U.S. patent application number 11/954842 was filed with the patent office on 2008-04-17 for biodegradable polymer for marking tissue and sealing tracts.
This patent application is currently assigned to BIOPSY SCIENCES, LLC. Invention is credited to John S. Fisher.
Application Number | 20080091120 11/954842 |
Document ID | / |
Family ID | 29399063 |
Filed Date | 2008-04-17 |
United States Patent
Application |
20080091120 |
Kind Code |
A1 |
Fisher; John S. |
April 17, 2008 |
BIODEGRADABLE POLYMER FOR MARKING TISSUE AND SEALING TRACTS
Abstract
A tissue marker formed of a biodegradable polymer having
drug-delivery capabilities is combined with a sealant that
encapsulates the tissue marker and which serves to help anchor the
tissue marker against migration. The sealant is delivered to a site
in dehydrated form and moisture inherent in tissue at the site
expands the sealant. The expanded sealant is formed of a hydrogel
and is therefore more compatible to the surrounding tissue than the
material of the tissue marker. The sealant and the tissue marker
are both bioabsorbed over time.
Inventors: |
Fisher; John S.; (Belleair,
FL) |
Correspondence
Address: |
SMITH HOPEN, PA
180 PINE AVENUE NORTH
OLDSMAR
FL
34677
US
|
Assignee: |
BIOPSY SCIENCES, LLC
3433 East Fort Lowell Ste. 103
Tucson
AZ
85716
|
Family ID: |
29399063 |
Appl. No.: |
11/954842 |
Filed: |
December 12, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10063620 |
May 3, 2002 |
7329414 |
|
|
11954842 |
Dec 12, 2007 |
|
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|
Current U.S.
Class: |
600/564 |
Current CPC
Class: |
A61B 2017/00898
20130101; A61L 24/0031 20130101; A61L 24/0015 20130101; A61B 90/39
20160201; A61L 2300/604 20130101; A61L 2300/41 20130101; A61B
2017/00893 20130101; A61L 2300/416 20130101; A61L 24/0042 20130101;
A61L 31/18 20130101; A61L 2300/406 20130101; A61L 2300/44 20130101;
A61B 2017/00004 20130101 |
Class at
Publication: |
600/564 |
International
Class: |
A61B 10/02 20060101
A61B010/02 |
Claims
1. A method for performing a hepatic biopsy, comprising the steps
of forming a bore in a liver by a biopsy procedure, providing a
plug formed of an expandable sealant material, and sealing said
bore at its surface with said plug to prevent bleeding, said plug
expanding to securely seal the opening when contacted by bodily
moisture.
2. The method of claim 1, further comprising the step of including
a marker housed within the expandable sealant material, said
markers having utility for viewing and drug delivery.
3. The method of claim 1, further comprising the step of including
marker particles housed within the expandable sealant material,
said marker particles having utility for viewing and drug delivery.
Description
CROSS-REFERENCE TO RELATED DISCLOSURES
[0001] This disclosure is a divisional application claiming the
benefit of the filing date of pending U.S. patent application
entitled: "Biodegradable Polymer for Marking Tissue and Sealing
Tracts," by the same inventors, filed on May 3, 2002, bearing Ser.
No. 10/063,620.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates, generally, to a biodegradable tissue
marker and sealant. More particularly, it relates to a tissue
marker formed of a biodegradable polymer having drug-delivery
capabilities. It further relates to a sealant that encapsulates the
tissue marker and which serves to help anchor the tissue marker
against migration.
[0004] 2. Description of the Prior Art
[0005] U.S. Pat. No. 6,350,244 entitled Bioabsorable Markers For
Use In Biopsy Procedures to the present inventor discloses a
bioabsorbable marker that is positioned near a lesion or tumor
during a biopsy procedure. The marker includes a contrast agent and
is bioabsorbed slowly so that the biopsy site can be located weeks
or even months later if needed. U.S. Pat. No. 6,350,244 is hereby
incorporated by reference into this disclosure, and is hereinafter
referred to as the first-incorporated patent.
[0006] Co-pending U.S. patent application Ser. No. 09/683,282,
filed Dec. 7, 2001, entitled Bioabsorbable Sealant, also to the
present inventor, discloses a sealant that expands upon contact
with water or other bodily fluid. It can also expand upon contact
with heat or other stimulus. The sealant has utility in sealing
various openings in the body such as a hole in a lung, an opening
in the myocardial septum, and the like. It is also useful in
sealing a blind bore that contains stem cells that promote
angiogenesis. U.S. patent application Ser. No. 09/683,282 is also
hereby incorporated by reference into this disclosure, and is
hereinafter referred to as the second-incorporated disclosure.
[0007] Prior to this disclosure, it was not known that the tissue
marker of the first-incorporated disclosure and the sealant of the
second incorporated disclosure could be combined and used in
combination with one another. Anchoring the tissue marker against
migration was problematic. Moreover, although the tissue marker
included a contrast solution to facilitate its imaging under
X-rays, it was unknown how to use the tissue marker or the sealant
as a drug delivery means.
[0008] Nor was it known that a tissue marker could be formed into a
shape that would enable it to serve as its own anchoring means.
[0009] Nor was it known how polymers having utility as tissue
markers could be formulated to achieve differing degradation rates.
More particularly, it was not known how to make different polymers
to contain contrast for different amounts of time, such as one
month to six months or more by using two different polymers.
[0010] Nor was it known how to formulate a marker polymer with a
therapeutic drug or other pharmaceutical agent so that the
degradation of the marker would gradually release the drug or agent
to a site.
[0011] Nor was it known how the polymers could be formulated to
exhibit differing expansion rates when exposed to water or other
liquid fluids.
[0012] The sealants of the prior art require in-situ curing. For
example, Focal Sealant.RTM. is an in-situ sealant available from
Genzyme Corporation. Prior art sealants such as Focal Sealant
require the application of a stimulant such as visible light, heat,
and the like thereto.
[0013] Accordingly, what is needed is a combination tissue marker
and sealant that can be formed into many different shapes and
sizes, depending upon the application, that can degrade at
different rates, depending upon the application, that can expand in
response to moisture or other bodily fluids at different rates,
depending upon the application, and that does not require in-situ
curing.
[0014] There is a need as well for a bioabsorbable tissue marker
that can deliver drugs or other therapeutic agents to a site over a
prolonged period of time.
[0015] There is a further need for a sealant that can anchor a
tissue marker against migration, that can provide a seal for
openings in tissue, and that biodegrades over a period of one to
six months or more.
[0016] Moreover, there is a need for a combination tissue marker
and sealant that requires no in-situ curing as aforesaid and which
therefore requires no initiators, buffers or other chemicals,
proteins, enzymes, visible light, UV, accelerator, nor addition of
foreign chemicals into the body.
[0017] A need also exists for a means for making tissue markers
more compatible with surrounding tissue. Tissue markers are hard
and have little compatibility with surrounding tissue. Thus there
is a need for a cushioning means that surrounds a marker and which
provides a more compatible interface means with surrounding
tissue.
[0018] Biodegradable polymers in general have been used in many
medical devices and implant applications. For example, they have
been used as orthopedic implants, tissue sealants, sutures, and as
ligating clips. The medical devices incorporating these polymers
are made, primarily, of biodegradable materials such as
poly(dioxanone) (PDO), polyethylene glycol (hydrogels, polylactides
(PLA), polyglycolides (PGA), polycaprolactone (PCL), and their
copolymers. Some of the polymers, such as hydrogels, are
hydrophilic. Others such as PCL are hydrophobic. Because these
polymers degrade by hydrolysis, the type of polymer and its
physical form used in a particular application has an effect in
defining the degradation period.
[0019] Traditional brain tumor treatment includes surgery,
radiotherapy, and chemotherapy. Alternative strategies are needed
due to the high rate of recurrence of tumors after such treatment
and their resistance to radiation and cytostatics. In the recent
past, gene therapy treatments such as reversion of the malignant
phenotype by down regulation of the oncogene expression or
insertion of normal tumor suppression genes have been tried. One
challenge with gene therapy treatments concerns the prevention of
immunorejection of genetically modified cells after intracranial
implantation. A further challenge is to achieve efficient gene
transfer, as well as prolonged gene expression within the relevant
cells.
[0020] Numerous other surgical procedures would be facilitated by
tissue markers that degrade over predetermined periods of time,
that include contrast agents so that they can easily be found, that
do not migrate, that interface well with surrounding tissue, and
that deliver drugs or other therapeutic agents to a site over a
predetermined length of time.
[0021] In view of the prior art considered as a whole at the time
the present invention was made, it was not obvious to those of
ordinary skill in the pertinent art how the identified needs could
be fulfilled.
SUMMARY OF THE INVENTION
[0022] Biodegradable polymers and co-polymers are combined with or
without ionic and non-ionic contrast agents, depending upon the
application. For example, no contrast agent is needed in an
application where there is no need to view a site at a later
date.
[0023] The novel formulations that include contrast agents are
designed to allow the radiopacity of the markers to last for an
extended period of time so that they can be seen under X-ray or
other imaging means for further diagnostic or intervention
procedures at a date that may be weeks or months after implanting
of the marker.
[0024] The novel plug is treated so that it is visible under
ultrasound, magnetic resonance imaging, and other imaging
techniques if an application requires such visibility. Accordingly,
it may contain or be impregnated with a contrast solution
containing radium, iodine, beryllium, or other contrasting
agent.
[0025] The plug is impregnated with a contrasting agent to
facilitate detection of the plug by imaging means selected from the
group of imaging means consisting of magnetic resonance imaging,
ultrasound, Doppler, and roentgenological means including x-ray,
computed axial tomography (CAT) scanning, also known as CT scan,
mammography, and fluoroscopy, or other known or hereafter known
imaging techniques.
[0026] The plug may also include a radioactive substance detectable
by a radiation detecting means including a gamma counter and a
scintillation counter. In another alternative, the plug includes a
transmitting means adapted to transmit signals in the
electromagnetic spectrum that are detectable by receivers adapted
to receive signals in the electromagnetic spectrum.
[0027] The novel polymers are based upon well-known polymers such
as polyactides (PLA), including polylactic acid, for example,
polyglycolides (PGA), including polyglycolic acid, for example,
polycaprolactone (PCL), poly(dioxanone) (PDO), collagen, renatured
collagen, gelatin, renatured gelatin, crosslinked gelatin, and
their co-polymers. The blend of polymers and copolymers is designed
to degrade as a result of hydrolysis of polymer chains into
biologically acceptable and progressively smaller components such
as polylactides, polyglycolides, and their copolymers. These break
down eventually into lactic and glycolic acid, enter the Kreb's
cycle and are broken down into carbon dioxide and water and
excreted.
[0028] Some of these polymers and copolymers do not possess the
mechanical properties that are required for certain applications.
For example, as implants for soft tissue PGA, PLA, PCL, PDO and
their copolymers may require increased flexibility and a modulus of
elasticity that is closer to soft tissue. Some hydrogels, due to
their water content, provide a more flexible structure that is
similar to soft tissue. Therefore, by combining the polymers that
lack certain required mechanical properties such as a suitable
modulus of rigidity or modulus of elasticity with hydrogels,
suitable degradation and drug delivery properties are obtainable
and an exterior is achieved that has mechanical properties similar
to the mechanical properties of soft tissue.
[0029] PLA, PGA, PCL, PDO and their copolymers are designed to
provide a sustainable and gradual degradation and therefore slow
release of drugs with the degradation of the polymer substrate.
Hydrogels are not suitable for prolonged drug delivery without
using additional bonding of the drug to the hydrogels especially
with small size molecule pharmaceutical agents.
[0030] Thus it is understood that a primary teaching of this
invention relates to biodegradable polymers having utility as
tissue markers as taught by the first-incorporated patent and as
sealants as taught by the second-incorporated disclosure. When
combined, the tissue marker and sealant serve as a drug-delivery
means as the substrate of the polymer degrades. Advantageously, the
expanded sealant prevents migration of the marker as well, and
provides a soft interface means between the marker and surrounding
soft tissue.
[0031] More particularly, poly (DL-lactide) is used to provide a
biodegradable substrate that allows slow degradation. However, it
swells as water or other bodily fluid penetrates into the
substrate. Different molecular weights could be used to achieve a
different hydration rate. Delayed hydration provides a better
visualization under ultrasound when further diagnosis or
intervention is required.
[0032] An alternative method for achieving a different degradation
rate is to employ a biodegradable hydrophobic polymer coating to
delay the penetration into the substrate by water or other bodily
fluid. The hydrophobic coating may be sprayed onto the substrate or
the substrate may be dipped into the coating. Either way, the
thickness of the coating is controlled because a thicker coating
resists penetration for a longer time than a thinner coating.
Polycaprolactone (PCL) degrades nicely, for example, and therefore
works well when sprayed or coated onto the substrate. Teflon.RTM.
does not work because it forms a substantially permanent
shield.
[0033] When anchoring an implant in a specific area is required, a
PGA/PLA/PCL/PDO based polymer combined with a contrast agent for
visibility if required for a particular application is encapsulated
within a hydrogel such as a PEG-based hydrogel. The encapsulation
is accomplished by any suitable means such as mechanically
combining the tissue marker and sealant in a mold, by compression,
and the like. The hydrogel part of the combined polymer is
dehydrated and delivered to the target site. Hydration of the
polymer causes its expansion and thus provides a mechanical
anchoring of the implant in the tissue. These properties are
attained by combining the teachings of the first and
second-incorporated disclosures. Where the polymer is used as a
tissue marker, it is molded or extruded into different shapes to
provide anchoring properties.
[0034] The contrast agent, if provided, is also accompanied by or
replaced with different pharmaceutical agents such as anti-cancer
drugs, antibiotics, anti-inflammatory drugs and the like that are
slowly released using PGA/PLA/PCL/PDO substrates of the
first-incorporated disclosure while the hydrogels of the
second-incorporated disclosure provides a suitable anchoring means.
The degradation of the external hydrogel may also be tailored to
have a prolonged degradation time while the PGA/PLA/PCL/PDO
combined with a drug agent could be degraded at a faster rate.
[0035] Examples of suitable bioabsorbable materials that expand
when contacted by water include hydrogels, collagen, polysalactic
acid, and any other suitable hydrophilic agents.
[0036] Examples of polymers that swell in the presence of aqueous
fluids such as biological fluids will now be disclosed. Virtually
all of the following polymers are hydrogels. Synthetic hydrogels
can be prepared from the following classes of polymers and these
are generally considered to be non-biodegradable:
[0037] poly(hydroxyalkyl methylacrylates) such as poly(glyceryl
methacrylate)
[0038] poly(acrylamide) and poly(methacrylamide) and
derivatives
[0039] poly(N-vinyl-2-pyrrolidone)
[0040] anionic and cationic hydrogels
[0041] poly(vinyl alcohol)
[0042] poly(ethylene glycol) diacrylate and derivatives from block
copolymers composed of poly(ethylene oxide)-poly(propylene
oxide)-poly(ethylene oxide) and poly(propylene oxide)-poly(ethylene
oxide)-poly(propylene oxide) blocks, respectively;
[0043] All of the above can be cross-linked with agents such as
ethylene glycol dimethacrylate or methylene-bis-acrylamide.
[0044] Biodegradable synthetic hydrogels can be prepared from
polymers such as those listed above by incorporating one or more of
the following monomers:
[0045] Glycolide, Lactide, e-Caprolactone, p-Dioxanone and
Trimethylene Carbonate
[0046] In addition, biodegradable hydrogels can be based on natural
products such as the following:
[0047] Polypeptides such gelatin which may be cross-linked with
formaldehyde or glutaraldehyde and various other dialdehydes.
[0048] Modified chitin hydrogels, which may be prepared from
partially N-deacetylated chitin which, may then be cross-linked
with agents such as glutaraldehyde.
[0049] Dextran, a polysaccharide, can be derivatized with groups
such as 3-acryloyl-2-hydroxypropyl esters and subsequently
cross-linked by free radical copolymerization with
N',N'-methylenebisacrylamide.
[0050] Starch may be similarly derivatized or using glycidyl
acrylate followed by free radical cross-linking as described
above.
[0051] The plug is impregnated with a contrasting agent to
facilitate detection of the plug by imaging means selected from the
group of imaging means consisting of magnetic resonance imaging,
ultrasound, Doppler, and roentgenological means including x-ray, CT
scan, mammography, and fluoroscopy.
[0052] Suitable contrast agents include a colored substance such as
a dye or colorant such as methylene blue, gentian violet, indigo,
dyes used in tattooing or colorant particles such as India, indigo,
carbon particles or carbon preparations described in Langlois, S.
L. P. and Carter, M. L. Carbon Localization of Impalpable
Mammographic Abnormalities, Australis Radiol. 35:237-241 (1991)
and/or Svane, G. A. Stereotaxis Technique for Preoperative Marking
of Non-Palpable Breast Lesions, Acta Radiol. 24(2): 145-151 (1983).
Chemical compounds that serve as suitable contrast agents include
AgCl, Agl, BaCO.sub.3 BaSO.sub.4, K, CaCO.sub.3, ZnO,
Al.sub.2O.sub.3, AGNO.sub.3, ammonium salts, sodium salts,
potassium salts, ethiodized oil, isohexyl, isopamidol, gas, lipid,
oil, and all possible combinations thereof.
[0053] Alternatively, the plug includes a radioactive substance
detectable by a radiation detecting means including a gamma counter
and a scintillation counter. In another alternative, the plug
includes a transmitting means adapted to transmit signals in the
electromagnetic spectrum that are detectable by receivers adapted
to receive signals in the electromagnetic spectrum.
[0054] This invention further includes the fabrication of tubular
implants for implanting in tubular organs. Such a structure
includes a lumen defined by a PGA/PLA/PCL/PDO polymer and a
hydrogel that provides the exterior of the implant. Thus, as the
hydrogel expands upon contact with a liquid fluid, it anchors
itself into the surrounding tissue. The inner layer of the hydrogel
contains a circular solid polymer made of PGA/PLA/PCL/PDO as a
structural support to maintain an open lumen. The lumen remains
open even when the hydrogel has fully expanded because the
expansion is radially outward, away from the PGA/PLA/PCL/PDO
polymer substrate that defines the lumen. A drug or drugs may be
added to the polymer substrate so that said drug or drugs are
delivered over time to the patient as the substrate degrades. As
mentioned above, in most cases the polymer substrate is designed to
degrade at a rate faster than the degradation rate of the hydrogel
cover.
[0055] The primary object of this invention is to provide a
combination tissue marker and sealant that prevents migration of
the marker.
[0056] Another important object is to provide biodegradable
polymers that perform the functions of marking a site, delivering
drugs or other therapeutic agents to a site, and sealing openings
or tracts left by a biopsy procedure or other surgical
procedure.
[0057] Another object is to provide a hydrophobic coating that
extends the degradation rate by shielding the substrate from
moisture or bodily fluids for a predetermined time.
[0058] Another important object is to provide a combination tissue
marker and sealant that does not require in-situ curing.
[0059] Yet another important object is to encapsulate a tissue
marker in a sealant material that is more compatible to soft tissue
than is a tissue marker.
[0060] These and other important objects, advantages, and features
of the invention will become clear as this description
proceeds.
[0061] The invention accordingly comprises the features of
construction, combination of elements, and arrangement of parts
that will be exemplified in the description set forth hereinafter
and the scope of the invention will be indicated in the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0062] For a fuller understanding of the nature and objects of the
invention, reference should be made to the following detailed
description, taken in connection with the accompanying drawings, in
which:
[0063] FIG. 1A is a perspective view diagrammatically depicting the
tissue marker material in the form of a solid rod. It may also be
interpreted as depicting said tissue marker material in the form of
a hollow cylinder;
[0064] FIG. 1B is a side elevation view diagrammatically depicting
the marker material in solid rod form or in hollow cylindrical
form, depending upon the interpretation of the drawing;
[0065] FIG. 1C is a perspective view diagrammatically depicting the
sealant material in solid rod form;
[0066] FIG. 1D is a side elevation view diagrammatically depicting
the sealant material in solid rod form;
[0067] FIG. 1E is a perspective view diagrammatically depicting the
marker of FIG. 1A housed within the sealant of FIG. 1C, in a
rod-in-rod arrangement;
[0068] FIG. 1F is a side elevation view that diagrammatically
depicts a marker of FIG. 1A or 1B encapsulated within the sealant
material of FIG. 1D;
[0069] FIG. 2A is a side elevation view diagrammatically depicting
the marker material formed into a dog bone shape and ensleeved
within the sealant material of FIG. 1E;
[0070] FIG. 2B is a side elevation view diagrammatically depicting
the marker material of FIG. 2A encapsulated within the sealant
material of FIG. 1F;
[0071] FIG. 3A is a longitudinal sectional view depicting the
marker of FIG. 1A ensleeved within the sealant material of FIG. 1C
in a tube-in-tube arrangement;
[0072] FIG. 3B is an end view of the parts depicted in FIG. 3A;
[0073] FIG. 4A is a longitudinal sectional view depicting a pair of
the markers of FIG. 1A ensleeved within a double-lumened sealant
material in dehydrated form;
[0074] FIG. 4B depicts the parts of FIG. 4A when the sealant
material is hydrated;
[0075] FIG. 4C is similar to FIG. 4B except it depicts the sealant
material having lumens that are larger in diameter than the lumens
of FIG. 4A and FIG. 4B;
[0076] FIG. 5 is a side elevation view of a marker or sealant
having a pointed distal end;
[0077] FIG. 6 is a side elevation view of a marker or sealant
having a harpoon-shaped distal end;
[0078] FIG. 7 is a side elevation view of a marker or sealant
having a "U"-shaped or clip-shaped configuration;
[0079] FIG. 8 is a side elevation view of a marker or sealant like
that of FIG. 7 but further equipped with a latch means;
[0080] FIG. 9 is a side elevation view of a sealant having marker
particles embedded therein;
[0081] FIG. 10 diagrammatically depicts the combination marker and
sealant when used to seal a liver biopsy tract;
[0082] FIG. 11A is a longitudinal sectional view of an artery
depicting how a section thereof is expanded by an angioplasty
procedure;
[0083] FIG. 11B is a view like FIG. 11A and adds a longitudinal
sectional view of the combination marker and sealant of this
invention positioned in said expanded section of said artery;
[0084] FIG. 11C is a cross-sectional view of the sealant when
hydrated and in annular form;
[0085] FIG. 11D is a view like FIG. 11A and depicts a plurality of
the ring-shaped sealants of FIG. 11C disposed in supporting
relation to said expanded area of said artery, said sealants being
used in conjunction with a metallic stent;
[0086] FIG. 11E is an end view depicting a tube-in-tube-in-tube
arrangement where the marker of FIG. 1A ensleeves a first sealant
of tubular configuration and is ensleeved by a second sealant of
tubular configuration having a diameter larger than the diameter of
the first sealant;
[0087] FIG. 12A is a diagrammatic view of a prostate gland and a
urethra;
[0088] FIG. 12B is a sectional view taken along line 12B-12B in
FIG. 12A;
[0089] FIG. 12C is a diagrammatic view of the prostate gland of
FIG. 12A after a tissue reduction procedure has been performed;
[0090] FIG. 12D is a sectional view taken along line 12D-12D in
FIG. 12C;
[0091] FIG. 12E is a diagrammatic view like that of FIG. 12C,
depicting the combination marker and sealant positioned in
structural support relation to the excised part of the gland;
[0092] FIG. 13 is a diagrammatic view of the marker and sealant
combination when positioned at the juncture of a bladder and a
urethra;
[0093] FIG. 14 is a diagrammatic view of the marker and sealant
combination when used in a biliary tract; and
[0094] FIG. 15 is a diagrammatic view of the marker and sealant
combination when used in a fallopian tube.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0095] How to achieve non-covalent bonding of ionic and non-ionic
contrast agent with polymers such as PGA/PLA/PCLUPDO will now be
described. Different techniques are employed to accomplish similar
results in connection with covalent bonding.
[0096] The starting materials employed in this invention for
synthesizing the novel tissue marker include poly(DL-lactide),
inherent viscosity (IV) of 0.63 dL/g (where the solvent is
CHCl.sub.3 and the concentration is approximately 0.5 g/dL at
30.degree. C.), 50/50 poly(DL-lactide-co-glycolide, IV of 0.17 dL/g
(hexafluoroisopropanol, concentration .about.0.5 g/dL at 30.degree.
C.) and 75/25 poly(DL-lactide-co-glycolides), having IVs of 0.44
dL/g (CHCl.sub.3, concentration .about.0.5 g/dL at 30.degree. C.)
and 0.69 dL/g (CHCl.sub.3, concentration .about.0.5 g/dL at
30.degree. C.). These materials are commercially available from
Birmingham Polymers, Inc., of Birmingham, Ala.
[0097] Further starting materials for synthesis of the novel tissue
marker include poly(DL-lactide), IV of 1.6 dL/g (CHCl.sub.3,
concentration 0.1% at 25.degree. C.), commercially available from
Boehringer Ingelheim of Petersburg, Va., under the trademark
RESOMER.RTM. R 207. Contrast agents sodium diatrizoate and
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl) isophthalamide (iohexyl) is commericially available from
Sigma Chemical Co. of Milwaukee, Wis. Glycolide and DL-lactide
monomers are commercially available from Purac America Inc. of
Lincolnshire, Ill. 1-Dodecanol and .epsilon.-caprolactone are
commercially available from Aldrich Inc. of Milwaukee, Wis. Tin
(II) 2-ethylhexanoate is commercially available from Air Products
and Chemicals, Inc. of Allentown, Pa. DL-lactic acid (JT Baker
reagent) is commercially available from VWR Scientific of
Bridegeport, N.J. Solvents such as tetrahydrofuran (THF), toluene,
methanol, and hexanes of reagent grade or better are commercially
available from multiple well-known sources.
[0098] As a first example, synthesis of 75/25
poly(DL-lactide-co-.epsilon.-caprolactone) copolymer, hereinafter
referred to as 75/25 (DL-PLC1, is performed by charging 22.5 grams
of .epsilon.-caprolactone, 310 mls of toluene, 0.422 grams in 3.02
mls of tolulene solution of 1-dodecanol and 0.382 grams in 2.34 mls
of tolulene solution of stannous octoate catalyst into a one liter,
three neck, round bottom flask. The reaction solution is placed in
an argon atmosphere, stirred with an overhead stirrer that includes
a glass stirrer shaft equipped with a Teflon.RTM. blade and
approximately 100 mls of the solvent is distilled off at
atmospheric pressure. The reaction temperature is lowered to
approximately 90.degree. C. and 67.5 grams of solid DL-lactide is
added to the solution in one portion. The reaction temperature is
raised to approximately 110.degree. C. to afford a gentle reflux.
After forty eight hours at that temperature, heating is
discontinued and the reaction solution temperature is allowed to
fall to 75.degree.. The solution is diluted with 600 mls of toluene
and stirred at 55-60.degree. for 1.5 hours. The diluted reaction
solution is transferred into a crystallizing dish and the polymer
is precipitated with one liter of hexanes. The supernatant is then
decanted off and the viscous residue dried for one to three days
under a vacuum at 40.degree. C. to a constant weight. The solid
polymer is removed from the dish and stored under an argon
atmosphere at -30.degree. C.
[0099] Synthesis of 20/80
poly(DL-lactite-co-.epsilon.-caprolactone), hereinafter referred to
as 20/80 DL-PLCl and 10/90
poly(glycolide-co-.epsilon.-caprolactone), hereinafter referred to
as 10/90 PGCl copolymers are prepared by the same process used for
the preparation of 75/25 DL-PLCl in the first example, with the
exception that, in the case of the 20/80 DL-PLCl copolymer,
DL-lactic acid is used as the initiator instead of 1-dodecanol. The
contents of each monomer in the final purified polymers are
determined by high resolution proton nuclear magnetic resonance
spectroscopy and these are summarized in Table 1. That table
further includes the melting points for 20/80 DL-PLCl and 10/90
PGCl copolymers, which are obtained by differential scanning
calorimetry (DSC). TABLE-US-00001 TABLE 1 Chemical and Physical
Properties of the Synthesized Polymers Copolymer Composition,
Weight % Melting Point Mol. Wt. Polymer Glycolide DL-Lactide
.epsilon.-Caprolactone .degree. C. Mn.sup.1 20/80 DL-PLC1 -- 20 80
46 40-70K 75/25 DL-PLC1 -- 75 25 Amorphous 20-30K 10/90 PGC1 9.4 --
90.6 55 30-60K .sup.1Molecular weights were determined by GPC using
methylene chloride solvent and polystyrene standards.
[0100] In a third example, the 75/25 poly(DL-lactide-co-glycolide)
with iohexyl is formulated by preparing a 2% by weight over volume
solution of the iohexyl contrast agent by mixing 5.15 grams of the
solid contrast agent in 130 mls of methanol in a 500 ml Erlenmeyer
flask for 5-10 minutes until the solid is fully dissolved. The
solution is then diluted with 130 mls of tetrahydrofuran (THF) to
provide the 2% solution. A 6% solution of the biodegradable polymer
is prepared in a one liter Erlenmeyer flask by addition of 330 mls
of THF to 20.6 grams of the solid 75/25 DL-PLG polymer. The mixture
is stirred with gentle heating (30-40.degree. C.) until the solid
is dissolved. The entire contrast solution is then slowly poured
into the stirred polymer solution to give a single-phase solution
of the polymer and the contrast agent. The combined solution is
stirred for an additional five minutes and then the polymer and
contrast agent are co-precipitated with hexanes. The precipitation
is achieved by rapid addition of two volumes of hexanes to a
rapidly mixed solution of the polymer/contrast solution. The
mixture is again stirred for an additional five minutes and then
allowed to sit unstirred at room temperature for five to ten
minutes to allow the solid to settle to the bottom of the flask.
The supernatant is then decanted and discarded and the semi-solid
residue is dried under vacuum for one to two days at 40.degree. C.
to a constant weight. Quantitative recovery of 100.8% of the solids
is obtained for the polymer and the contrast agent in this example.
The solid, which is used for fabrication of the novel markers,
contains 20% by weight of contrast agent as a homogenous mixture
with the biodegradable polymer.
[0101] To study the effect of the contrast agent content in the
biodegradable markers on their visualization under X-ray imaging,
two different DL-PLG polymers are formulated with the iohexyl
contrast agent in which the contrast is varied between 5 and 40% by
weight. These markers are formulated by a procedure similar to the
procedure for the marker prepared in the third example. The
composition of these biodegradable marker solids is summarized in
Table 2. The recovery of the solids after the hexanes precipitation
step is greater than 97% for all of the marker compositions listed
in Table 2. TABLE-US-00002 TABLE 2 Compositions of the
Biodegradable Markers Source and Inherent Viscosity Contrast Agent
Contrast Content Polymer Lot # dL/g Type Name %(w/w) 50/50 DL-PLG
BPID00120 0.17 Non-ionic Iohexol 5 50/50 DL-PLG BPID00120 0.17
Non-ionic Iohexol 10 50/50 DL-PLG BPID00120 0.17 Non-ionic Iohexol
20 50/50 DL-PLG BPID00120 0.17 Non-ionic Iohexol 30 50/50 DL-PLG
BPID00120 0.17 Non-ionic Iohexol 40 75/25 DL-PLG BPID98054 0.44
Non-ionic Iohexol 5 75/25 DL-PLG BPID98054 0.44 Non-ionic Iohexol
10 75/25 DL-PLG BPID98054 0.44 Non-ionic Iohexol 20 75/25 DL-PLG
BPID98054 0.44 Non-ionic Iohexol 30 75/25 DL-PLG BPID98054 0.44
Non-ionic Iohexol 40
[0102] The contrast solution may also be an ionic contrast solution
such as sodium diatrizoate, for example.
[0103] The novel biomarkers may be fabricated by extrusion,
injection molding, or compression molding. Multiple sizes and
shapes may be fabricated using these or similar manufacturing
processes. By controlling pressure, temperature, and extrusion
speed rate during the extrusion process, differing sizes and
properties are obtainable. During the development of this
invention, different extrusion and compression molding processes
were used to fabricate the markers.
[0104] The novel biomarkers and the novel sealant material may be
combined in a variety of fabrication processes. During the
development of this invention, insert molding was used to combine
the marker and the sealant to one another. Different sizes and
shapes having differing properties may be manufactured using insert
injection and compression molding, for example.
[0105] To extend the biodegradable marker's range of properties
such as degradation times, ability to be visualized under
ultrasound, hardness and fabrication temperatures, marker solids
are prepared from additional types of polymers with both ionic and
non-ionic contrast agents as indicated in Table 3. Most of these
biodegradable markers are formulated with 20% contrast agent. The
recovery of the solids after the hexanes precipitation step is
greater than 91% in all of these formulations. TABLE-US-00003 TABLE
3 Compositions of the Biodegradable Markers Source and Inherent
Viscosity Contrast Agent Contrast Content Polymer Lot # dL/g Type
Name %(w/w) DL-PLA BI 260911 1.6 Ionic Sodium Diatrizoate 10 DL-PLA
BI 260911 1.6 Ionic Sodium Diatrizoate 20 DL-PLA BI 260911 1.6
Non-ionic Iohexol 10 DL-PLA BI 260911 1.6 Non-ionic Iohexol 20
DL-PLA BPI D00004 0.63 Non-ionic Iohexol 20 PGC1 See example 3 --
Non-ionic Iohexol 20 20/80DL-PLC1 See example 3 -- Non-ionic
Iohexol 20 20/80DL-PLC1 See example 3 -- Ionic Sodium Diatrizoate
20 75/25DL-PLC1 See example 3 -- Non-ionic Iohexol 20
[0106] The type of polymer used can be any of the biodegradable
polymers such as other PLGA polymers, e.g., 50/50 DL-PLGA, 50/50
L-PLGA, etc., or the L-PLCl, PGCl, etc.
[0107] The contrast agent can be formulated in these polymers at
any concentration ranging from 0 to 50% by weight, but preferably
at 70% by weight. (That statement contradicts itself).
[0108] The solvent combinations can also be varied as well as the
precipitation methods.
[0109] There are many applications for the novel implants. For
example, during diagnosis of hepatic carcinoma or other hepatic
disease using a liver biopsy under CT visualization, a biopsy tract
is formed. The tract may be plugged to prevent bleeding by using
the above-mentioned PGA/PLA/PCL/PDO based polymer combined with a
contrast agent for visibility and encapsulated within a hydrogel.
Drugs or any other pharmaceutical agents could be delivered to the
liver by replacing the contrast agent with such drugs or
agents.
[0110] As another example, a heart biopsy may be conducted near
diseased heart tissue using a mechanical biopsy gun. The biopsy
tract or tracts are then filled with different growth factors and
stem cells to promote angiogenesis in the heart muscle tissue. One
method for sealing the tract so that the stem cells and growth
factor are constrained to stay in the biopsy tract for a prolonged
period of time is disclosed in the second-incorporated disclosure.
The present disclosure teaches the integration of two polymers
where a PGA/PLA/PCL/PDO with a drug agent is encapsulated within a
dehydrated hydrogel. The dehydrated hydrogel becomes hydrated
within a few minutes and its expansion provides an anchoring
means.
[0111] This invention also has utility in connection with prostate
cancer biopsies where a biopsy needle is inserted though the rectum
into the prostate gland under ultrasound visualization.
Introduction into the biopsy tract of a sealing means by means of a
coaxial needle will prevent leakage through the bowel into the
prostate. Moreover, the plug may be used to deliver drugs or other
therapeutic agents.
[0112] Similarly, the novel plugs have utility in connection with
the sealing of cavities formed in a prostate gland by tissue
reduction procedures undertaken after a diagnosis of BHP. Different
drug agents are released over time to reduce inflammation or any
other side effects.
[0113] In another application, a tubular urethral stent has a thin
wall formed of a PGA/PLA/PCL/PDC/PDO polymer substrate with or
without pharmaceutical agents. A layer of dehydrated hydrogel
covers the thin wall but does not block the lumen of the tube. The
stent is introduced into the urethra and the hydrogel expands
radially outwardly, anchoring to the urethral wall. This procedure
is similar to the conventional placement of a urethral stent, but
it is more advantageous because it is not permanent like metallic
stents and does not require in situ curing like other biodegradable
stents.
[0114] The marker material that forms the inner tube also provides
a drug-delivery means for the benefit of the patient.
[0115] Growth factors or pharmaceutical agents encapsulated within
the novel polymers may be used advantageously in the treatment of
malignant brain tumors. The combination marker and sealant of this
invention has utility in the context of gene therapy treatment as
the carrier for the bio-active agents and as the anchoring means to
position and secure the marker to the target area.
[0116] The polymers disclosed herein are formulated to exhibit
differing properties depending upon the application. Some are
designed to degrade more slowly than others, some are more
hydrophilic or more hydrophobic, and so on. In most applications,
the contrast agent-containing polymers are formulated so that the
marker is visible under X-ray and/or other imaging means for one
month to six months or even longer.
[0117] Turning now to the drawings, FIG. 1A depicts a tissue marker
made in accordance with the teachings of the first-incorporated
disclosure. It is provided in the form of a solid rod 10. Its
interior is filled with a contrast agent or other pharmaceutical
agent. FIG. 1B depicts marker 10 in solid rod form.
[0118] FIG. 1C depicts a hydrogel-based sealant 12 made in
accordance with the teachings of the second-incorporated
disclosure. In this embodiment, it is of hollow cylindrical or
tubular construction and is made of hydrogels. FIG. 1D depicts
sealant 12 in solid rod form.
[0119] FIGS. 1E and 1F depict the basic conception behind the
present disclosure which teaches the combination of marker 10 and
sealant 12 of the incorporated disclosures. The combination marker
and sealant member 14 of FIG. 1E has an interior 10 formed of the
FIG. 1B solid rod marker and an exterior housing 12 formed of the
FIG. 1C sealant. In FIG. 1E, marker 10 is co-extensive with sealant
12. In FIG. 1F, interior marker 10 is again formed in the solid rod
structure of FIG. 1B, but said solid rod 10 has an extent less than
that of sealant 12 so that it is encapsulated therein as
depicted.
[0120] The novel combination marker and sealant member 14 is
delivered to a site that requires sealing; the sealant is in
dehydrated condition when delivered to the site. The sealant
expands when activated by contact with water or moisture. The
expansion of the hydrogel-based sealant 12 holds it in place. The
contrast agent in marker 10 facilitates viewing of the site under
various imaging techniques for a prolonged period of time. Marker
10 may also include therapeutic agents that are released over time
as marker 10 is bioabsorbed. Hydrogels 12 are also bioabsorbed over
time, but the time for such absorption is selected to exceed that
of the absorption time of marker 10 if required by an
application.
[0121] FIG. 2A depicts a marker 10 having bulbous anchoring means
at its opposite ends that extend beyond the opposite ends of
hydrogel housing 12. FIG. 2B depicts marker 10 having said bulbous
anchoring means when fully encased within hydrogel housing 12.
[0122] FIG. 3A is a side elevational view depicting a tube-in-tube
arrangement where marker 10 is provided in tubular form and is
ensleeved within sealant 12 which is also provided in tubular form.
FIG. 3B provides an end view thereof.
[0123] Sealant 12 has a pair of open lumens in the embodiment of
FIGS. 4A-C, and each of said open lumens has a marker 10 positioned
therewithin. The sealant material of which outer housing 12 is
formed is depicted in dehydrated form in FIG. 4A. In
[0124] FIGS. 4B and 4C, the sealant has expanded due to hydration.
In the embodiment of FIG. 4B, the lumen is small and in the
embodiment of FIG. 4C the lumen is large.
[0125] In addition to the cylindrical and rod-shaped markers 10 of
FIGS. 1A and 1B, marker 10 could also be provided in the form of a
rod having a pointed leading end as depicted in FIG. 5. The pointed
leading end could serve as an anchoring means that prevents
migration of marker 10 from its intended location.
[0126] The harpoon shape of the leading end of the marker depicted
in FIG. 6 would also provide an anchoring means.
[0127] The embodiment of FIG. 7 provides a U-shaped tissue marker
10. This clip shape also has utility as an anchoring means. When
the tissue marker is shaped such that it is self-anchoring, the
hydrogel sealant is not required unless there is a need to seal a
surgical or trauma-created opening.
[0128] A latch means is added to the embodiment of FIG. 7 to
produce the embodiment of FIG. 8. The latch means is provided to
enhance the anchoring of marker 10.
[0129] Hydrogel sealant 12 may also be provided in the form of a
rod, tube, pointed rod, harpoon, clip, latched clip, and the
like.
[0130] Moreover, as depicted in FIG. 9, tissue marker particles,
collectively denoted 10a, may be dispersed within sealant 12. Such
dispersal of tissue marker particles 10a within hydrogel sealant 12
may be applied to any form of hydrogel 12. For example, marker
particles 10a could be dispersed throughout a harpoon-shaped
sealant 12, a "U"-shaped sealant 12, and so on.
[0131] The number of shapes is inexhaustible and these Figures are
not intended to illustrate all possible shapes within the scope of
this invention but are intended as exemplary only. The novel
combined marker and sealant can be manufactured in any geometrical
shape and size and the invention is not limited to the finite
number of examples provided herein.
[0132] Six (6) examples of applications for the novel
marker/sealant combination will now be disclosed.
[0133] FIG. 10 depicts a hepatic (liver) biopsy. Bore 20 is formed
in liver 22 by the biopsy procedure. Plug 24 seals the bore at its
surface to prevent bleeding at the biopsy site. Plug 24 may be
formed of expandable sealant material 12 only so that it expands to
securely seal the opening when contacted by bodily moisture, or it
may include a marker 10 or marker particles 10a housed within
expandable hydrogel sealant material 12. These markers have utility
for viewing or drug delivery or both.
[0134] A diagrammatic longitudinal sectional view of an expanded
artery after an angioplasty procedure is denoted 24 in FIG. 11A.
Hydrogel sealant 12, in tubular form, is initially positioned
within lumen 25 of the artery in unhydrated form; it then expands
to the position depicted in FIG. 11B to hold the artery open.
Marker material 10, also in tubular form, is positioned radially
inwardly of sealant 12 and provides support therefor.
[0135] In the alternative, expandable sealant material 12 may be
provided in annular, i.e., ring form as depicted in FIG. 11C and a
plurality of said rings may be disposed in longitudinally and
equidistantly spaced relation to one another along the extent of
the expanded section of artery, in transverse relation to the
longitudinal axis of the artery, as indicated in FIG. 11D.
Moreover, as depicted in FIG. 11E, marker material 10 in annular
form may be sandwiched between inner and outer layers of sealant
material 12. Where the bioabsorbable marker material contains a
contrast agent, the location of the site is made apparent under
imaging for a prolonged period of time. Where therapeutic agents
are contained within the marker material, a time-release of said
agents is provided as the marker material is slowly
bioabsorbed.
[0136] Still another application for the novel combination of
materials is depicted in FIGS. 12A-F. FIG. 12A diagrammatically
depicts a prostate gland 30 and a urethra 32 in perspective and
FIG. 12B provide s a diagrammatic cross-sectional view thereof. If
gland 32 is enlarged, a condition known as BHP, it can compress the
urethra and cause a restricted urine flow. As indicated in FIG.
12C, the condition is surgically treated by removing the part of
gland 30 that is applying pressure to urethra 32; the resulting
opening is denoted 34 in FIGS. 12C and 12D. FIG. 12E indicates how
a tubular-in-configuration marker 10 is housed within a
tubular-in-configuration sealant 12 to provide support for said
sealant and to provide a slow delivery of therapeutic agents to the
surgical site. The moisture-activated expansion of sealant 12
anchors it to urethra 32 and to prostate gland 30. The urethra is
usually damaged during TURP. The lumen serves as a temporary
urethra until the prostate grows back.
[0137] FIG. 13 depicts an application where drugs or other
pharmaceutical agents are delivered to a bladder 40. This is a
tube-in-tube-in-tube arrangement where a first tubular section of
sealant material 12 is entubed within a tubular section of marker
material 10 which is entubed within a second section of sealant
material 12. The structure in dehydrated condition is positioned at
the neck of bladder 40 where it joins urethra 32. Upon activation,
sealant material 12 expands to secure the marker 10 in position. As
sealant 12 is bioabsorbed, drugs for treatment of bladder disease
are released from said sealant 12 and administered to the bladder.
Pharmaceutical agents of smaller molecular size could be carried by
bioabsorbable marker 10.
[0138] The novel sealant, when hydrated, makes the site more
visible under ultrasound.
[0139] FIG. 14 depicts a biliary tract 50 where an opening therein
is sealed by the structure depicted in FIGS. 3A and 3B, i.e.,
tubular marker 10 is housed within tubular sealant 12 in a
tube-in-tube arrangement. The open lumen of marker 10 enables fluid
to flow through the structure. As in the other embodiments, sealant
12 expands in response to contact with moisture to hold the
tube-in-tube structure in position and marker 10 contains either
contrast agent or therapeutic agents, or both, for gradual release
as the tube-in-tube structure biodegrades.
[0140] The same tube-in-tube structure may be used to seal openings
in fallopian tubes 60a, 60b, as diagrammatically depicted in FIG.
15.
[0141] The invention is not limited to liver, artery, prostate
gland, bladder, biliary tract and fallopian tube applications. In
view of these exemplary applications, other applications will
become apparent to those of ordinary skill in the medical arts.
Expandable sealant material 12 has utility in sealing any opening
and in providing an anchoring means for the marker material even if
no sealing is required. The marker material may contain a contrast
agent or a therapeutical agent, or both, that are released over
time as the marker is bioabsorbed.
[0142] It will thus be seen that the objects set forth above, and
those made apparent from he foregoing description, are efficiently
attained. Since certain changes may be made in the above
construction without departing from the scope of the invention, it
intended that all matters contained in the foregoing description or
shown in the accompanying drawings shall be interpreted as
illustrative and not in a limiting sense.
[0143] It is also to be understood that the following claims are
intended to cover all of the generic and specific features of the
invention herein described, and all statements of the scope of the
invention that, as a matter of language, might be said to fall
therebetween.
[0144] Now that the invention has been described,
* * * * *