor and possibly surrounding healthy tissue can
be removed. For example, the particular treatment plan for a given
patient may require the surgeon to remove the tumor tissue and 1
centimeter of the tissue surrounding the tumor. A co-pending
application for United States Letters Patent by the same inventors
discloses markers which are particularly well adapted for marking
biopsy sites in the human breast, and which markers remain
detectable by X-ray, ultrasound or some other detection technique
only for a given time period (i. e. for 6 months) and slowly
disappear thereafter, for example by absorption into the body. The
purpose of such markers is to facilitate the surgical procedure
that is performed while the marker is still detectable. The
disappearance of the marker after a longer period of time may be
advantageous to avoid obscuring or interfering with follow-up
studies or further mammography or other imaging studies.
[0010] In connection with the background art the following specific
printed art is mentioned. U.S. Pat. Nos. 2,192,270 and 5,147,307
describe visually discernible markers that are applied externally
to the patient's skin. Radiographically (X-ray) detectable tissue
markers (e.g., clips or staples) that are attached to tissue
adjacent to the site from which the biopsy specimen has been
removed, are described in International Patent Publication No. WO
98/06346. Radiographically visible markers (e. g. marker wires)
that may be introduced into the biopsy site and are inserted
through the biopsy needle after a tissue sample is removed and
which are thereafter allowed to remain protruding from the
patient's body, are also described in WO 98/06346. However, due to
the consistency of breast tissue and the fact that these biopsy
site markers are typically introduced while the breast is still
compressed between the mammography plates, these biopsy markers of
the prior art may become attached to adjacent bands of connective
tissue that do not remain at the specific location of the biopsy
after the breast has been decompressed and removed from the
mammography apparatus, and may suffer from additional disadvantages
as well.
[0011] Thus, there is still a need in the art for of biopsy site
markers that are deliverable into the cavity created by removal of
the biopsy specimen and not into tissue that is located outside of
that biopsy cavity, and which will not migrate from the biopsy
cavity even when the breast tissue is moved, manipulated or
decompressed. Moreover, such desired markers should remain
detectable at the biopsy site i. e. within the biopsy cavity for an
indefinite time period, and still should not interfere with imaging
of the biopsy site and adjacent tissues at a later point of time,
and most importantly should be readily distinguishable in the
various imaging procedures from lines of calcifications which
frequently are signs for a developing malignancy. The present
invention provides such permanent biopsy site markers as well as
apparatus and method for delivering such markers into the biopsy
cavity.
SUMMARY OF THE INVENTION
[0012] It is an object of the present invention to provide a biopsy
site marker that is deliverable into the cavity created by removal
of the biopsy specimen.
[0013] It is another object of the present invention to provide a
biopsy site marker that does not migrate from the biopsy cavity
even when the surrounding tissue is moved, manipulated or
decompressed.
[0014] It is still another object of the present invention to
provide a biopsy site marker that meets the foregoing requirements
and that remains detectable at the biopsy site for an indefinite
period of time.
[0015] It is yet another object of the present invention to provide
a biopsy site marker that meets the foregoing requirements and that
is readily distinguishable by X-ray from granules or lines of
calcifications which frequently are signs for a developing
malignancy.
[0016] It is a further object of the present invention to provide
an apparatus and method for placing into the biopsy cavity a biopsy
site marker that meets the foregoing requirements.
[0017] These and other objects and advantages are attained by a
biopsy site marker that comprises small bodies or pellets of
gelatin which enclose substantially in their interior a radio
(X-ray) opaque object. The gelatin pellets are deposited into the
biopsy site, typically a cylindrical opening in the tissue created
by the recent use of a vacuum assisted large core biopsy device, by
injection from an applicator through a tube that is placed into the
biopsy site. Typically, several gelatin pellets, only some of which
typically do, but all of which may contain the radio opaque object,
are deposited sequentially from the applicator into the site
through the tube. The radio opaque objects contained in the gelatin
bodies have a non-biological shape or configuration to be
identifiable as a man-made object such that in observation by
typical mammography equipment, that is when viewed from at least
two different viewing angles, they do not assume the shape of a
line, whereby they are readily distinguishable from granules or
lines of calcification.
[0018] The features of the present invention can be best understood
together with further objects and advantages by reference to the
following description, taken in connection with the accompanying
drawings, wherein like numerals indicate like parts.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a perspective view of a preferred embodiment of
the biopsy site marker of the present invention.
[0020] FIG. 2 is a perspective view of a plurality of biopsy site
markers in accordance with the first embodiment of the present
invention.
[0021] FIG. 3 is a perspective view of an applicator apparatus in
accordance with the present invention, for depositing the biopsy
site marker at a biopsy site.
[0022] FIG. 4 is a perspective view of the applicator apparatus of
FIG. 3, showing the applicator with an extended piston indicating
that the applicator is loaded with biopsy site markers.
[0023] FIG. 5 is a cross-sectional view of the site marker shown in
FIG. 4, the cross section taken on lines 5,5 of FIG. 4.
[0024] FIG. 6 is an enlarged cross sectional view showing the
applicator of FIG. 4 loaded with biopsy site markers in accordance
with the present invention.
[0025] FIG. 7 is a schematic view of a human breast, showing a
biopsy cavity of the type obtained by a vacuum assisted large core
biopsy sampler, into which a plurality of biopsy markers are
deposited in accordance with the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] The following specification taken in conjunction with the
drawings sets forth the preferred embodiments of the present
invention. The embodiments of the invention disclosed herein are
the best modes contemplated by the inventors for carrying out their
invention in a commercial environment, although it should be
understood that various modifications can be accomplished within
the parameters of the present invention.
[0027] Referring now to the drawing figures and particularly to
FIGS. 1 and 2, a body 20 of gelatin or reconstituted collagen in
the shape of a pellet that includes or incorporates a radio-opaque
marker 22 of a definite shape is disclosed. The gelatin or
reconstituted collagen body 20 can be of virtually any shape or
configuration, however the herein shown shape of a cylinder or
pellet is preferred. The gelatin body of pellet 20 is of such size
that several of the pellets can be deposited in a biopsy site, such
as a typical biopsy site obtained by using the vacuum assisted
large core biopsy device that is frequently used in current medical
practice. The gelatin body or pellet 20 is stored and is applied,
that is deposited in the biopsy site, in a dehydrated form through
an applicator device that forms another aspect of this invention.
However, when the gelatin body or pellet 20 of the invention is not
deposited through the applicator device, it does not necessarily
need to be stored and applied in a dehydrated form. Nevertheless,
storing the gelatin pellets 20 in dehydrated form increases their
useful shelf-life and renders it easier to keep them sterile.
[0028] After having been deposited at the biopsy site the gelatin
marker 20 slowly absorbs moisture from the surrounding tissue and
becomes hydrated. In the dehydrated form, shown in the appended
drawing figures, the gelatin body or pellet 20 is approximately 1
to 3 mm in diameter and is approximately 5 to 10 mm long. The
presently preferred embodiment of the gelatin pellet 20 is
approximately 2 mm in diameter and is approximately 8 mm long.
After the pellet 20 has reached hydration equilibrium with the
surrounding tissue it becomes approximately 3 to 5 mm in diameter
and approximately 10 to 15 mm long. After hydration the presently
preferred embodiment of the pellet 20 is approximately 4 mm in
diameter and approximately 10 mm long.
[0029] The gelatin or reconstituted collagen material itself is
observed under ultrasound examination as a white spot because of
the air pockets usually entrapped in its matrix. In mammography the
gelatin is observed as dark spots in normal breast, because of the
presence of the air pockets. In a fatty breast viewed by
mammography the gelatin marker is observed as a lighter area
containing dark spots, due to the water in the hydrated gelatin
absorbing more energy than the surrounding matrix and the air
pockets within the matrix. A pellet 20 or plurality of pellets 20
due to their bulk may also be palpable and locatable by tactile
means within the breast tissue or other tissue. The gelatin or
reconstituted collagen marker itself can be made even more
radio-opaque by ion-impregnation and chelation techniques which are
described in detail in the aforesaid co-pending application Ser.
No. 09/241,936 filed on Feb. 2, 1999 by the same inventors in
connection with the description of biopsy markers of that
application, and the description of this method of rendering the
gelatin markers radio-opaque is also provided here below. The
disclosure of co-pending application Ser. No. 09/241,936 is
incorporated herein by reference in its entirety. The gelatin or
reconstituted collagen material can also be made more
radio-translucent by entrapping (mixing) a substantial amount of
air in the gelatin. Moreover, a visually detectable substance, such
as carbon particles, or a suitable dye (e. g. methylene blue or
indigo) may also be added to the gelatin to make the marker visible
by a surgeon during dissection of the surrounding breast
tissue.
[0030] The gelatin or reconstituted collagen per se does not serve
as a permanent marker of the biopsy site because it is eventually
reabsorbed by the body, although the dye or even ionic material
that made the gelatin visible or radio-opaque, respectively, may
remain at the site for longer time period than the palpable gelatin
pellet, and may remain there indefinitely. Factors which influence
how long the gelatin or reconstituted collagen pellet remains at
the site, and various means to adjust this time period are
described in the afore-mentioned co-pending application Ser. No.
09/241,936.
[0031] It is a novel and important aspect of the present invention
to incorporate into the gelatin or reconstituted collagen body or
pellet 20 the radio-opaque marker 22. The radio-opaque or X-ray
detectable marker 22 that is incorporated or enclosed in the
gelatin pellet 20 must have the following properties. First, by its
very nature it must be detectable by X-ray, including the type of
radiography used in the practice of mammography. It must be
comprised of a material or composition that is not absorbed by the
body and stays for indefinite time at the biopsy site, retains its
shape and remains X-ray detectable at the biopsy site also for an
indefinite time. The material or composition of the radio-opaque
marker 22 must, of course, be biocompatible at the site where it is
deposited. Another important requirement is that the biocompatible
marker must have an identifiable specific non-biological shape or
form. The purpose of specific form for the marker is to render the
marker distinguishable under X-ray or in a mamographic examination
from naturally formed calcification granules or a line of such
granules, which are also X-ray opaque. As is known, a line of
calcification which normally forms along ducts is considered a sign
of developing malignancy. Thus, the marker 22 should be of such
specific configuration that when it is viewed sterically, as during
a mammography examination, it should be distinguishable from an
X-ray opaque line. Numerous specific shapes or configurations
satisfy the foregoing requirements, however amorphous X-ray opaque
material that would be uniformly (or substantially uniformly)
distributed in the gelatin pellet 20 is unlikely to satisfy these
requirements.
[0032] Materials or compositions which are suitable for the marker
22 include metal, such as stainless steel, tantalum, titanium,
gold, platinum, palladium, various alloys that are normally used in
bioprosthesis and ceramics and metal oxides that can be compressed
into specific shapes or configurations. Among these the use of
biocompatible metals is presently preferred, and the herein
described preferred embodiment of the marker 22 is made of
stainless steel. Generally speaking the marker 22 is approximately
0.010 to 0.060 inches wide, approximately 0.030 to 0.200" long and
approximately 0.002 to 0.020" thick. The presently preferred
permanent marker 22 shown in the drawing figures has the
configuration or shape approximating an upside down turned Greek
letter gamma (.gamma.), is approximately 0.10" long and
approximately 0.040" wide. The upside-down Greek letter gamma
(.gamma.) shape is believed to be unique, has some resemblance to
the popular breast cancer awareness ribbon and is readily
distinguishable under X-ray and mammography as a "man-made" marker
object from any naturally formed X-ray opaque body. Various
manufacturing techniques which per se are well known in the art,
can be utilized to manufacture the X-ray opaque permanent marker
22. Thus, the marker 22 can be formed from wire, or can be
electrochemically etched or laser cut from metal plates. The
presently preferred embodiment of the gamma (.gamma.) shaped marker
22 is formed by electrochemical etching from stainless steel
plates.
[0033] FIGS. 1, 2 and the other drawing figures, as applicable,
show only one marker in the gelatin pellet 20, although more than
marker may be incorporated in the pellet 20. FIG. 1 discloses a
cylindrically shaped gelatin pellet 20 that in accordance with the
present invention includes the gamma (.gamma.) shaped stainless
marker 22, and as an optional feature also includes a dye or other
coloring material (e. g. indigo) that also stays substantially
permanently at the biopsy site and is visible by a surgeon when the
breast tissue is dissected, as in an operation where tumor tissue
is removed (lumpectomy).
[0034] Gelatin bodies or pellets 20 all of which include one or
more permanent radio opaque markers 22 in accordance with the
present invention may be deposited at a biopsy site. Alternatively,
a series of gelatin bodies or pellets 20 where only some but not
all include a permanent X-ray opaque marker 22 of unique
non-biological shape, may be deposited at the biopsy site.
Preferably, a series of pellets 20 are deposited where each second,
each third, or each fourth etc., pellet includes the marker 22.
FIG. 2 discloses an example of a series or sequence of pellets 20
where each second pellet 20 includes the metal marker 22 and where
each pellet 20 that does not include the metal marker 22 includes
carbon black or dye that is visible to the surgeon during
operation. In this connection it should be understood and
appreciated that as noted above the gelatin bodies or pellets 20
themselves serve a purpose of marking the biopsy site for a
predetermined length of time, that is until they become absorbed by
the body.
[0035] The drawing figures, particularly FIGS. 1 and 2 show the
metal marker 22 disposed substantially in the center of the
cylindrical gelatin pellet 20. This is preferred but is not
necessary for the present invention. The metal marker 22 can be
embodied in or included in the gelatin body 20 virtually anywhere.
The gelatin body or pellet 20 however has to have sufficient
integrity or firmness to retain the metal marker 22 and air bubbles
which are usually deliberately entrapped in the gelatin. As is
known, the firmness or bodily integrity of gelatin is measured in
units of Bloom. Generally speaking it was found in accordance with
the present invention that the higher the Bloom strength of the
gelatin used in the marker 20 the better the marker performs. The
higher Bloom strength gelatin holds gas bubbles within its matrix
better than lower Bloom strength gelatin. Gelatin with a Bloom
strength of approximately 150 especially 175 is adequate for the
practice of the present invention, but a more preferred range is
200 to 300 Bloom, the most preferred range being between 250 and
300. (For comparison, typical food gelatin is approximately 75
Bloom, and gelatin of 300 Bloom feels like a soft rubber
eraser.)
[0036] A description how to obtain gelatin or reconstituted
collagen bodies suitable for use as markers 20 with various
properties, before the permanent radio-opaque metal or like marker
22 of specific form is incorporated therein, is provided below in
connection with following examples.
Example of Radiographically Visible/Palpable Marker Material Formed
of Metal Ions In Combination With a Collagenous or Gelatinous
Matrix
[0037] U.S. Pat. No. 4,847,049 (Yamamoto incorporated herein by
reference) describes an ion-impregnation or chelation technique
whereby an ion may be impregnated or chelated to collagen for the
purpose of imparting antimicrobial properties to the collagen
preparation. Thus, using this technique, imageable ions such as
radiographically visible metal ions, may be bound to a bulky
collagenous material to form a marker 10 that may be a) imaged by
radiographic means and b) located by palpation of tissue
surrounding the biopsy site. For example, a silver ion-renatured
collagen composition may be prepared by the following process:
Step 1--Renaturation of Collagen (or Gelatin)
[0038] Collagen may be renatured to an insoluble form by processing
of denatured collagen that has been obtained from a natural source
such as bovine corium (hide), bovine tendon, and porcine skin.
Alternatively, pre-processed, insoluble collagen may be purchased
in the form of a commercially available hemostatic material such as
Collastat.TM. and Avitene.TM. nonwoven web. Methods for renaturing
collagen are known in the literature, including, for example, those
methods described in U.S. Pat. Nos. 4,294,241 and 3,823,212. The
specifications of U.S. Pat. Nos. 4,294,241 and 3,823,212 are
incorporated herein by reference.
[0039] A particularly preferred form of renatured collagen for
utilization in accordance with the present invention is one that
has been renatured and covalently cross-linked. This collagen may
be prepared by utilizing readily available polyfunctional cross
linking agents or fixatives, such as dialdehydes, dicarboxylic
acids, diamines, and the like. Typically, tropocollagen is
dissolved in a buffer of pH 3.0 to 5.0 to provide a solution
containing approximately 1 to 2% by weight of the collagen. Then 1%
of a dialdehyde cross-linking agent such as glutaraldehyde or
formaldehyde is then added. The mixture is then frozen and stored
for approximately 24 hours. After thawing and washing to remove
unreacted cross linking agent, the renatured cross-linked collagen
is then ready for contact with a silver ion-containing
solution.
Step 2--Binding of Metal Ions to the Renatured Collagen
[0040] The source of silver ion may be a water soluble silver salt,
preferably silver nitrate. While the concentration of the silver
ion in the solution is not particularly critical, it will be
usually convenient to utilize solutions in the concentration range
of about 10 to 10 millimolar.
[0041] The renatured collagen is preferably contacted with a silver
ion-containing solution in the pH range of about 4 to 9. The pH of
the silver ion-containing solution can be controlled by the
addition of an appropriate titrating agent, such as nitric acid, or
potassium hydroxide, as required, to maintain the pH at less than
about 9.0 to avoid the degradation of the silver. There is not
believed to be any lower limit for the pH, however, normally a pH
above 4.0 will be convenient. A particularly preferred range for
the pH is from 7.0 to 7.5. The binding capacity of silver by
collagen is particularly effective within this preferred pH range,
although the amount of binding by silver by the collagen is further
controllable by the concentration of the silver ion-containing
solution and/or exposure time of the collagen to the silver
ion-containing solution. Simultaneous with or subsequent to
exposure of the collagen to the silver ion-containing solution, the
collagen is then exposed to ultraviolet radiation of energy and
duration sufficient to strengthen the binding of the silver ions to
the collagen without substantial formation of metallic silver
formed as a result of oxidation of various functional groups in the
collagen by the silver ion. While the exact limits of the ranges of
the conditions which will be sufficient to strengthen the binding
of the silver ions without substantial formation of metallic silver
are not precisely determinable, it will generally suffice to
maintain the pH of the silver-collagen environment at less than 8.0
while exposing the collagen to ultraviolet radiation in the range
of about 210 to 310 nm wavelength for about from 5 to 15 minutes.
The time of UV exposure for complete reaction is inversely
proportional to the light intensity which is preferably in the
range of 100 to 1,000 microwatts/cm.sup.2. A slight coloration of
the collagen due to the exposure to ultraviolet radiation is
acceptable, i.e., a turning from white to a light brown to yellow
color, indicating a slight oxidation reaction occurring in the
collagen, however, the radiation should not be to the extent that
dark brown or black areas in the collagen occur due to
over-oxidation and/or substantial formation of metallic silver.
Normally the exposure will be performed at ambient temperatures,
i.e., in the range of about 20 degrees to 25 degrees C., however,
there is not believed to be any reason why the exposure could not
occur at higher or lower temperatures providing that the
temperature is not high enough to cause degradation of the collagen
and/or silver ion. There is not believed to be any lower limit to
the temperature at which the exposure may take place, provided it
is above the freezing point of the ion-containing solution.
[0042] Ultraviolet radiation may be provided by any conventional
ultraviolet radiation source of appropriate wavelength, such as
germicidal lamps and mercury/xenon lamps.
Step 3 (optional)-Addition of Visible Marker Component to the
Collagen or Gelatin Matrix:
[0043] If it is desired for the marker to be detectable visually,
as well as by imaging and palpation, a quantity of a visible
substance having a color dissimilar blood or tissue may be added.
For example, carbon particles or a dye (e.g., methylene blue,
indigo) may be added to the above-prepared silver ion/collagen
preparation to provide a colored silver ion/collagen marker 10 that
is imageable (by radiographic means), palpable (by hand) and
visible (under white light in the operating room).
[0044] The above-described collagen-metal ion marker 10 (with or
without visible marker component) is introduced into the cavity
created by removal of the biopsy specimen. The quantity of this
marker 10 introduced may be sufficient to distend or stretch the
biopsy cavity somewhat, thereby creating a more palpable and
obvious mass of marker material at the biopsy site.
[0045] Renatured gelatin or a cross-linked gelatin preparation such
as Gelfoam.TM. may be impregnated or combined with a metal ion to
provide a gelatin-metal ion marker material. The gelatin may be
prepared and ion-bound by the same method as set forth hereabove
for collagen.
Example of Radiographically or Ultrasonically Visible/Palpable
Marker Material Formed of a Gas in Combination with a Collagenous
or Gelatinous Matrix
Step 1--Renaturation of Collagen (or Gelatin)
[0046] Collagen or gelatin is renatured, as by the method described
in Step 1 of the immediately preceding example and described in the
literature, including, for example, those methods described in U.S.
Pat. Nos. 4,294,241 and 3,823,212.
Step 2--Dispersing of Air or Other Gas in the Renatured Collagen or
Gelatin Matrix
[0047] Air or another biologically inert gas (e.g., carbon dioxide)
is then dispersed throughout the renatured collagen or gelatin
matrix by a suitable means such as mixing, mechanical blending,
nucleation, bubbling, etc. This results in the formation of many
small gas bubbles throughout the collagenous or gelatinous matrix
and provides a marker substance that can be introduced into the
biopsy cavity through a cannula or tube and is substantially more
radio-lucent than the tissue surrounding the biopsy cavity. In this
regard, this marker can be imaged by x-ray or ultrasound but will
not block or obscure imaging of tissue that lies immediately
adjacent the biopsy cavity. Also, because of the bulk of the
collagen or gelatin matrix, the marker is readily palpable and
locatable by tactile means within the surrounding breast tissue or
other tissue.
Step 3 (Optional)--Addition of Visible Marker Component
[0048] If it is desired for the marker to be detectable visually,
as well as by imaging and palpation, a quantity of a visible
substance having a color dissimilar to blood or tissue may be
added. For example, carbon particles or a dye (e.g., methylene
blue, indigo) may be added to the above-prepared silver
ion/collagen preparation to provide a colored silver ion/collagen
marker 10 that is imageable (by radiographic means), palpable (by
hand) and visible (under white light in the operating room).
[0049] In routine use, the above-described collagen/gas or
gelatin/gas marker 10 (with or without visible marker component) is
introduced into the cavity created by removal of the biopsy
specimen. The quantity of this marker 10 introduced may be
sufficient to distend or stretch the biopsy cavity somewhat,
thereby creating a more palpable and obvious mass of marker
material at the biopsy site.
Preferred Example of Preparing Cylindrically Shaped Gelatin Pellets
20 Having a Colorant and Including the Permanent Marker 22
[0050] 80 grams of dry gelatin obtained from porcine skin is mixed
into 1000 ml of hot water (180.degree. F.). Variations in gelatin
to water ratio will change the consistency but are nevertheless
permissible within the scope of the invention. The 80 grams of
gelatin is about the maximum amount which will dissolve in water
without modifications to pH. The gelatin is then fully dissolved in
the water with slight mixing. In a separate container, 1.6 grams of
indigo colorant is mixed into 20 ml of ethyl alcohol. Then the
ethanol solution of the colorant is added by mixing to gelatin
dissolved in water. Air is then whipped into gelatin mixture to
froth the mixture.
[0051] The gelatin dissolved in water is then poured into molds
(not shown) which have the shape of the desired gelatin body. In
the preferred embodiment the mold is shaped to provide the
cylindrical pellet shown in the drawing figures. One gamma
(.gamma.) shaped permanent marker 22, made by chemical etching from
stainless steel plates, is deposited into the gelatin in each mold.
(In alternative embodiments more than one marker 22 may be
deposited into each mold.) Due to the viscosity of the gelatin
solution the marker 22 does not usually sink to the bottom of the
mold. The top of the plate (not shown) holding a plurality of molds
is squeegeed to level the mixture.
[0052] After cooling to approximately 40.degree. F. or cooler
temperature the gelatin sets and provides the gelatin body 20 that
incorporates the permanent marker 22 However, in order to dehydrate
the marker it is first frozen and thereafter lyophilized in
commercial lyophilization apparatus. Gelatin pellets containing the
permanent marker 22 but not having a colorant can be prepared in
the same manner, but without adding indigo dye or other colorant.
Gelatin bodies or markers 20 that do not include or incorporate a
permanent marker 22 can also be made in this manner, but without
depositing the marker 22 into the gelatin after it has been placed
into the mold. The gelatin body 20 prepared in this manner is
reabsorbed from the biopsy site by the human body in approximately
three weeks, whereas the permanent marker 22 remains
indefinitely.
Description of the Applicator Apparatus and its Use in Conjunction
with the Biopsy Marker of the Invention
[0053] Referring now to FIGS. 3-7 the applicator device or
apparatus 24 with which the biopsy markers of the invention are
preferably applied or deposited, is disclosed. In this connection
it should be understood that the biopsy markers of the invention
can be used without the applicator, and can be deposited in
accordance with the various methods and techniques utilized in the
state-of-the-art. However, a preferred technique of applying the
biopsy markers of the invention is to place or deposit them in a
biopsy cavity that is obtained with a vacuum assisted large core
biopsy device of the type presently used in the state-of-the-art.
Such a device, distributed for example by Johnson and Johnson Endo
Surgery is well known in the art, and is schematically shown in
FIG. 7.
[0054] The applicator 24 of the invention comprises an elongated
cylindrical body 26 having an interior cavity and a piston 28 that
fits and slides back and forth in the elongated cylindrical body
26. The cylindrical body 26 has an enlarged disk 30 at one end 32.
The disk 30 serves to render it convenient for a user (not shown)
to operate the applicator 24, as is described below. The
cylindrical body 26 that can also be described as an elongated
flexible tube has an opening 34 that commences a relatively short
distance, that is approximately 0.3" before its other, closed end
36. The opening 34 is configured to form a ramp in the side of the
tube 26. The outer diameter of the tube 26 is such that it fits
through the vacuum assisted large core biopsy device 38 shown in
FIG. 7. In this connection it should of course be understood that
the precise dimensions of the tube 26 are coordinated with the
dimensions of the piston 28 and with the vacuum assisted large core
biopsy device 38. Moreover, the diameter of the gelatin pellets 20
in their dehydrated form are also coordinated with the inner
diameter of the cylinder or tube 26. The cylinder or tube 26 and
the piston 28 can be made from any appropriate medical grade
plastic material, and is preferably made of high density
polyethylene. The outer diameter of the presently preferred
embodiment of the cylinder or tube 26 is approximately 0.093" and
its inner diameter is approximately 0.070".
[0055] In the preferred manner of using the biopsy markers of the
present invention having the permanent markers 22 incorporated in a
gelatin body 20, as well as using biopsy markers that have only the
gelatin body 20 without a permanent marker 22, the applicator
device 24, more precisely the tube 26 is loaded with a desired
number of pellets 20, as is shown in FIGS. 4-6. Any number of
pellets 20 within the range of 1 to approximately 30 may be loaded
within the tube 26, however presently it appears that approximately
8 pellets 20 are optimal for being loaded into the tube 26 and to
be deposited in a biopsy cavity where approximately 1 gram of
tissue had been removed. Such a biopsy cavity 40 in a human breast
42 is schematically illustrated in FIG. 7. The pellets 20 which are
loaded into the applicator tube 26 may all include the permanent
marker 22, but it is presently preferred that only every other
pellet 20 loaded into the applicator tube 26 have the permanent
marker 22. Such an array of 8 pellets 20, alternating between
pellets with and without permanent markers 22 is shown in FIG.
2.
[0056] When the pellets 20 are in the tube 26 the piston 28 is
extended, as is shown in FIGS. 4 and 5. The pellets 20 are expelled
one-by-one from the tube 26 through the ramp-shaped opening 34 as
the piston 28 is pushed into the cylinder or tube 26. During this
process the closed end 36 of the tube 26 is disposed in the cavity
40 formed by biopsy sampling. It is contemplated that the dispersed
radio-opaque permanent markers 22 provide a good definition of the
entire biopsy cavity 40 for subsequent observation or surgical
procedure. FIG. 3 illustrates the applicator device 24 after the
pellets 20 have been expelled from the applicator tube 26.
* * * * *