U.S. patent application number 15/712660 was filed with the patent office on 2018-01-11 for side-chain crystallizable polymers for medical applications.
The applicant listed for this patent is REVA Medical, Inc.. Invention is credited to Donald K. Brandom, James E. McGrath, Eric V. Schmid, Robert K. Schultz, Joan Zeltinger.
Application Number | 20180008753 15/712660 |
Document ID | / |
Family ID | 38171618 |
Filed Date | 2018-01-11 |
United States Patent
Application |
20180008753 |
Kind Code |
A1 |
Brandom; Donald K. ; et
al. |
January 11, 2018 |
SIDE-CHAIN CRYSTALLIZABLE POLYMERS FOR MEDICAL APPLICATIONS
Abstract
Side-chain crystallizable (SCC) polymers are useful in various
medical applications. In certain applications, heavy atom
containing side-chain crystallizable polymers (HACSCCP's) are
particularly useful. An example of a HACSCCP is a polymer that
comprises a main chain, a plurality of crystallizable side chains,
and a plurality of heavy atoms attached to the polymer. In certain
configurations, the heavy atoms are present in an amount that is
effective to render the polymer radiopaque. A polymeric material
that includes an HACSCCP may be fabricated into a medical device
useful for at least partially occluding a body cavity. For example,
such a medical device may be an embolotherapy product. A polymeric
material that includes a SCC polymer may also be fabricated into
other medical devices, such as stents.
Inventors: |
Brandom; Donald K.;
(Colorado Springs, CO) ; McGrath; James E.;
(Blacksburg, VA) ; Zeltinger; Joan; (Encinitas,
CA) ; Schmid; Eric V.; (San Diego, CA) ;
Schultz; Robert K.; (Poway, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
REVA Medical, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
38171618 |
Appl. No.: |
15/712660 |
Filed: |
September 22, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13101391 |
May 5, 2011 |
9782523 |
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15712660 |
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11335771 |
Jan 18, 2006 |
8703113 |
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13101391 |
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11176638 |
Jul 7, 2005 |
7939611 |
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11335771 |
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60586796 |
Jul 8, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2/92 20130101; C08F
220/00 20130101; A61L 31/06 20130101; A61K 49/128 20130101; A61K
49/12 20130101; A61L 31/06 20130101; C08G 63/00 20130101; A61L
31/18 20130101; A61K 49/126 20130101; C08G 63/08 20130101 |
International
Class: |
A61L 31/18 20060101
A61L031/18; C08G 63/00 20060101 C08G063/00; A61L 31/06 20060101
A61L031/06; C08F 220/00 20060101 C08F220/00 |
Claims
1. A method of treatment comprising: introducing a medical device
into a body cavity of a mammal in an amount that is effective to at
least partially occlude the body cavity, and forming a channel
through the medical device; wherein the medical device comprises a
polymeric material; and wherein the polymeric material comprises an
inherently radiopaque, side chain crystallizable polymer.
2. The method of claim 1, wherein the polymeric material is
introduced into the body cavity in the presence of a mold.
3. The method of claim 2, wherein forming the channel comprises
removing the mold from the body cavity.
4. The method of claim 1, wherein the side chain crystallizable
polymer comprises heavy atoms.
5. The method of claim 1, wherein the side chain crystallizable
polymer is biocompatible.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application, and claims the
benefit and priority of, U.S. application Ser. No. 13/101,391,
filed May 5, 2011, issued as U.S. Pat. No. 9,782,523, which is a
divisional of U.S. patent application Ser. No. 11/335,771, filed
Jan. 18, 2006, issued as U.S. Pat. No. 8,703,113, which is a
continuation-in part of U.S. patent application Ser. No.
11/176,638, filed Jul. 7, 2005, issued as U.S. Pat. No. 7,939,611,
which claims priority to U.S. Provisional Patent Application No.
60/586,796, filed Jul. 8, 2004, each of which is hereby
incorporated by reference in its entireties.
BACKGROUND
Field of the Invention
[0002] This invention relates to side-chain crystallizable
polymers, and particularly to side-chain crystallizable polymers
useful in medical applications.
Description of the Related Art
[0003] Polymeric materials are widely used in numerous
applications. For example, therapeutic embolization is the
selective blockage of blood vessels or diseased vascular
structures. Examples of polymeric embolotherapy devices and
reagents include embolic coils, gel foams, glues, and particulate
polymeric embolic agents used, for example, to control bleeding,
prevent blood loss prior to or during a surgical procedure,
restrict or block blood supply to tumors and vascular
malformations, e.g., for uterine fibroids, tumors (i.e.,
chemo-embolization), hemorrhage (e.g., during trauma with bleeding)
and arteriovenous malformations, fistulas (e.g., AVF's) and
aneurysms.
[0004] Polymeric liquid embolic agents include precipitative and
reactive systems. For example, in a precipitative system, a polymer
may be dissolved in a biologically acceptable solvent that
dissipates upon vascular delivery, leaving the polymer to
precipitate in situ. Reactive systems include cyanoacrylate systems
in which, e.g., a liquid monomeric and/or oligomeric cyanoacrylate
mixture is introduced to the vascular site through a catheter and
polymerized in situ. In this system, polymerization is initiated by
the available water in the blood.
[0005] A number of technological applications involve the use of a
polymer that undergoes a transition upon a change in temperature.
For example, in the medical field, one way to introduce a solid
polymer into a particular body region is to heat the polymer into a
flowable state, then inject the polymer into the region and allow
it to cool and solidify. U.S. Pat. No. 5,469,867 discloses
side-chain crystallizable polymers that are said to be useful for
occluding channels in a living mammal. Such polymers are said to be
designed such that they can be melted so that they are flowable
slightly above body temperature but solidify when cooled to body
temperature.
SUMMARY
[0006] An embodiment provides a polymer that includes a main chain,
a plurality of crystallizable side chains, and a plurality of heavy
atoms attached to the polymer. The heavy atoms may be present in an
amount that is effective to render the polymer radiopaque. In an
embodiment, the polymer comprises a recurring unit of the formula
(VI) as set forth below. Another embodiment provides a medical
device that comprises such a polymer.
[0007] Another embodiment provides a medical device that includes a
polymeric material, the polymeric material comprising a
biocompatible inherently radiopaque side chain crystallizable
polymer. In an embodiment, the medical device comprises at least a
stent.
[0008] Another embodiment provides a method of treatment that
includes introducing a medical device into a body cavity of a
mammal in an amount that is effective to at least partially occlude
the body cavity, wherein the medical device comprises a polymeric
material, and wherein the polymeric material comprises a side chain
crystallizable polymer. In an embodiment, the method further
includes forming a channel through the medical device.
[0009] Another embodiment provides a method for making an
inherently radiopaque side chain crystallizable polymer, comprising
copolymerizing a first monomer and a second monomer, the first
monomer comprising a heavy atom and the second monomer comprising a
crystallizable group.
[0010] Another embodiment provides a method for making an
inherently radiopaque side chain crystallizable polymer, comprising
reacting a side chain crystallizable polymer with a heavy metal
reagent under conditions selected to attach a plurality of heavy
atoms to the side chain crystallizable polymer.
[0011] Another embodiment provides a stent that comprises a side
chain crystallizable polymer.
[0012] These and other embodiments are described in greater detail
below.
BRIEF DESCRIPTION OF THE DRAWING
[0013] FIG. 1 is a detailed view of a slide-and-lock stent
configuration in accordance with one preferred embodiment of the
present invention, comprising deflectable teeth which deflect
downward to provide a stent exhibiting mono-directional
expansion.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] An embodiment provides a heavy atom-containing side-chain
crystallizable polymer ("HACSCCP"). Many polymers contain
relatively low atomic number atoms such as hydrogen, carbon,
nitrogen, oxygen, silicon and sulfur. However, it has been found
that the attachment of relatively higher atomic number atoms to the
polymer may affect various physical and mechanical properties of
the polymer. For example, attachment of heavy atoms to a polymer in
sufficient amounts may advantageously render the polymer easier to
detect by various medical imaging techniques. The term "heavy atom"
is used herein to refer to atoms having an atomic number of 17 or
greater. Preferred heavy atoms have an atomic number of 35 or
greater, and include bromine, iodine, bismuth, gold, platinum
tantalum, tungsten, and barium. In certain configurations, HACSCCP'
s may be inherently radiopaque. The term "inherently radiopaque" is
used herein to refer to a polymer to which a sufficient number of
heavy atoms are attached by covalent or ionic bonds to render the
polymer easier to detect by medical imaging techniques (e.g., by
X-rays and/or during fluoroscopy). HACSCCP' s may be used in a
variety of applications, including medical applications in which
they are configured to provide a degree of inherent radiopacity
that may provide significant advantages. It will be understood that
the degree to which the attached heavy atoms render the polymer
easier to detect by medical imaging techniques will generally
depend on the amount of heavy atoms incorporated into the polymer
and the configuration (e.g., thickness) of the polymer.
[0015] In addition to heavy atoms, HACSCCP's also contain
crystallizable side chains. Side chain crystallizable (SCC)
polymers, sometimes called "comb-like" polymers, are well-known,
see N. A. Plate and V. P. Shibaev, J. Polymer Sci.: Macromol. Rev.
8:117-253 (1974), the disclosure of which is hereby incorporated by
reference. It will be understood that HACSCCP' s are a type of SCC
polymer, and that reference herein to SCC polymers includes
HACSCCP' s, unless otherwise stated. In an embodiment, the SCC
polymer is substantially free of heavy atoms. HACSCCP's may be SCC
polymers that have been modified to include heavy atoms, e.g., by
bonding heavy atoms to an SCC polymer and/or by making a HACSCCP by
polymerizing monomers that contain heavy atoms. SCC polymers may
have various configurations, e.g., homopolymer, copolymer (e.g.,
random copolymer, alternating copolymer, block copolymer, graft
copolymer), various tacticities (e.g., random, isotactic, atactic,
syndiotactic), etc. A SCC polymer may be a mixture or blend of two
or more SCC polymers, each of the individual SCC polymers in the
mixture or blend having different configurations, different levels
of heavy atom content, molecular weights, melting points, etc. The
polymer backbone or main chain of the SCC polymer, to which the
crystallizable side chains are attached, may be configured in
various ways, e.g., linear, branched, crosslinked, dendritic,
single-stranded, double-stranded, etc. Preferred SCC polymers for
medical applications are inherently radiopaque, biocompatible
and/or bioresorbable. The heavy atoms may be attached to the main
chain and/or the side chains of a HACSCCP.
[0016] The crystallizable side chains of SCC polymers (including,
e.g., HACSCCP's) are preferably selected to crystallize with one
another to form crystalline regions and may comprise, for example,
--(CH.sub.2).sub.n-- and/or --((CH.sub.2).sub.m--O--).sub.n groups.
The side chains are preferably linear to facilitate
crystallization. For SCC polymers that contain --(CH.sub.2).sub.n--
groups in the crystallizable side chain, n is preferably in the
range of about 6 to about 30, more preferably in the range of about
20 to about 30. For SCC polymers that
contain--((CH.sub.2).sub.m--O--).sub.n groups in the crystallizable
side chain, n is preferably in the range of about 6 to about 30 and
m is preferably in the range of about 1 to about 8. More
preferably, m and n are selected so that the
((CH.sub.2).sub.m--O--).sub.n groups contain from about 6 to about
30 carbon atoms, even more preferably from about 20 to about 30
carbon atoms. The spacing between side chains and the length and
type of side chain are preferably selected to provide the resulting
SCC polymer with a desired melting point. For example, for medical
applications (e.g., embolotherapy), the spacing between side chains
and the length and type of the side chains are preferably selected
to provide the SCC polymer (and/or the material into which it is
incorporated) with a melting point in the range of about 30.degree.
C. to about 80.degree. C. As the spacing between side chains
increases, the tendency for the side chains to be crystallizable
tends to decrease. Likewise, as the flexibility of the side chains
increases, the tendency for the side chains to be crystallizable
tends to decrease. On the other hand, as the length of the side
chains increases, the tendency for the side chains to be
crystallizable tends to increase. In many cases, the length of the
crystallizable side chain may be in the range of about two times to
about ten times the average distance between crystallizable side
chains of the SCC polymer.
[0017] Examples of SCC polymers include versions of the following
polymers that are selected so that the alkyl group is sufficiently
long (e.g., greater than about 6 carbons) to provide the desired
melting point and, for HACSCCP's, modified to include heavy atoms,
e.g., sufficient heavy atoms to render them radiopaque:
poly(1-alkene)s, poly(alkyl acrylate)s, poly(alkyl methacrylate)s,
poly(alkyl vinyl ether)s, and poly(alkyl styrene)s. Examples of SCC
polymers further include versions of the polymers disclosed in the
following references that include (or have been modified to
include) crystallizable side chains and, for HACSCCP's, heavy
atoms, e.g., sufficient heavy atoms to render them radiopaque: U.S.
Pat. Nos. 4,638,045; 4,863,735; 5,198,507; 5,469,867; 5,912,225;
and 6,238,687; as well as U.S. Provisional Patent Application No.
60/601,526, filed 13 August 2004; all of which are incorporated by
reference in their entireties, and particularly for the purpose of
describing SCC polymers and methods for making them.
[0018] In an embodiment, the side chains are selected to provide
the SCC polymer (or material into which the SCC polymer is
incorporated) with a controllable melting temperature. In a
preferred embodiment, polymeric embolotherapy products include
HACSCCP' s configured to render the embolotherapy product
detectable by a technique such as X-ray. The side chains of the
included HACSCCP may be selected so that the polymeric
embolotherapy product has a melting point higher than the body
temperature of the mammal for which the product is intended. Such a
polymeric embolotherapy product may, for example, be heated above
the melting temperature to render it more flowable, thereby
facilitating delivery to the target vasculature, where it may cool
and solidify to embolize the vasculature. The use of inherently
radiopaque HACSCCP' s to provide radiopacity and a controlled
melting point may be particularly advantageous in medical
applications, but those skilled in the art will recognize
additional applications as well. Thus, while the various
descriptions herein regarding the use of SCC polymers may indicate
a preference for medical applications, it will be understood that
various technologies outside the medical area may also benefit from
the use of SCC polymers, and particularly HACSCCP's.
[0019] Furthermore, in some embodiments, the present SCC polymers
may be used to develop various medical devices. For instance,
pre-fabricated off-the-shelf devices, rapidly prototyped devices,
real-time prototype devices using computer technology. Additionally
present polymers may be delivered directly to a non-lumen or
non-cavity of the body. The various medical devices may include but
are not limited to stents and stent grafts for vascular and body
lumen applications, pins, screws, sutures, anchors and plates for
reconstructive skeletal or soft tissue applications, cartilage
replacements. SCC polymers may be placed directly in body tissue
for example in subcutaneous and intramuscular tissue.
[0020] An embodiment of a HACSCCP is a polymer comprising a main
chain, a plurality of crystallizable side chains, and a plurality
of heavy atoms attached to the polymer, the heavy atoms being
present in an amount that is effective to render the polymer
radiopaque. A polymer that comprises a recurring unit of the
formula (I) is an example of such an HACSCCP:
##STR00001##
[0021] In formula (I), X.sup.1 and X.sup.2 are each independently
selected from the group consisting of Br and I; y.sup.1 and y.sup.2
are each independently zero or an integer in the range of 1 to 4;
and A.sup.1 is selected from the group consisting of
##STR00002##
[0022] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.30 alkyl, C.sub.1-C.sub.30 heteroalkyl,
C.sub.5-C.sub.30 aryl, C.sub.6-C.sub.30 alkylaryl, and
C.sub.2-C.sub.30 heteroaryl; R.sup.4 selected from the group
consisting of H, C.sub.1-C.sub.30 alkyl, and C.sub.1-C.sub.30
heteroalkyl; R.sup.1 is
##STR00003##
[0023] R.sup.5 and R.sup.6 are each independently selected from the
group consisting of --CH.dbd.CH--, --CHJ.sup.1-CHJ.sup.2-, and
--(CH.sub.2).sub.a--; a is zero or an integer in the range of 1 to
8; J.sup.1 and J.sup.2 are each independently selected from the
group consisting of Br and I; and Z is an O or an S; and Q is a
crystallizable group comprising from about 6 to about 30 carbon
atoms, preferably from about 20 to about 30 carbon atoms. In an
embodiment, Q is:
##STR00004##
[0024] Polymers of the formula (I) may be prepared by modifying the
general methods described in U.S. Provisional Patent Application
No. 60/601,526, filed 13 Aug. 2004, to select the appropriate side
chain length, side chain spacing and halogen content.
[0025] It will be recognized that Q and/or R.sup.4 may comprise
crystallizable side chains, that each of X, J.sup.1 and J.sup.2 is
a heavy atom, and that y may be adjusted so that the number of
heavy atoms in the polymer is sufficient to render the polymer
radiopaque. Q and R.sup.4 may each independently comprise units
selected from the group consisting of --(CH.sub.2).sub.n1-- and
--((CH.sub.2).sub.m1--O--).sub.n1; where ml and n1 are each
independently selected so that Q and/or R.sup.4 each independently
contain from about 1 to about 30 carbon atoms, preferably from
about 6 to about 30 carbon atoms, and more preferably from about 20
to 30 carbon atoms. Moreover, Q and R.sup.4 may include other
functional groups such as ester and amide, and/or heavy atoms such
as iodine and bromine. Non-limiting examples of Q and R.sup.4 thus
include --C.sub.n1H.sub.2n1+1, --CO.sub.2--C.sub.n1H.sub.2n1+1,
--CONH--C.sub.n1H.sub.2n1+1, --(CH.sub.2).sub.n1--Br,
--(CH.sub.2).sub.n1--I, --CO.sub.2--(CH.sub.2).sub.n1--Br,
--CO.sub.2--(CH.sub.2).sub.n1--I,
--CONH--CO.sub.2--(CH.sub.2).sub.n1--Br, and
--CONH--CO.sub.2--(CH.sub.2).sub.n1--I. In an embodiment, R.sup.5
is --CH.dbd.CH-- or --(CH.sub.2).sub.a--; R.sup.6 is
--(CH.sub.2).sub.a--; and Q is an ester group comprising from about
10 to about 30 carbon atoms.
[0026] It will be understood that a polymer that comprises a
recurring unit of the formula (I) may be a copolymer, e.g., a
polymer of the formula (I) that further comprises recurring
--R.sup.2-A.sup.2-units, where R.sup.2 is selected from the group
consisting of --(CH.sub.2).sub.n2-- and --((CH.sub.2).sub.n2; where
m2 and n2 are each independently selected so that R.sup.2 contains
from about 1 to about 30 carbon atoms; and where A.sup.2 is defined
in the same manner as A.sup.1 above. Thus, an embodiment provides a
polymer comprising recurring units of the formula (Ia):
##STR00005##
[0027] In formula (Ia), X.sup.1, X.sup.2, y.sup.1, y.sup.2, R.sup.1
and A.sup.1 are defined as described above for formula (I); p and q
may each be independently varied over a broad range to provide a
polymer having the desired properties, e.g., melting point,
radiopacity, and viscosity, using routine experimentation. In an
embodiment, p and q are each independently an integer in the range
of 1 to about 10,000. It will be appreciated that the formula (I)
units and --(R.sup.2-A.sup.2)-units in a polymer comprising
recurring units of the formula (Ia) may be arranged in various
ways, e.g., in the form of a block copolymer, random copolymer,
alternating copolymer, etc.
[0028] Another embodiment of a HACSCCP (e.g., a polymer comprising
a main chain, a plurality of crystallizable side chains, and a
plurality of heavy atoms attached to the polymer, the heavy atoms
being present in an amount that is effective to render the polymer
radiopaque) comprises a recurring unit of the formula (II):
##STR00006##
[0029] In formula (II), R.sup.7 is H or CH.sub.3; A.sup.3 is a
chemical group having a molecular weight of about 500 or less; and
A.sup.3 bears at least one of the heavy atoms attached to the
polymer. Non-limiting examples of A.sup.3 include metal carboxylate
(e.g., --CO.sub.2Cs), metal sulfonate (e.g., --SO.sub.4Ba),
halogenated alkyl ester (e.g., --CO.sub.2--(CH.sub.2).sub.b--Br),
halogenated alkyl amide (e.g., --CONH--(CH.sub.2).sub.b--Br), and
halogenated aromatic (e.g., --C.sub.6H.sub.4--I), where b is an
integer in the range of about 1 to about 4. In an embodiment,
A.sup.3 comprises an aromatic group bearing at least one halogen
atom selected from the group consisting of bromine and iodine. In
another embodiment, A.sup.3 comprises a chemical group of the
formula-L.sub.1-(CH.sub.2).sub.n3-L.sub.2-Ar.sup.1, wherein L.sub.1
and L.sub.2 each independently represent a nullity (i.e., are not
present), ester, ether or amide group; n3 is zero or an integer in
the range of about 1 to about 30; and Ar.sup.1 comprises a
halogenated aromatic group containing from about 2 to about 20
carbon atoms. HACSCCP's that comprise a recurring unit of the
formula (II) may be formed by polymerization of the corresponding
monomers or by post-reaction of appropriate polymeric precursors.
HACSCCP's that comprise a recurring unit of the formula (II) may be
copolymers that include additional recurring units.
[0030] Side chain A.sup.3 groups in a HACSCCP comprising a
recurring unit of the formula (II) may be crystallizable and/or the
HACSCCP comprising a recurring unit of the formula (II) may further
comprise a second recurring unit that comprises a crystallizable
side chain. Examples of suitable second recurring units having
crystallizable side chains include the following: poly(1-alkene)s,
poly(alkyl acrylate)s, poly(alkyl methacrylate)s, poly(alkyl vinyl
ether)s, and poly(alkyl styrene)s. The alkyl groups of the
foregoing exemplary second recurring units preferably contain more
than 6 carbon atoms, and more preferably contain from about 6 to
about 30 carbon atoms. For example, in an embodiment, the second
recurring unit is of the formula (III):
##STR00007##
[0031] In formula (III), R.sup.8 is H or CH.sub.3; L.sup.3 is an
ester or amide linkage; and R.sup.9 comprises a C.sub.6 to C.sub.30
hydrocarbon group. HACSCCP's comprising a recurring unit of the
formula (II) and a second recurring unit (such as a recurring unit
of the formula (III)) may be formed by copolymerization of the
corresponding monomers and/or by post-reaction of appropriate
polymeric precursors.
[0032] Another embodiment of a HACSCCP (e.g., a polymer comprising
a main chain, a plurality of crystallizable side chains, and a
plurality of heavy atoms attached to the polymer, the heavy atoms
being present in an amount that is effective to render the polymer
radiopaque) comprises a recurring unit of the formula (IV), where
A.sup.3 is defined above:
##STR00008##
[0033] In formula (IV), A.sup.4 represents H or a group containing
from about 1 to about 30 carbons, e.g., a C.sub.1-C.sub.30
hydrocarbon. Side chain A.sup.3 and/or A.sup.4 groups in a HACSCCP
comprising a recurring unit of the formula (IV) may be
crystallizable and/or the HACSCCP comprising a recurring unit of
the formula (IV) may further comprise a second recurring unit that
comprises a crystallizable side chain. For example, in an
embodiment, the second recurring unit is of the formula (V), where
R.sup.10 comprises a C.sub.6 to C.sub.30 hydrocarbon group and
R.sup.11 represents H or a group containing from about 1 to about
30 carbons, e.g., a C.sub.1-C.sub.30 hydrocarbon:
##STR00009##
[0034] Another embodiment of a HACSCCP comprises a recurring unit
of the formula (VI):
##STR00010##
[0035] wherein R.sup.12 is H or CH.sub.3 and n4 is an integer in
the range of about 1 to about 1,000. In preferred embodiments, a
HACSCCP comprising a recurring unit of the formula (VI) is
biocompatible. In another embodiment, a medical device (e.g., a
stent, catheter or any other medical device described herein)
comprises a polymer that comprises a recurring unit of the formula
(VI). Recurring units of the formula (VI) may be formed in various
ways. For example, a starting polymer comprising recurring
hydroxyethylmethacrylate (HEMA) units may be provided, and at least
a portion of those recurring hydroxyethylmethacrylate (HEMA) units
may be reacted with caprolactone to form recurring units of the
formula (VIa) having crystallizable poly(caprolactone) (PCL) groups
in the side chain as illustrated in Scheme A below.
##STR00011##
[0036] Polymerization of the caprolactone to form the
crystallizable PCL groups may be conducted by using an appropriate
catalyst, e.g., stannous octoate. The melting point of the side
chain (and the HACSCCP) may be controlled by manipulating the
degree of polymerization (n4) of the PCL groups, e.g., by adjusting
the relative amounts of HEMA recurring units and caprolactone
monomer during polymerization, in a manner generally know to those
skilled in the art. The melting point may also be controlled by
manipulating the spacing along the polymer backbone between PCL
groups, e.g., by appropriate selection of the amount of HEMA
recurring units in the starting polymer. In an embodiment, n4 is an
integer in the range of about 2 to about 10. Heavy atoms may be
included in a HACSCCP that comprises a recurring unit of the
formula (VI) in various ways, e.g., the HACSCCP may further
comprise a recurring unit of the formula (II) as described
above.
[0037] SCC polymers are not limited to those described above (e.g.,
not limited to HACSCCP's comprising recurring units of the formulae
(I) to (VI)), and further include versions of known polymers that
have been modified to include side-chain crystallizable groups
and/or sufficient heavy atoms to render the resulting polymer
radiopaque. Those skilled in the art will understand that HACSCCP's
may be prepared in various ways, e.g., by employing routine
experimentation to modify known methods for making SCC polymers to
thereby incorporate heavy atoms into the resulting polymers. For
example, inherently radiopaque versions of the side chain
crystallizable polymers described in U.S. Pat. No. 5,469,867 may be
prepared by copolymerizing the corresponding monomers with monomers
that contain heavy atoms. U.S. Pat. No. 5,469,867 is incorporated
by reference and particularly for the purpose of describing
monomers, polymers and methods of polymerization. Examples of
suitable monomers that contain heavy atoms are disclosed in Kruft,
et al., "Studies On Radio-opaque Polymeric Biomaterials With
Potential Applications To Endovascular Prostheses," Biomaterials 17
(1996) 1803-1812; and Jayakrishnan et al., "Synthesis and
Polymerization of Some Iodine-Containing Monomers for Biomedical
Applications," J. Appl. Polm. Sci., 44 (1992) 743-748. HACSCCP's
may also be prepared by post-reaction, e.g., by attaching heavy
atoms to the polymers described in U.S. Pat. No. 5,469,867.
Specific examples of SCC polymers that may be modified with heavy
atoms to make HACSCCP's include the acrylate, fluoroacrylate,
methacrylate and vinyl ester polymers described in J. Poly. Sci,
10.3347 (1972); J. Poly. Sci. 10:1657 (1972); J. Poly. Sci. 9:3367
(1971); J. Poly. Sci. 9:3349 (1971); J. Poly. Sci. 9:1835 (1971);
J.A.C.S. 76:6280 (1954); J. Poly. Sci. 7:3053 (1969); Polymer J.
17:991 (1985), corresponding acrylamides, substituted acrylamide
and maleimide polymers (J. Poly. Sci.: Poly. Physics Ed. 11:2197
(1980); polyolefin polymers such as those described in J. Poly.
Sci.: Macromol. Rev. 8:117-253 (1974) and Macromolecules 13:12
(1980), polyalkyl vinylethers, polyalkylethylene oxides such as
those described in Macromolecules 13:15 (1980), alkylphosphazene
polymers, polyamino acids such as those described in Poly. Sci.
USSR 21:241, Macromolecules 18:2141, polyisocyanates such as those
described in Macromolecules 12:94 (1979), polyurethanes made by
reacting amine- or alcohol-containing monomers with long-chain
alkyl isocyanates, polyesters and polyethers, polysiloxanes and
polysilanes such as those described in Macromolecules 19:611
(1986), and p-alkylstyrene polymers such as those described in
J.A.C.S. 75:3326 (1953) and J. Poly. Sci. 60:19 (1962). The
foregoing SCC polymers may be modified with heavy atoms to make
HACSCCP's in various ways. For example, monomers bearing heavy
atoms may be prepared by iodinating and/or brominating the monomers
used to make the foregoing polymers. Those heavy atom-bearing
monomers may then be copolymerized with the unmodified monomers to
prepare HACSCCP's. Those skilled in the art may identify conditions
for making the heavy atom-bearing monomers and corresponding
HACSCCP's by routine experimentation.
[0038] In another embodiment, a HACSCCP is prepared by reacting a
side chain crystallizable polymer with a heavy metal reagent under
conditions selected to attach a plurality of heavy atoms to the
side chain crystallizable polymer. For example, the side chain
crystallizable polymer may be exposed to a heavy metal reagent that
comprises bromine and/or iodine. Examples of heavy metal reagents
include bromine vapor, iodine vapor, bromine solution and iodine
solution. The side chain crystallizable polymer may be exposed to
the heavy metal reagent by, e.g., exposing or intermixing the solid
polymer with heavy metal reagent and/or by dissolving or dispersing
the side chain crystallizable polymer in a solvent and intermixing
with the heavy metal reagent. Other methods may also be used.
[0039] SCC polymers may contain various amounts of heavy atoms
and/or crystallizable side chains, depending on the properties
desired for the SCC polymer. Preferably, the content of
crystallizable side chains is sufficient to substantially reduce or
prevent main chain crystallization. In many cases, the amount of
crystallizable side chain in the SCC polymer is in the range of
about 20% to about 80% by weight, based on total polymer weight,
and in some cases may be in the range of about 35% to about 65%,
same basis. The length of the SCC polymer crystallizable side chain
is preferably in the range of about two times to about ten times
the average distance between crystallizable side chains. SCC
polymers may comprise a crystalline region (e.g., formed by
crystallization of the side chains below the melting point of the
polymer) and a non-crystalline region (e.g., a glassy or
elastomeric region formed by the non-crystallizable portions of the
SCC polymer). In an embodiment, the non-crystalline region has a
glass transition temperature that is higher than the body
temperature of a mammal, e.g., higher than about 37.degree. C.; in
another embodiment, the non-crystalline region has a glass
transition temperature that is lower than the body temperature of a
mammal, e.g., lower than about 37.degree. C. The amount of heavy
atoms in a particular SCC polymer may be selected based on the
degree of radiopacity and/or material (mechanical) properties
desired. For example, for medical applications, a HACSCCP
preferably contains from about 1% to about 90% heavy atoms, more
preferably about 20% to about 50% by heavy atoms, by weight based
on total weight of HACSCCP. In some cases, the SCC polymer is
incorporated into a polymeric material and/or formed into a medical
device as described below. When the SCC polymer is a HACSCCP, the
amount of heavy atoms in the HACSCCP may be adjusted to provide the
resulting polymeric material and/or medical device with the desired
degree of radiopacity.
[0040] The indiscriminate incorporation of heavy atoms into side
chain crystallizable polymers often disrupts or prevents otherwise
crystallizable side chains from crystallizing, particularly when
the levels of heavy atom incorporation are high, the side chains
are relatively short, the side chains are relatively flexible,
and/or the distance between side chains is relatively large.
Preferably, the heavy atoms are attached to the HACSCCP in a manner
that minimizes or eliminates disruption of side chain
crystallinity. For example, in an embodiment, at least about 50%,
preferably at least about 80%, of the heavy atoms are attached to
the main chain of the HACSCCP. In another embodiment, at least
about 50%, preferably at least about 80%, of the heavy atoms are
attached to the ends of the side chains of the HACSCCP, e.g., to
the ends of the crystallizable side chains and/or to
non-crystallizable side chains. In another embodiment, at least
about 50%, preferably at least about 80%, of the heavy atoms are
attached to either the main chain or the side chains
(crystallizable and/or non-crystallizable) of the HACSCCP. In
another embodiment, the HACSCCP is a block copolymer that comprises
a crystalline block and an amorphous block, and at least about 50%,
preferably at least about 80%, of the heavy atoms are attached to
the amorphous block.
[0041] The molecular weight of SCC polymers may be selected in view
of the intended application for the polymer. For example, in some
medical applications, e.g., for certain embolotherapy applications,
it is desirable for the SCC polymer to flow at temperatures higher
than the polymer melting point and to form a solid at temperatures
below the polymer melting point. The viscosity of a molten SCC
polymer generally increases as the molecular weight of the polymer
increases, and thus the molecular weight of a particular SCC
polymer is preferably selected to provide the desired molten
polymer viscosity. For example, a suitable molecular weight range
for SCC polymers used in embolotherapy products may be in the range
of from about 2,000 to about 250,000, preferably from about 5,000
to about 150,000. Molecular weights are weight average as
determined by high pressure size exclusion chromatography using
light scattering detection.
[0042] In some cases, it may be desirable to mix or blend the SCC
polymer with a second material (e.g., a second polymer) to form a
polymeric material, which may then be employed in the intended
application. For example, an embodiment provides a polymeric
material that comprises a SCC polymer (e.g., a HACSCCP) and a
second polymer. Preferably, the second polymer is biocompatible
and/or bioresorbable. Examples of second polymers suitable for
mixing or blending with SCC polymers to form polymeric materials
include the non-inherently radiopaque polymers disclosed in U.S.
Pat. No. 5,469,867 and the radiopaque polymers described in U.S.
Provisional Patent Application No. 60/601,526, filed 13 Aug. 2004,
both of which are incorporated by reference. Depending on the
intended application, the relative amounts of SCC polymer and
second polymer in the polymeric material may vary over a broad
range. For example, in an embodiment, a polymeric material
comprises from about 1% to about 100% of a SCC polymer and up to
about 99% of a second polymer, by weight based on total. Since a
polymeric material may consist solely of SCC polymer, it will be
appreciated that the term "polymeric material" as used herein
includes SCC polymers (such as HACSCCP's). As noted above, it will
be understood that the SCC polymer itself may be a mixture or blend
of two or more individual SCC polymers, each having, for example,
different molecular weights, configurations and/or melting
points.
[0043] A polymeric material that comprises a SCC polymer may be
formed into various configurations or pre-formed shapes, e.g., a
rod, a particle, or a sheet. A rod may be linear, coiled, hollow,
highly elongated (e.g., a string or strand), and may have various
cross-sections shapes, e.g., substantially round, substantially
elliptical, substantially triangular, substantially rectangular,
irregular, etc. A particle may be a spherical particle, a
geometrically non-uniform particle (e.g., a flake or chip), a
porous particle, a hollow particle, a solid particle, etc. A
particle preferably has a excluded diameter of from about 10
microns to about 5,000 microns.
[0044] The configuration of the polymeric material may depend on
various factors such as the intended application, shipping
constraints, processing constraints, etc. For example, an
embodiment provides a medical device that comprises a polymeric
material. The polymeric material may comprise a SCC polymer.
Non-limiting examples of medical devices that may comprise an SCC
polymer include, for example, a stent (e.g., an expandable stent),
stent graft, annuloplasty ring, vascular graft, suture, vascular
cuff, septal defect repair device, heart valve, heart valve
component, heart valve repair device, closure device, inducer of
vasculature and connective tissue proliferation, catheter (e.g.,
balloon catheter configured to deliver a stent) and/or a tissue
engineered implant. Various medical device embodiments are
described in greater detail below. It will be appreciated that a
medical device may consist solely of a polymeric material that
consists solely of a SCC polymer. For example, in an embodiment, a
medical device is configured to be deliverable (e.g., by injection,
catheter, physical insertion, pouring, a heated rod, spraying
and/or squirting) to a body cavity of a mammal. Such a device may
be, for example, an embolotherapy product formed primarily of a
polymeric material that comprises a HACSCCP. Thus, while certain
descriptions below may be directed to medical devices, it will be
understood that such descriptions also apply to polymeric materials
and to SCC polymers (including HACSCCP's), unless the context
indicates otherwise. Likewise, descriptions herein of polymeric
materials and of SCC polymers also apply to medical devices, unless
the context indicates otherwise.
[0045] A medical device that comprises a SCC polymer may be a
medical device in which at least a portion of the SCC polymer is
positioned at a surface of the medical device. It has been found
that such positioning of the SCC polymer at a surface of the
medical device allows the surface properties of the medical device
to be manipulated as a function of temperature, e.g., the SCC
polymer at the surface may provide increased biocompatibility
and/or function as a temperature-dependent lubricant and/or
adhesive, e.g., at an interface with one or more other medical
devices and/or medical device components. The SCC polymer may be
positioned at the surface of the medical device in various ways.
For example, amounts of a SCC polymer may be applied to selected
locations on the surface of the medical device; a SCC polymer may
be coated onto the surface of a medical device; a film of SCC
polymer may be applied to a medical device; and/or a medical device
may be manufactured in such a way that a SCC polymer is formed at a
surface. For example, in an embodiment, radiopaque and/or
crystallizable groups may be grafted onto the surface of a
polymeric medical device, e.g., by reacting radiopaque and/or
crystallizable groups with functional groups on the surface and/or
by polymerizing radiopaque and/or crystallizable monomers from
initiation sites on the surface to thereby form polymeric
radiopaque and/or crystallizable groups. Functional groups and
initiation sites may be created on the surface of a polymeric
medical device in various ways. For example, treatment of a polymer
surface with ionizing radiation (e.g., e-beam and/or gamma
radiation) and/or plasma in the presence of oxygen may result in
the formation of --OH groups on the polymer surface. Such --OH
groups may then be reacted with an isocyanate-functionalized
radiopaque and/or crystallizable group to thereby attach those
groups to the surface by forming urethane linkages. Polymerization
of an appropriate monomer such as caprolactone may be initiated
from the --OH groups in the presence of a suitable catalyst (such
as stannous octoate) to form crystallizable PCL groups that are
attached to the polymer surface. As another example, treatment of a
polymer surface with ionizing radiation and/or plasma may produce
active surface sites capable of initiating the polymerization of
photo- and/or radiation-sensitive crystallizable monomers
(1-alkenes containing from about 6 to about 30 carbons), thereby
grafting a side-chain crystallizable polymer onto the surface of
the polymeric medical device. The group attached to the surface may
be radiopaque and/or crystallizable. In an embodiment, the
polymeric medical device comprises a SCC polymer attached to the
surface thereof.
[0046] The temperature-dependent properties (e.g., adhesion,
lubrication, etc.) of a particular SCC polymer positioned at a
surface of a medical device typically depend on the nature of the
surface, the nature of the SCC polymer and the nature of the
interactions between them. For example, in some cases, relatively
low molecular weight SCC polymers tend to have better adhesive
properties at temperatures above the melting point of the SCC
polymer, as compared to the adhesive properties of those SCC
polymers at temperatures below the melting point. On the other
hand, in some cases, relatively high molecular weight SCC polymers
tend to have better adhesive properties at temperatures below the
melting point than at temperatures above the melting point.
Relatively non-polar SCC polymers capable of forming relatively
weak intermolecular interactions, such as heavily fluorinated SCC
polymers, tend to be better lubricants than relatively polar SCC
polymers capable of forming relatively strong intermolecular
interactions, depending on the nature of the surface of the medical
device. The use of a particular SCC polymer to provide
temperature-dependent functionality at a surface of a medical
device is preferably determined by routine experimentation, in view
of general principles of adhesion known to those skilled in the art
as informed by the guidance provided herein.
[0047] A medical device that comprises a polymeric material may
include one or more additional components, e.g., a plasticizer, a
filler, a crystallization nucleating agent, a preservative, a
stabilizer, a photoactivation agent, etc., depending on the
intended application. For example, in an embodiment, a medical
device comprises an effective amount of at least one therapeutic
agent and/or a magnetic resonance enhancing agent. Non-limiting
examples of preferred therapeutic agents include a chemotherapeutic
agent, a non-steroidal anti-inflammatory, a steroidal
anti-inflammatory, and a wound healing agent. Therapeutic agents
may be co-administered with the polymeric material. In a preferred
embodiment, at least a portion of the therapeutic agent is
contained within the polymeric material. In another embodiment, at
least a portion of the therapeutic agent is contained within a
coating on the surface of the medical device.
[0048] Non-limiting examples of preferred chemotherapeutic agents
include taxanes, taxinines, taxols, paclitaxel, dioxorubicin,
cis-platin, adriamycin, and bleomycin. Non-limiting examples of
preferred non-steroidal anti-inflammatory compounds include
aspirin, dexamethasone, ibuprofen, naproxen, and Cox-2 inhibitors
(e.g., Rofexcoxib, Celecoxib and Valdecoxib). Non-limiting examples
of preferred steroidal anti-inflammatory compounds include
dexamethasone, beclomethasone, hydrocortisone, and prednisone.
Mixtures comprising one or more therapeutic agents may be used.
Non-limiting examples of preferred magnetic resonance enhancing
agents include gadolinium salts such as gadolinium carbonate,
gadolinium oxide, gadolinium chloride, and mixtures thereof.
[0049] Nucleating agents are materials that, in the presence of a
polymer, make crystallization of the polymer more thermodynamically
favorable. For example, a nucleating agent may accelerate polymer
crystallization at a given temperature and/or induce
crystallization (e.g., of a supercooled polymer) at a higher
temperature than in the absence of the nucleating agent.
Non-limiting examples of preferred nucleating agents include low
molecular weight analogs of the SCC polymers with higher peak
crystallization temperatures than the bulk polymer being
crystallized, carboxylate salts (such as sodium benzoate),
inorganic salts (such as barium sulfate) and various particulate
materials with relatively high surface area to volume ratios.
[0050] The amounts of additional components present in the medical
device are preferably selected to be effective for the intended
application. For example, a therapeutic agent is preferably present
in the medical device in an amount that is effective to achieve the
desired therapeutic effect in the patient to whom the medical
device is administered or implanted. Such amounts may be determined
by routine experimentation. In certain embodiments, the desired
therapeutic effect is a biological response. In an embodiment, the
therapeutic agent in the medical device is selected to promote at
least one biological response, preferably a biological response
selected from the group consisting of thrombosis, cell attachment,
cell proliferation, attraction of inflammatory cells, deposition of
matrix proteins, inhibition of thrombosis, inhibition of cell
attachment, inhibition of cell proliferation, inhibition of
inflammatory cells, and inhibition of deposition of matrix
proteins. The amount of magnetic resonance enhancing agent in a
medical devices is preferably an amount that is effective to
facilitate radiologic imaging, and may be determined by routine
experimentation.
[0051] The viscosity and/or melting point of a medical device that
comprises a SCC polymer typically depends on the relative amounts
of the SCC polymer and other components, if any, present in the
medical device. The viscosity and/or melting point of the medical
device (or polymeric material in the medical device) may be
controlled by manipulating the amount of SCC polymer in the medical
device and by selecting a SCC polymer that provides the resulting
medical device with the desired viscosity and/or melting point.
Thus, for example, to provide a polymeric material that has a
melting point of 40.degree. C., it may be desirable to select a SCC
polymer that has a somewhat higher melting point, e.g., about
45.degree. C., for incorporation into the polymeric material, to
compensate for the presence of a second polymer or other component
that has a tendency to lower the melting point of the SCC polymer
when in admixture with it. In an embodiment, a medical device
comprises a polymeric material that has a melting point in the
range of about 30.degree. C. to about 80.degree. C.
[0052] The polymeric material of the medical device is preferably
configured to flow at a temperature above the melting point. The
viscosity of the polymeric material at the temperature above the
melting point may vary over a broad range, depending on factors
such as the intended application. For example, for embolotherapy
products, the polymeric material preferably has a viscosity above
the melting point that allows the medical device to be delivered to
the target vasculature by a convenient technique such as by
injection through a syringe and/or by flowing through a catheter.
In such cases, the desired viscosity often depends on the diameter
of the syringe needle or catheter, e.g., lower viscosities are
typically preferred at smaller diameters. On the other hand, if the
viscosity is too low, the polymeric material may migrate away from
the target vasculature prior to cooling and solidifying. In an
embodiment, the polymeric material of the medical device has a
viscosity in the range of about 50 cP to about 500 cP at the
temperature above the melting point. In another embodiment, the
polymeric material has a viscosity in the range of about 500 cP to
about 5,000 cP at the temperature above the melting point. In
another embodiment, the polymeric material has a viscosity in the
range of about 5,000 cP to about 250,000 cP at the temperature
above the melting point. In another embodiment, the polymeric
material has a viscosity in the range of about 250,000 cP to about
1,000,000 cP at the temperature above the melting point.
[0053] In an embodiment, the polymeric material is configured to
form a solid mass upon delivery to a body cavity. The solid mass
may wholly or partially conform to an interior dimension of the
body cavity. For example, the polymeric material may be configured
to contain an amount of an SCC polymer that provides the polymeric
material with a melting point of about 40.degree. C. The polymeric
material may be further configured to be deliverable to the body
cavity, e.g., the polymeric material may be in the form of a rod
that may be heated to a molten state to facilitate flow. The molten
polymeric material may then be delivered to a body cavity by
flowing through a delivery device in the molten state. Upon arrival
in the body cavity, the molten polymeric material may at least
partially conform to the interior dimension of the body cavity,
then cool to form a solid mass. As another example, the polymeric
material may be in the form of small particles suspended in a
relatively low viscosity biocompatible carrier liquid such as water
or saline. The polymeric material may then be caused to flow
through a delivery device to the target body cavity. The small
particle of polymeric material may be heated prior to delivery,
during delivery and/or within the target cavity by, thereby causing
the polymeric material to flow and conform to an interior dimension
of the body cavity. Upon cooling, the polymeric material may form a
solid mass that continues to conform to the interior dimension of
the body cavity. It will be understood that polymeric materials of
various configurations and formulations before heating may vary in
their ability to conform to the body cavity once warmed and may
therefore be selected for this reason to tailor the treatment.
Further, it will be understood that the polymeric material need not
be completely melted to achieve delivery. For example, a polymeric
material may be formed into a particular shape, such as a coil,
then implanted into the target body cavity while retaining the
preformed shape. The polymeric material (e.g., coil) may be heated
prior to and/or during implantation for various reasons, e.g., to
render the coil more resilient and thus easier to deliver, and/or
to enable the coil to better conform to the body cavity into which
it is implanted. The polymeric material may also be caused to flow
outside the body then be delivered to the body cavity in a flowable
state.
[0054] An embodiment provides a shape memory polymeric material
that comprises a SCC polymer. For example, a SCC polymer may be
configured into a first shape such as a coiled shape by a standard
thermoplastic formation process and crosslinked to fix the memory
of the first shape. The formed SCC polymer coil may then be heated
to melt the SCC polymer, allowing it to be re-configured into a
second shape such as a rod shape. The cross-linking limits or
prevents thermoplastic flow while the SCC polymer is in the melted
state. The SCC polymer while still in the second shape may then be
cooled to a temperature at which the SCC polymer recrystallizes.
The recrystallization of the SCC polymer limits or prevents the
second shape (e.g., the rod shape) from returning to the first
shape (e.g., the coil shape). Upon re-heating to a temperature
above the melting point of the SCC polymer, the second shape
returns to the first shape, e.g., the rod reverts to its memory
state of a coil. Crosslinking of the SCC polymer may be carried out
in various ways known to those skilled in the art.
[0055] An embodiment provides a method of treatment that comprises
introducing a medical device as described herein (e.g., a medical
device that comprises a SCC polymer) into a body cavity of a mammal
in an amount that is effective to at least partially occlude the
body cavity. In general, such a method may be used to occlude any
type body cavity including, e.g., various body cavities that may
commonly be referred to as tubes, tubules, ducts, channels,
foramens, vessels, voids, and canals. In a preferred embodiment,
the medical device is an embolotherapy product. Preferably, the SCC
polymer is a HACSCCP. In another preferred embodiment, the body
cavity comprises vasculature, e.g., an arteriovenous malformation
or a blood vessel such as a varicose vein. The medical device may
be introduced to the body cavity in a variety of ways, including by
injection, by catheter and by surgical implantation. For a
particular body cavity, the medical device is preferably selected
so that the polymeric material has a melting point that is
sufficiently high that the polymer forms a solid mass at the normal
temperature of the body cavity, and sufficiently low so that that
softened or molten polymeric material may conform to a dimension of
the body cavity with little or no thermal damage to the mammal into
which it is introduced. Introduction of such a polymeric material
into the body cavity thus may comprise heating the polymeric
material to a temperature that is higher than the melting point
and/or cooling it to a temperature that is lower than the melting
point.
[0056] Various types of delivery devices may be used to introduce
the medical device to the body cavity, e.g., plastic tubes,
catheters, fine cannula, tapered cannula and various types of
syringes and hypodermic needles which are generally known to and
available to those in the medical profession. An embodiment
provides a medical apparatus that comprises a polymeric material
and a delivery device, where the polymeric material is an SCC
polymer, and where the polymeric material and the delivery device
are mutually configured to facilitate delivery of the polymeric
material to a body cavity by the delivery device. The polymeric
material is preferably contained within the delivery device, in an
amount that may vary somewhat depending on the particular body
cavity to be occluded and the amount and type of occlusion desired.
Those skilled in the art will be aware of the size of the cavity
being occluded based on the size of the patient, general knowledge
of anatomy, and thus use of diagnostic methods such as X-ray and
MRI. Those skilled in the art will be able to determine the amount
of polymer material to be included within the delivery device. In
general, an excess amount of polymeric material should be included
in the delivery device in order to provide for a certain margin of
error. In an embodiment, the medical apparatus comprises an
embolotherapy product and a tube, where the embolotherapy product
comprises a SCC polymer as described herein and where the tube is
configured to facilitate flow of the embolotherapy product to a
body cavity. For example, the tube may comprise a needle, cannula,
syringe, and/or catheter, and may be equipped with a heater
configured to heat the embolotherapy product to a temperature above
its melting point, e.g., to a temperature in the range of about
30.degree. C. to about 80.degree. C. The polymeric material may be
included within the delivery device in a solid form or heated
separately and provided in the delivery device in a flowable form.
In one embodiment, the medical apparatus may be prepackaged with
the polymeric material present within the delivery device and may
thereafter be heated in order to make the polymeric material
flowable. Heating may be applied from an exterior source such as an
air, water or oil bath or an electrical heater, in which case both
the delivery device and the polymeric material may be heated.
Heating can also be applied from an interior source, e.g., using a
small electrical resistive element at the end of a catheter through
which a thin rod of the solid polymeric material is passed, or
using a small laser directed at the tip of a rod of polymeric
material emerging from the end of a catheter.
[0057] The delivery device may include an extrusion nozzle which is
preferably relatively small in diameter such that it will not
seriously damage the tissue in the vicinity of the body cavity to
be occluded, but sufficiently large such that the polymeric
material can be readily extruded from the nozzle. For example, in
application that involves the occlusion of a body channel, the size
of the nozzle is generally related to the inside diameter of the
channel into which it is placed. For example, a 24 gauge needle
typically fits within the opening of the punctum which leads to the
canaliculus. A 2 mm catheter is typically appropriate for
introducing the polymeric material into the fallopian tubes. A 1/4
inch cannula is preferred for introducing the polymeric material
into the inner cavity of an adult humerus. When delivered in the
molten state, the polymeric material is preferably selected to have
a viscosity that facilitates passage of the polymeric material
through the extrusion nozzle. In general, relatively lower
viscosities are preferred for relatively smaller diameter
nozzles.
[0058] It will be understood that the delivery device may include
an extrusion nozzle with one or more delivery ports. The polymeric
material may be dispensed through multiple ports serially or
simultaneously. This approach may accommodate better packing and/or
stabilization of the polymeric material that cools and it may allow
for delivery of more polymeric material across a large surface
area. That various configurations and formulations may be
simultaneously delivered by the use of various delivery ports.
[0059] For example, in an embodiment, two or more polymeric
materials (each comprising a SCC polymer) may be delivered
sequentially to a body cavity. In an embolotherapy embodiment, a
first polymeric material is delivered to vascular structure. The
first polymeric material may have a first configuration, such as a
coil. The coil may be preformed, e.g., a shape memory coil as
described above that is delivered in a rod shape (forming a coil
upon delivery), or may be a coil that is formed during delivery by
extruding the polymeric material through a delivery port of the
delivery device having an appropriately configured die. The first
polymeric material is preferably delivered at a temperature higher
than its melting point, e.g., higher than the melting point of a
first SCC polymer in the first polymeric material.
[0060] A coil may be a relatively open structure that partially
occludes the vascular structure, reducing the blood flow without
completely stopping it. Although such partial occlusion may be
appropriate in some cases, in other cases further occlusion may be
desired. Such further occlusion may be accomplished by delivering a
second polymeric to the vascular structure in operable proximity to
the first polymeric material. The second polymeric material is
preferably delivered at a temperature higher than the its melting
point, e.g., higher than the melting point of a second SCC polymer
in the second polymeric material. The second polymeric material
preferably has a lower viscosity than the first polymeric material,
such that it may at least partially fill interstices or gaps in the
first polymeric material and/or between the first polymeric
material and the interior of the vascular structure. Thus, for
example, the second polymeric material may have the consistency of
a paste at a temperature above its melting point during delivery,
allowing it to fill in the spaces of the first polymeric material
coil.
[0061] One or more additional polymeric materials may be delivered
to a location in operable proximity to the first and second
polymeric materials. For example, the first and second polymeric
materials may only partially occlude the vascular structure,
although typically to a greater extend than the first polymer
alone. In such a case, it may be desirable to deliver a third
polymeric material to provide further occlusion. The third
polymeric material is preferably delivered at a temperature higher
than its melting point, e.g., higher than the melting point of a
third SCC polymer in the third polymeric material. The third
polymeric material preferably has a lower viscosity than the first
polymeric material, and more preferably lower than the second
polymeric material, such that it may at least partially fill
interstices or gaps in the polymeric mass formed by the first and
second polymeric materials and/or between the mass and the interior
of the vascular structure.
[0062] Those skilled in the art will appreciate that multiple
variations of the embodiments described above may be practiced. For
example, a single polymeric material may be delivered in multiple
doses or in different forms, e.g., as a coil in a first delivery
and as a paste in a second delivery, or as a paste in both the
first and second deliveries. Two or more polymeric materials may be
delivered simultaneously, e.g., a first polymeric material in a
coil shape may be coated or mixed with a second polymeric material
in a paste or liquid form to form a composite that comprises both
polymers, and the resulting composite may then be delivered to the
body cavity. Various body cavities may be the target of the
delivery, and/or the order in which the various polymeric materials
and forms are delivered may be varied. Delivery of a polymeric
material that comprises a SCC polymer may be combined, sequentially
or simultaneously, with the delivery of a different material, e.g.,
a metal embolic coil. Thus, for example, a polymeric material may
be delivered to a body cavity, and a metal embolic coil may be
delivered to the body cavity in contact with the polymeric
material. Various periods of time may pass between deliveries,
e.g., a polymeric material coil may be delivered to provide partial
occlusion of a body cavity, and a second polymeric material paste
may be delivered to a location in operable proximity to the coil
minutes, hours, days, weeks, months, or years later.
[0063] For embodiments in which the polymeric material is delivered
in the molten state, once a polymeric material has been included
within the delivery device and heated to a flowable state, the
nozzle of the delivery device (e.g., such as the tip of a needle,
catheter, and/or squirt nozzle) may be inserted into an opening of
a channel (or through the wall of cavity) to be occluded and the
polymer may be dispensed out of the nozzle into the body cavity.
The injection is preferably continued until the desired amount of
occlusion (e.g., vasculature blockage) is obtained. In some
instances, it may be desirable to occlude only part of a cavity.
Thereafter, the nozzle of the delivery device may be withdrawn.
[0064] After the polymeric material has been delivered, the method
may continue without operator interaction. For example, in the case
of embolotherapy, the circulatory system of the mammal will
typically cause a cooling effect on the surrounding tissues which
will cool the injected polymeric material. The polymeric material
is preferably selected such that it cools and solidifies after
losing only a small amount of energy, i.e., hardens after
decreasing in temperature by only a few degrees centigrade.
Usually, cooling takes only a few seconds or minutes to occur,
although there are times when it may be desirable for cooling to
occur more slowly, e.g., in the case where a bone is reset after
delivery. After cooling has taken place, the polymer preferably
solidifies within the cavity in a manner conforming to the shape of
the cavity and the channel is at least partially filled or blocked.
The polymeric material may remain in place in the cavity over long
periods of time. For preferred medical devices comprising
biocompatible, non-immunogenic material, little or no adverse
reaction is obtained. In certain embodiment, the polymer is
bioresorbable, and thus may diminish over time, in which case
surrounding tissue may fill the previously occluded region.
[0065] An effective cavity occlusion may also be achieved through
the use of SCC polymer material and various excipients. For
instance, the SCC polymer material may be delivered with (1) a
photopolymerizable material that cross links through the use of a
light; (2) a blood reactive substance that stimulates clotting such
as collagen or thrombin, and/or (3) a nucleating agent.
[0066] In an embodiment, the polymeric material may be readily
removed so as to again provide a cavity which functions in a normal
manner. For example, it may be desirable to remove the polymeric
material from a vas deferens or fallopian tube to restore
fertility. The polymeric material may be removed in various ways.
For example, the polymeric material may be removed by simple
mechanical extraction. In certain instances, devices such as
forceps and/or catheters with various attachment prongs connected
thereto can be inserted into the channel and used to attach to the
polymeric material and pull the polymeric material out of the
cavity or force it forward into a second cavity so that the first
cavity is no longer occluded and the polymeric material will not
cause any damage. Alternatively, a device such as a heated wire may
be brought into contact with the solidified polymeric material. By
heating the polymeric material with the heated wire, the
temperature of the polymeric material is raised above the melting
point of the polymeric material so that it again becomes flowable.
In the case of a channel (such as a duct or vein), the heating may
be continued until the flowable polymeric material flows from the
channel and the channel is reopened to provide normal function. In
certain circumstances, the liquid plug can be drawn, aspirated or
forced out of a channel, e.g., by suction with a gentle vacuum or
by using mild pressure created by air or a saline flow and/or by
mechanical breakup along with trapping and aspiration.
[0067] A preferred method of removing the solidified polymeric
material from a channel or other cavity is to inject a lipophilic
material such as a naturally occurring oil or a fatty acid ester
into the channel in the area surrounding the solidified polymeric
material. Preferably, a lipophilic material is selected that has a
tendency to diffuse into the polymeric material, thereby reducing
its melting point. The lipophilic material is preferably added in
an amount that is effective to reduce the melting point of the
polymeric material below body temperature to such an extent that
the polymer becomes flowable. Once the polymer becomes flowable,
the natural mechanical movement that occurs within channels of
living beings will tend to move the polymer from the channel,
thereby restoring the normal function of the channel.
[0068] In a preferred embodiment, the medical device comprises a
stent. The stent may comprise various configurations, e.g., a
configuration selected from the group consisting of a sheet stent,
a braided stent, a self-expanding stent, a wire stent, a deformable
stent, and a slide-and-lock stent.
[0069] In a preferred embodiment, the stent comprises at least two
substantially non-deforming elements arranged to form a tubular
member, the non-deforming elements being slidably interconnected
for allowing the tubular member to expand from a collapsed diameter
to an expanded diameter. In another variation the tubular member
comprises a series of slideably engaged radial elements and at
least one locking mechanism which permits one-way sliding of the
radial elements from a first collapsed diameter to a second
expanded diameter.
[0070] A stent on a catheter is commonly collectively referred to
as a stent system. Catheters include but are not limited to
over-the-wire catheters, coaxial rapid-exchange designs and the
Medtronic Zipper Technology that is a relatively new multi-exchange
delivery platform. Such catheters may include, for instance, those
described in U.S. Pat. Nos. 4,762,129; 5,232,445; 4,748,982;
5,496,346; 5,626,600; 5,040,548; 5,061,273; 5,350,395; 5,451,233
and 5,749,888. Additional examples of suitable catheter designs
include those described in U.S. Pat. Nos. 4,762,129; 5,092,877;
5,108,416; 5,197,978; 5,232,445; 5,300,085; 5,445,646; 5,496,275;
5,545,135; 5,545,138; 5,549,556; 5,755,708; 5,769,868; 5,800,393;
5,836,965; 5,989,280; 6,019,785; 6,036,715; 5,242,399; 5,158,548;
and 6,007,545. The disclosures of the above-cited patents are
incorporated herein in their entirety by reference thereto.
[0071] Catheters may be specialized for various purposes such as to
produce an ultrasound effect, electric field, magnetic field, light
and/or temperature effect. Heating catheters may include for
example those described in U.S. Pat. Nos. 5,151,100, 5,230,349;
6,447,508; and 6,562,021 as well as WO 90\14046 A1. Infrared light
emitting catheters may include for example those described in U. S.
Patent Nos. 5,910,816 and 5,423,321. The disclosures of the
above-cited patents and patent publications are incorporated herein
in their entirety by reference thereto.
[0072] In another preferred variation, the stent further comprises
an amount of a therapeutic agent (for example, a pharmaceutical
agent and/or a biologic agent) sufficient to exert a selected
therapeutic effect. The term "pharmaceutical agent", as used
herein, encompasses a substance intended for mitigation, treatment,
or prevention of disease that stimulates a specific physiologic
(metabolic) response. The term "biological agent", as used herein,
encompasses any substance that possesses structural and/or
functional activity in a biological system, including without
limitation, organ, tissue or cell based derivatives, cells,
viruses, vectors, nucleic acids (animal, plant, microbial, and
viral) that are natural and recombinant and synthetic in origin and
of any sequence and size, antibodies, polynucleotides,
oligonucleotides, cDNA's, oncogenes, proteins, peptides, amino
acids, lipoproteins, glycoproteins, lipids, carbohydrates,
polysaccharides, lipids, liposomes, or other cellular components or
organelles for instance receptors and ligands. Further the term
"biological agent", as used herein, includes virus, serum, toxin,
antitoxin, vaccine, blood, blood component or derivative,
allergenic product, or analogous product, or arsphenamine or its
derivatives (or any trivalent organic arsenic compound) applicable
to the prevention, treatment, or cure of diseases or injuries of
man (per Section 351(a) of the Public Health Service Act (42 U.S.C.
262(a)). Further the term "biological agent" may include 1)
"biomolecule", as used herein, encompassing a biologically active
peptide, protein, carbohydrate, vitamin, lipid, or nucleic acid
produced by and purified from naturally occurring or recombinant
organisms, antibodies, tissues or cell lines or synthetic analogs
of such molecules; 2) "genetic material" as used herein,
encompassing nucleic acid (either deoxyribonucleic acid (DNA) or
ribonucleic acid (RNA), genetic element, gene, factor, allele,
operon, structural gene, regulator gene, operator gene, gene
complement, genome, genetic code, codon, anticodon, messenger RNA
(mRNA), transfer RNA (tRNA), ribosomal extrachromosomal genetic
element, plasmagene, plasmid, transposon, gene mutation, gene
sequence, exon, intron, and, 3) "processed biologics", as used
herein, such as cells, tissues or organs that have undergone
manipulation. The therapeutic agent may also include vitamin or
mineral substances or other natural elements.
[0073] For devices placed in the vascular system, e.g., a stent,
the amount of the therapeutic agent is preferably sufficient to
inhibit restenosis or thrombosis or to affect some other state of
the stented tissue, for instance, heal a vulnerable plaque, and/or
prevent rupture or stimulate endothelialization. The agent(s) may
be selected from the group consisting of antiproliferative agents,
anti-inflammatory, anti-matrix metalloproteinase, and lipid
lowering, cholesterol modifying, anti-thrombotic and antiplatelet
agents, in accordance with preferred embodiments of the present
invention. In some preferred embodiments of the stent, the
therapeutic agent is contained within the stent as the agent is
blended with the polymer or admixed by other means known to those
skilled in the art. In other preferred embodiments of the stent,
the therapeutic agent is delivered from a polymer coating on the
stent surface. In another preferred variation the therapeutic agent
is delivered by means of no polymer coating. In other preferred
embodiments of the stent, the therapeutic agent is delivered from
at least one region or one surface of the stent. The therapeutic
may be chemically bonded to the polymer or carrier used for
delivery of the therapeutic of at least one portion of the stent
and/or the therapeutic may be chemically bonded to the polymer that
comprises at least one portion of the stent body. In one preferred
embodiment, more than one therapeutic agent may be delivered.
[0074] A preferred SCC polymer for use in the fabrication of a
stent should fulfill at least some of the following criteria:
[0075] Radiopacity is preferably sufficient to ensure visibility of
the stent structure against the background of a human chest by
X-ray fluoroscopy, the standard method used in the clinic. [0076]
Stents according to aspects of the present invention are preferably
formed with walls for providing a low crossing profile and for
allowing excellent longitudinal flexibility. In preferred
embodiments, the wall thickness is about 0.0001 inches to about
0.0250 inches, and more preferably about 0.0010 to about 0.0100
inches. However, the wall thickness depends, at least in part, on
the selected material. For example, the thickness may be less than
about 0.0060 inches for plastic and degradable materials and may be
less than about 0.0020 inches for metal materials. More
particularly, for a 3.00 mm stent application, when a plastic
material is used, the thickness is preferably in the range of about
0.0040 inches to about 0.0045 inches. However, a stent having
various diameters may employ different thicknesses for biliary and
other peripheral vascular applications. The above thickness ranges
have been found to provide preferred characteristics through all
aspects of the device including assembly and deployment. However,
it will be appreciated that the above thickness ranges should not
be limiting with respect to the scope of the invention and that the
teachings of the present invention may be applied to devices having
dimensions not discussed herein. [0077] The stents are preferably
hemocompatible to prevent acute thrombosis. Accordingly, the device
surfaces are preferably resistant to protein adsorption and
platelet/monocyte attachment. Further, the device surfaces ideally
favor endothelial overgrowth but discourage attachment and growth
of smooth muscle cells (which are responsible for the occurrence of
restenosis). [0078] Stents preferably maintain their mechanical
strength (e.g., hoop strength) for a period of about 1-24 months,
more preferably about 3-18 months, more preferably still about 3-12
months, and most preferably about 3-6 months.
[0079] Stents preferably have a desirable biodegradation and
bioresorption profile such that the stents reside for a period of
time in the body lumen such that at a later time any stent,
bioresorbable or metal or other, may be used to re-treat the
approximate same region of the blood vessel or allow for other
forms of vessel re-intervention such as vessel bypass.
[0080] In an embodiment, an SCC polymer-containing medical device
comprises a stent and/or a catheter, and thus an SCC
polymer-containing medical device may be a stent, or a stent system
comprising a stent and a delivery catheter. The SCC polymer may be
incorporated into such a medical device in various ways. For
example, in various embodiments, the body of the stent and/or
catheter may comprise or consist essentially of a SCC polymer; the
stent and/or catheter may be coated with a SCC polymer; the SCC
polymer may be located at an interface between parts of the medical
device, e.g., a between a stent and a catheter; the SCC polymer may
be a HACSCCP; and/or the SCC polymer may be positioned at a surface
of the stent and/or catheter. In medical device embodiments, the
SCC polymer is preferably biocompatible, and preferably has a
melting point in the in the range of about 30.degree. C. to about
80.degree. C.
[0081] A stent comprising a SCC polymer may be of any design (e.g.,
slide-and-lock stents, sheet stents (sometimes referred to as
jelly-roll stents), deformable stents, and self-expanding stents)
suitable for a given application. Preferably, a stent comprising an
SCC polymer is designed to be readily implantable in the artery or
tissue of an animal, such as a human, and to be expandable and/or
suitable for holding open an artery, e.g., after said artery is
opened via a medical procedure, such as an angioplasty. Examples of
suitable stent designs for use in the present invention include
"slide-and-lock" stents, including those disclosed in U.S. Pat.
Nos. 6,033,436; 6,224,626 and 6,623,521, co-pending U.S. patent
application Ser. No. 11/016,269, filed Dec. 17, 2004, and
co-pending U.S. patent application Ser. No. 11/200,656, filed Aug.
10, 2005, all of which are incorporated herein by reference.
[0082] With reference now to FIG. 1, a portion of a preferred stent
embodiment 320 is illustrated wherein radial elements 320(1),
320(2) are slidably interconnected. Each radial element is provided
with a rail 328 having a plurality of deflectable teeth 326. Each
of the teeth is angled upward and is configured to deflect downward
(i.e., in a radial direction). As the locking tabs 322, 324 slide
along the deflectable teeth 326, the teeth are caused to deflect
downward for allowing the tabs 322, 324 to pass over the teeth 326
during deployment. However, due to the angle of the teeth, the
locking tabs may only move in one direction. More particularly, if
a compressive force pushes the radial elements 320(1), 320(2) back
toward the collapsed condition, the locking tabs 322, 324 will abut
against the teeth 326, thereby preventing further relative
movement. All or some of the various elements (e.g., the elements
320(1), 320(2), 322, 324, 326, 328) of the stent embodiment 320 may
comprise or consist essentially of a SCC polymer.
[0083] Other suitable stent designs adaptable for use herein
include those used traditionally in metal and polymeric stents,
including various mesh, jelly-roll, sheet, zigzag, and helical coil
designs, e.g., the deformable stents by Palmaz such as U.S. Pat.
No. 4,733,665 and its successors which have controllable expansion
and a portion of the prosthesis that deforms with a force in excess
of the elastic limit. Other stent designs include the following
designs and their successors: U.S. Pat. No. 5,344,426 by Lau, U.S.
Pat. Nos. 5,549,662 and 5,733,328 by Fordenbacher, U.S. Pat. Nos.
5,735,872 and 5,876,419 by Carpenter, U.S. Pat. No. 5,741,293 by
Wijay, U.S. Pat. No. 5,984,963 by Ryan, U.S. Pat. Nos. 5,441,515
and 5,618,299 by Khosravi, U.S. Pat. Nos. 5,059,211; 5,306,286 and
5,527,337 by Stack, U.S. Pat. No. 5,443,500 by Sigwart, U.S. Patent
No. 5,449,382 by Dayton, U.S. Patent No. 6,409,752 by Boatman, and
the like.
[0084] Various temperature-dependent properties of the SCC polymer
(e.g., strength, flexibility, crystallinity, adhesion, etc.) may be
manipulated to enhance the performance of the medical device. For
example, the stent may be an expandable stent, e.g., a stent that
is designed or configured to have a changeable cross-sectional
dimension, e.g., a cross-sectional dimension that may be increased
upon positioning of the stent within a blood vessel where expansion
is desired. The stent may be mechanically expandable, heat
expandable, or it may be a hybrid stent that is both mechanically
and thermally expandable. In an embodiment, the body of the
expandable stent comprises an amount of SCC polymer that is
effective to allow the stent to be expandable at a temperature
above a melting point of the SCC polymer. For example, the
expandable stent may be positioned within the blood vessel,
expanded at a temperature above a melting point of the
biocompatible inherently radiopaque side chain crystallizable
polymer, then cooled (actively or passively) to a temperature below
the melting point. In an embodiment, at least a portion of the
expandable stent is heat expandable. Preferably, the heat
expandable portion is expandable at a temperature above a melting
point of the side chain crystallizable polymer. In an embodiment,
the expandable stent or a portion thereof comprises an amount of
SCC polymer that is effective to allow the stent to be expandable
at a temperature that is above body temperature (about 38.degree.
C.). For example, the stent may consist essentially of an SCC
polymer having a melting point in the range of about 40.degree. C.
to about 80.degree. C. Heating such a stent to a temperature above
the melting temperature increases the flexibility of the stent,
allowing it to assume the size and shape desired for adequate
function, e.g., support of the blood vessel. In an embodiment,
[0085] Prior to, during and/or after appropriate positioning within
the blood vessel, the expandable stent may be heated to a
temperature above the melting point and expanded by, e.g., use of a
balloon catheter positioned within the stent, in a manner generally
known to those skilled in the art. Optionally, a heated liquid may
be circulated through the balloon catheter to provide heating to
the expandable stent. After expansion, the stent may be cooled,
e.g., by allowing it to cool to the temperature of the surrounding
blood and/or tissue, and/or by circulating a cooling liquid through
the balloon catheter. Upon cooling below the recrystallization
temperature of the SCC polymer (which may be different from or the
same as the melting temperature), the stent becomes much more rigid
and thus capable of providing the desired function, e.g., support
of the blood vessel. The amount and type of SCC polymer in the
stent may be selected based on the temperature-dependent
flexibility properties desired for the stent, as determined by
routine experimentation.
[0086] In an embodiment, the medical device (comprising a SCC
polymer) is a catheter, e.g., a device having any of the catheter
designs described above. The SCC polymer may be incorporated into
such a catheter in various ways, as discussed above. In an
embodiment, at least a portion of the SCC polymer is positioned at
a surface of the catheter. It has been found that such positioning
of the SCC polymer at a surface of the catheter allows the surface
properties of the catheter to be manipulated as a function of
temperature, e.g., the SCC polymer may function as a
temperature-dependent lubricant and/or adhesive as discussed
above.
[0087] In an embodiment, the medical device (comprising a SCC
polymer) is a stent system comprising a stent and a catheter. The
SCC polymer may be incorporated into such a stent system in various
ways, e.g., in the body or at a surface of the stent, in the body
or at a surface of the catheter, and/or at an interface between the
stent and the catheter. The SCC polymer may be positioned at an
interface between two medical devices in various ways. For example,
amounts of a SCC polymer may be applied to selected locations on
the surface of one or both of the stent and catheter; a SCC polymer
may be coated onto one or both of the surfaces of the stent and
catheter; a film of SCC polymer may be applied to one or both of
the surfaces of the stent and catheter; and/or a one or both of the
surfaces of the stent and catheter may be manufactured in such a
way that a SCC polymer is formed at the surface(s). Methods for
positioning a SCC polymer at a surface and/or interface are
described above.
[0088] In an embodiment, the SCC polymer is configured to provide
temperature-dependent adhesion between the stent and the catheter.
For example, as discussed above, a SCC polymer may be selected to
provide greater adhesion at temperatures above the melting point of
the SCC polymer. Such a SCC polymer may be provided at an interface
between the stent and the catheter and heated to temperature above
the melting point, thus increasing the amount of adhesion between
the stent and the catheter. The stent may then be positioned at the
desired site within the vascular system. During such positioning,
the adhesive properties of the SCC polymer desirably reduce or
prevent slippage between the stent and catheter. After expansion of
the stent, the SCC polymer may be allowed to cool (and/or actively
cooled by circulating a liquid through the catheter) to a
temperature below the melting point of the SCC polymer. Upon such
cooling, the adhesive character of the SCC polymer is reduced,
allowing the catheter to be cleanly withdrawn from the vicinity of
the stent without undesirable re-positioning of the stent. In other
embodiments, the SCC polymer is selected to provide greater
adhesion at temperatures below the melting point of the SCC
polymer. In such embodiments, the stent is preferably positioned at
a temperature below the melting point of the SCC polymer, while
adhesion is greater (for the SCC polymer of this embodiment),
expanded to the desired diameter within the vasculature, then
heated to reduce the adhesion between the stent and catheter,
thereby facilitating detachment and withdrawal of the catheter
while minimizing undesirable re-positioning of the stent. Thus, in
some embodiments, the SCC polymer is heated to increase adhesion
and/or cooled to decrease adhesion; in other embodiments the SCC
polymer is cooled to increase adhesion and/or heated to decrease
adhesion. Preferably, the SCC polymer is a HACSCCP.
[0089] In another embodiment, a medical device is formed in vivo by
introducing a polymeric material into a body cavity, then forming a
channel through the polymeric material. For example, a stent may be
formed by introducing a polymeric material (containing a SCC
polymer) into a blood vessel in a manner similar to that described
above for embolization, then forming a channel through the
polymeric material. Preferably, the SCC polymer is a HACSCCP. The
channel is preferably substantially coaxial to the blood vessel,
thus allowing blood to flow through the channel. The channel may be
formed in various ways. For example, in one embodiment, the
polymeric material is formed around a cylindrical mold. The SCC
polymer in the polymeric material is selected so that the adhesion
between the mold and the polymeric material is greater at
temperatures below the melting point of the SCC polymer. The mold
and polymeric material are then inserted into the vasculature and
positioned to at least partially occlude a blood vessel. The mold
is then heated to a temperature slightly above the melting point of
the polymeric material, thereby reducing adhesion between the
polymeric material and the mold. The mold is then withdrawn,
leaving behind a cylindrical hole in the polymeric material.
Withdrawal of the mold without undesirable repositioning of the
polymeric material is facilitated by the temperature-dependent
adhesive properties of the SCC polymer. Other methods may also be
used to form channels in polymeric materials, e.g., other mold
shapes and configurations and/or by heating a portion of the
polymeric material to a temperature above the melting point of the
SCC polymer or polymeric material. The size, shape, number and
configuration of the channels may be controlled in various ways.
For example, heat energy may be applied at various levels and in
various forms, e.g., by laser and/or by inserting heated implements
(such as a heated wire) into the polymeric material.
EXAMPLE 1
[0090] To a resin flask equipped with a thermometer, stirrer and
reflux condenser is added 500 grams (g) of
octamethylcyclotetrasiloxane, 250 g of
octaphenylcyclotetrasiloxane, and 250 g of
octa(iodophenyl)cyclotetrasiloxane, a heavy atom-bearing monomer.
The flask and contents are heated to 150.degree. C. and 0.11 g of
potassium hydroxide-isopropanol complex (neutral equivalent=193.5)
is added (Si:K ratio about 4470:1). The solution is allowed to stir
for approximately 30 minutes. Once the solution becomes too viscous
to stir effectively (due to polymer formation), the polymer is
heated to approximately 165.degree. C. for 3 to 4 hours, then
cooled to room temperature. The resulting polymer is a HACSCCP
comprising recurring units of the formula (IV) in which A.sup.3 and
A.sup.4 are iodinated phenyl groups, recurring units of the formula
(V) in which R.sup.10 and R.sup.11 are phenyl groups, and
dimethylsiloxane recurring units.
EXAMPLE 2
[0091] To a resin flask equipped with a thermometer, stirrer,
reflux condenser and 250 g of xylene stirred at approximately
135.degree. C., a solution of 20 g of 4-iodo styrene, 60 g of
docosanyl acrylate, and 11 g of di-tent-butyl peroxide is added
over a period of approximately 3 hours. After addition is complete,
the mixture is allowed to continue stirring for approximately
another 3 hours to affect a more complete conversion, then cooled
to room temperature. The resulting polymer is a HACSCCP comprising
recurring units of the formula (II) in which R.sup.7 and R.sup.8
are H, A.sup.3 is C.sub.6H.sub.4--I, and recurring units of the
formula (III) in which L.sup.3 is an ester linkage and R.sup.9
comprises a C.sub.22 hydrocarbon group.
EXAMPLE 3
[0092] To a 500 mL 2-necked round-bottom flask equipped with a
mechanical stirrer and a rubber septum, 30 g of a monomer of the
formula (VII) (I2DT-docosanyl) and 240 ml of methylene chloride are
added. The solids are dissolved with stirring. About 4.34 g of
triphosgene dissolved in 30 mL of methylene chloride is placed in a
airtight syringe and added to the reaction flask with a syringe
pump at a constant rate over a period of about 2 to 3 hours. The
resulting viscous polymer solution is diluted by adding about 150
mL of tetrahydrofuran and 10 mL of water. The polymer is isolated
by precipitating the polymer solution in isopropanol, filtering the
resulting solid and drying under vacuum. The polymer is a HACSCCP
comprising a recurring unit of the formula (I) in which X.sup.1 is
I, y.sup.1 is 2, y.sup.2 is zero, A.sup.1 is --(C.dbd.O)--, R.sup.5
is --CH.sub.2CH.sub.2--, R.sup.6 is --CH.sub.2--, and Q is a
crystallizable ester group containing 23 carbons.
##STR00012##
EXAMPLE 4
[0093] An embolization is carried out as follows: A HACSCCP
prepared as described in Example 3 is formed into a rod-shaped
embolic medical device and loaded into a heated catheter. A
physician delivers the catheter to a Arteriovenous Fistula (AVF) to
be embolized. A baseline angiogram is performed with fluoroscopy to
better determine the region to be embolized. The rod of HACSCCP
embolic agent is pushed through the catheter to the target site.
Localized heating in the catheter melts the HACSCCP, allowing it to
flow through the catheter and to the target site in an liquid form
that conforms to the AVF and embolizes the tissue. The HACSCCP
cools and recrystallizes at the target site. Delivery of the
HACSCCP is continued until blood flow ceases in the target area.
Blood flow cessation is confirmed by injecting contrast agent and
viewing by fluoroscopy. The HACSCCP is visible under fluoroscopy.
The catheter is cooled to stop the flow of unneeded HACSCCP. The
catheter is withdrawn.
EXAMPLE 5
[0094] An embolization is carried out as described in Example 4,
except that a higher viscosity HACSCCP is utilized and the HACSCCP
is delivered to an artery for the treatment of an aneurysm.
Embolization is achieved.
EXAMPLE 6
[0095] Embolization of a traumatic bleeding artery is carried out
as generally described in Example 4, except that, prior to
delivery, the HACSCCP is formed into the shape of a coil and
crosslinked by irradiation, thereby forming a memory coil. During
heating, the memory coil softens and forms a flexible rod that is
delivered to the artery through the catheter. Upon delivery, the
flexible rod cools and resumes a coil shape within the artery,
thereby reducing the blood flow.
EXAMPLE 7
[0096] Into a one-liter reactor is charged 90 grams of iodostyrene
and 10 grams of hydroxy ethyl methacrylate (HEMA). About 200 ml of
the toluene (solvent) is added and the reactor is carefully purged
with argon. Then 0.5 mol percent of azobisisobutyronitrile (AIBN,
polymerization initiator) is added and the reaction is brought to
70 degrees C. for about 24 hours. The composition of the resulting
copolymer of iodotyrene and HEMA is confirmed by nuclear magnetic
resonance (NMR) spectroscopy. Then, 30 grams of caprolactone is
added. To azeotropically dehydrate the reaction system, about 10%
of the toluene is removed by distillation, and then 100 parts per
million of stannous octoate catalyst is added. The temperature is
raised to 100.degree. C. and the caprolactone is polymerized by
grafting off the pendant hydroxyl groups of the iodostyrene/HEMA
copolymer. The resulting HACSCCP is coagulated in alcohol and
dried. The HACSCCP contains about 23% (NMR) semicrystalline
polycaprolactone (PCL) in the form of crystallizable PCL side
chains. The intrinsic viscosity of the HACSCCP is greater than 1.0
in toluene at 30.degree. C., indicating a relatively high molecular
weight.
EXAMPLE 8
[0097] A series of HACSCCP materials are prepared in a manner
similar to that described in Example 7, except that the relative
amounts of HEMA and iodostyrene are varied, along with the
molecular weights of the backbone and PCL side chains. The series
of HACSCCP polymers exhibits a range of melting points, depending
on the length and spacing between the PCL crystallizable side
chains (longer lengths and/or closer spacing resulting in higher
melting points, e.g., up to about 60.degree. C.). The series of
HACSCCP polymers also exhibits a range of radiopacities, depending
on the number of iodostyrene recurring units incorporated into the
HACSCCP.
[0098] It will be appreciated by those skilled in the art that
various omissions, additions and modifications may be made to the
materials and methods described above without departing from the
scope of the invention, and all such modifications and changes are
intended to fall within the scope of the invention, as defined by
the appended claims.
* * * * *