Note: Descriptions are shown in the official language in which they were submitted.
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BIODEGRADABLE POLYMER PROTEIN BASED COILS FOR
INTRALUMENAL IMPLANTS
Background of the Invention
Related Applications
The present application is related to U.S.
Patent No.6,423,085 issued July 23, 2002 and to PCT
Publication No. WO 00/44306 filed January 27,1999.
1. Field of the Invention
The invention relates generally to the field of
surgical and endovascular interventional instruments and
specially to Intraluminal implants for occlusion of
vessels or aneurysms.
2. Description of the Prior Art
Brain aneurysms are the commonest cause of
nontraumatic subarachnoid hemorrhage (SAH) which is a
significant life-threatening disease in adults. Annually
in North America. the rupture of saccular aneurysms
accounts for 25000 new cases of SAH. Microsurgical
clipping of an aneurysm has been considered the gold
standard for the treatment of this disease. Recently,
intravascular treatment of aneurysms has become an
accepted alternative technique. With the availability of
microcatheters capable of accessing the
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intracranial circulation it has become possible to obliterate an aneurysm by
filling
it with soft platinum detachable coils (Guglielmi Detachable Coils; GDC). Use
of
the GDC system allows controlled delivery and detachment of platinum coils
within an aneurysm.
Recent advances in endovascular techniques have proved valuable in the
treatment of cerebral saccular aneurysms. GDCs have contributed especially to
improvements in the endovascular management of cerebral aneurysms.
However, the size of an aneurysm neck has an important effect on the anatomic
results of aneurysm obliteration. It has been reported that in one study
complete
obliteration of aneurysms was achieved in 85% of small-necked aneurysms and
15% of wide-necked aneurysms.
Early experience with experimental and clinical use of Guglielmi
detachable coils (GDCs) as manufactured by Target Therapeutics, Fremont,
California, points to their effectiveness in the occlusion of endovascular
small-
necked intracraniai saccuiar aneurysms.
However; the anatomical results of obliteration of either wide-necked
(neck size z 4 mm) or giant aneurysms using GDCs are generally unsatisfactory.
The reasons for these incomplete anatomical results in wide-necked lesions
include coil compaction, aneurysmal recanalization and the potential for
distal
migration of detached coils, i.e. the downstream loss of the coils from the
aneurysm. Early intravascular re-endotheliatization at the necks of aneurysms
and the acceleration of wound healing in the aneurysmal sac and dome are
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potential solutions that may help achieve successful permanent cures of this
type
of aneurysm.
Some investigators have applied simple protein coatings on GDCs to
enhance their thrombogenicity and wound healing properties. However,
intravascular embolization techniques generally make use of small-diametered
microcatheters for delivery of these coils. Simple protein coating, therefore,
results in the problem of increasing the diameter of these coils which in turn
causes them to stick within the lumen of a microcatheter during coil delivery.
Occlusion coils are used to occlude a site within a body lumen, such as a
blood vessel, brain aneurysm, or vascular malformation. The coils are
typically
ptaced at a desired site within the lumen by means of a microcatheter. The
coils
are normally made of a radioopaque, biocompatible metals such as platinum,
gold, or tungsten. In treating brain aneurysms the coils occlude the aneurysm
by
posing a physical barrier to blood flow and by promoting thrombus formation.
The formation of the neo-endothelium and mature intra-aneurysmal thrombus is
necessary prior to subsequent organization and scar formation that, in turn,
yields a permanently occluded aneurysm.
In the presence of continued exposure of intra-aneurysmal coils to
circulating blood, metallic coils can be insufficiently thrombogenic to
promote the
establishment of firm and mature thrombus within the aneurysm. They have
difficulty in promoting endothelialization across the wide neck of an
aneurysm.
Therefore, it is advantageous to tightly pack the aneurysm with coils for
complete
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cure of the aneurysms. This may cause a mass effect on adjacent the brain
parenchyma or cranial nerves.
To accelerate wound healing in the aneurysm (i.e., promotion of scar
formation) and to decrease the mass effect of the aneurysm, "biologically
active"
bioabsorbable embolic material may be useful. Bioabsorbable polymers, such as
polyglycolic acid and polyglycoliclpoly-L-lactic acid copolymers, or
bioabsorbabie
proteins, such as collagen and gelatins, have been used to make Intraluminal
implants. These bioabsorbable polymers or proteins are also used to provide a
the drug delivery vehicle (such as for continuous local delivery of growth
factors).
It is necessary to modify biological cellular response in preparation for
acceleration of wound healing. Coil thrornbogenicity was enhanced previously
by
increasing the surface area of the coils with fabric strands, such as Dacron,
and
by placing such coils into a thrombin solution. More recently, some
investigators
have modified the surfaces of platinum coils by coating them with collagen or
polyurethane. This has resulted in some advantages, such as an increase in
thrombogenicity of these coils. However, protein coatings on platinum surfaces
are usually weak and may be removed easily during the delivery of the coils.
Additionally, weakly coated proteins may be washed off by high-velocity
arterial
flow and may be a potential source of distal thromboemboli. There is also the
potential problem of increases in the diameters of these coils; polyurethane
coatings in particular also have the disadvantage of producing unfavorable
changes in GDC performance, affecting their softness, thinness, smoothness,
and memory shape.
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In summary, GDCs and surrounding thrombus within an aneurysm are
continuously exposed to and interact with circulating blood at the neck of the
aneurysm. Coil compaction resulting from the force of pulsatile arterial blood
flow is one of the reasons for incomplete obliteration of aneurysms. When this
5 occurs, there is a potential risk of aneurysm recanalization and
(re)rupture. Re-
endothelialization and the promotion of wound healing in the aneurysmal sac
and
across its neck are necessary for complete aneurysm cure. Despite the many
advantages of GDCs in the treatment of aneurysms, several recent clinical and
experimental reports have highlighted their potential limitations in achieving
an
anatomic cure for wide-necked lesions. For example, two human autopsy cases
treated with GDCs were reported for which the long-term (up to 6 months)
histological findings revealed unorganized thrombus in the aneurysms, with no
evidence of endotheliaiization across the aneurysmal neck in either case.
Others
have reported the histological findings for a patient with an anterior
communicating artery aneurysm that had been previously treated with GDCs, in
whom the compaction of coils resulted in an aneurysm remnant that was
subsequently (6 months later) treated surgically. Histological examination of
this
resected aneurysm also revealed the presence of unorganized intra-aneurysmal
thrombus that was exposed directly to the blood circulation without neointimal
formation. It has been reported that in a long-term GDC study with
experimental
canine aneurysms, three of nine initially completely embolized aneurysms
yielding to subsequent recanalization. Experimental GDC studies in monkey
aneurysms were reported in which one of four of cases at 14 days of follow-up
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showed an aneurysmai "shoulder," indicative of aneurysm recanalization. More
recently, in a study of experimental bifurcation aneurysms in rabbits,
demonstrated the absence of organized thrombus and no neck endothelialization
in treated aneurysms, even after follow-up periods of 3 to 6 months.
What is needed is a method to promote an inflammatory response and
healing of the aneurysm with reduction of its mass effect.
Brief Summary of the Invention
The invention is an intravascular device that modifies either accelerating
or decreasing biological cellular response comprising a separable tip or coil
comprised at least in part of at least one biocompatible and absorbable
polymer
or protein, and a placement device associated with the separable coil adapted
to
dispose the coil into a selected body lumen. The biocompatible and absorbable
polymer or protein promotes an intra-aneurysmal inflammatory response and
healing of the aneurysms. This device may carry growth factors, such as a
vascular endothelial growth factor, a basic fibroblast growth factor or a
mixtura of
several growth factors or cytokines. The separable tip, which also need not be
a
coil, need not be comprised of a polymer or protein, but may be comprised of
any
material now known or later devised which is biocompatible, absorbable and
which promotes an intra-aneurysmal inflammatory response and promotes
healing of the aneurysm.
The biocompatible and absorbable polymer is in the illustrated
embodiment at least one polymer selected from the group consisting of
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polyglycolic acid, polyglycolic acid/poly-L-lactic acid
copolymers, polycaprolactive,
polyhydroxybutyrate/hydroxyvalerate copolymers, poly-L-lactide,
polydioxanone, polycarbonates, and polyanhydrides.
The biocompatible and absorbable protein is at least
one protein selected from the group consisting of collagen,
fibrinogen, fibronectin, vitronectin, laminin, and gelatin.
In one embodiment the coil is composed of the
biocompatible and absorbable polymer or protein with a
radio-opaque material is disposed thereon.
Alternatively, the coil is composed of a radio-opaque
material, and the biocompatible and absorbable polymer or
protein is disposed thereon.
The invention is also characterized as a method for
forming a thrombus comprising the steps of providing a
separable coil comprised at least in part of at least one
biocompatible and absorbable polymer or protein and disposing
the separable coil into a body lumen including the various
combinations and examples described above.
The method further of comprises the step of providing
the coil with a growth factor, and in particular a vascular
endothelial growth factor (VEGF), a basic fibroblast growth
factor (bFGF), or other growth factors.
In some embodiments, the invention provides an
endovascular apparatus of biodegradable and biocompatible
polymers for developing a controlled inflammatory response with
cellular manipulation and a selected aneurysm. The
endovascular apparatus may comprise a separable coil comprised
at least in part of at least one biocompatible and
biodegradable polymer. The biodegradable polymer may produce
or enhance the inflammatory response with cellular
manipulation, for example to effect wound healing of an
aneurysm. The coil may be adapted to be disposable into an
aneurysm. An endovascular placement device may be associated
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with the separable coil. The coil may be composed of the
biocompatible and biodegradable polymer, and a radio-opaque
material may be disposed thereon. Alternatively, the coil may
be composed of radio-opaque material, and a biocompatible and
biodegradable polymer may be disposed thereon. The polymer may
control a controlled inflammatory response and/or controlled
vascular healing. Aneurysms treatable with the apparatus of
the invention may for example be located within brain tissue,
such as aneurysms having a mass effect. In such embodiments,
the polymer may be suitable to reduce the mass effect.
Biocompatible and biodegradable polymers of the
invention may comprise a synthetic biodegradable polymer or
copolymer. For example, polymers of the invention may be
comprised of at least one synthetic polymer selected from the
group consisting of polyglycolic acid, polyglycolic
acid/poly-L-lactic acid copolymers, polycaprolactive,
polyhydroxybutyrate/hydroxyvalerate copolymers, poly-L-lactide,
polydioxanone, polycarbonates, and polyanhydrides.
In one aspect of the invention, a separable coil
comprised at least in part of one biocompatible and
biodegradable polymer may be used to bioactively produce or
enhance an inflammatory response with cellular manipulation,
for example to effect wound healing of an aneurysm. For
example, such coils may be disposable within an aneurysm to
produce an endovascular inflammatory response with cellular
manipulation. Such coils may for example be comprised of the
polymers recited above. Such coils may for example be comprised
of polymers with a radio-opaque material disposed thereon, or
may comprise radio-opaque material having a polymer disposed
thereon. Such coils may for example be adapted to reduce the
mass effect of an aneurysm located within brain tissue.
In an alternative aspect, the invention provides a
kit for developing a controlled inflammatory response in a
selected aneurysm. Such kits may comprise the endovascular
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apparatus of the invention, together with instructions for use
of the endovascular apparatus to develop the controlled
inflammatory response.
In an alternative aspect, the invention provides an
endovascular apparatus for developing an inflammatory response
in a body cavity with cellular manipulation. The apparatus may
for example comprise a separable implant comprised at least in
part of at least one biocompatible and bioabsorbable polymer.
The apparatus may further include an endovascular placement
device associated with the separable implant, adapted to
dispose the implant into a body cavity. Implants may also
comprise at least in part a growth factor. Growth factors may
for example be selected from one or more of the group
consisting of a vascular endothelial growth factor (VEGF), a
basic fibroblast growth factor (b-FGF), a transforming growth
factor (TGF), a platelet derived~growth factor (PDGF), or
combinations thereof.
Implants of the invention may for example comprise at
least one protein selected from the group consisting of
fibrinogen, fibronectin, vitronectin, laminin, and gelatin.
In some embodiments, separable implants of the
invention comprised of a biocompatible and bioabsorbable
polymer may be used to create a controlled inflammatory
response in a body cavity, and may be adapted to be disposable
in the body cavity. Such implants may for example comprise a
growth factor, a vascular endothelial growth factor, a basic
fibroblast growth factor, or combinations thereof. Separable
implants of the invention may for example be comprised of the
polymers and proteins listed above. Separable implants may
have a radio-opaque material disposed thereon, or may be
comprised of a radio-opaque material with a bioabsorbable
polymer disposed thereon.
In some embodiments, the endovascular placement
device of the invention may be suitable to dispose an implant
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at an implantation site. In some embodiments, the
biocompatible and bioabsorbable polymer may be gradually
absorbable, so as not to leave residua in the implantation
site.
In some embodiments, the coils may for example be a
composite of a biocompatible and bioabsorbable polymer and an
inert biocompatible coil. For example, inert biocompatible
coils may be platinum coils. Composites of biocompatible and
bioabsorbable polymers and an inert biocompatible coil may
for example comprise a layer of the biocompatible and
bioabsorbable polymer on the inert biocompatible coil.
In some embodiments, there is provided the
apparatus disclosed herein wherein the composite of the
biocompatible and bioabsorbable polymer and an inert
biocompatible coil comprises the biocompatible and
bioabsorbable polymer body which is mounted on or attached to
the inert biocompatible coil.
Detailed Description of the Preferred Embodiments
In various aspects, the invention provides for the use
of a separable implant for creating an inflammatory tissue
response to promote wound healing in a brain aneurysm, the
separable implant being comprised of at least one
biocompatible and bioabsorbable polymer in combination with
at least one growth factor, the implant being adapted to be
disposable in the brain aneurysm.
The growth factor may, for example, be a vascular
endothelial growth factor, a basic fibroblast growth factor,
or both.
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The polymer may, for example, be selected from the group
consisting of polyglycolic acid, polyglycolic acid/poly-L-
lactic acid copolymers, polycaprolactive,
polyhydroxybutyrate/hydroxyvalerate copolymers, poly-L-
lactide, polydioxanone, polycarbonates, and polyanhydrides.
The implant may further include at least one protein
selected from the group consisting of fibrinogen,
fibronectin, vitronectin, laminin, and gelatin.
The implant may, for example, include a radio-opaque
material disposed thereon, for example a radio-opaque
material having the biocompatible and bioabsorbable polymer
disposed thereon.
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In the present invention a biodegradable polymer (or protein} coils are
used to control thrombosis or accelerate wound healing of the brain aneurysms
far which platinum coils sometimes have often proven unsatisfactory.
Another aspect of the invention is a method of drug delivery system using
biodegradable polymer (or proteins) in the combination with growth factors
such
as vascular endothelial growth factor (VEGF}, basic fibroblast growth factor
(bFGF) or other growth factors which promote long lasting effect of the wound
healing
These biodegradable coils are useful for treating giant brain aneurysms to
prevent the mass effect on the brain parenchyma or cranial nerves by shrinkage
of scaring aneurysm.
Modes For Carrying Out The Invention
The implants of the invention may be placed within body lumens, e.g.,
blood vessels, Fallopian tubes, etc., of any mammalian species, including
humans. The implant coils are made of biocompatible end absorbable polymers
or proteins. Examples of bioabsorbable polymers that have been used in the
illustrated embodiment to make Intraluminal implants include but are not
limited
to polyglycolic acid, poly-gycolic/poly-L-lactic acid copolymers,
~polycaprolactive,
polyhydroxybutyrate Ihydroxyvalerate copolymers, poly-L-lactide,
polydioxanone,
polycarbonates, and polyanhydrides. Examples of bioabsorbable proteins that
have been used in the illustrated embodiment to make Intraiuminal implants
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include but are not limited to collagen, fibrinogen, fibronectin, vitronectin,
laminin
and gelatin.
To achieve radioopacity, the bioabsorbable polymer coils may be coated
or mixed with radioopaque materials such as tantalum or platinum. The
bioabsorbable polymer or protein itself may be mounted or coated onto coils or
wires of metals such as platinum or nitonol.
Preferred growth factors for use in the invention are the naturally occurring
mammalian angiogenic growth such as VEGF, or b-FGF. Mixtures of such
growth factors may also be used if desired.
The biodegradable polymer coils of the invention can be placed within the
body lumen, vascular system or vessels using procedures weH known in the art.
Generally, the desired site within the vessel is accessed with a catheter. For
small diameter torturous vessels the catheter may be guided to the site by the
use of guide wires. Once the site has been reached, the catheter lumen is
cleared by removing guide wire. In the case of polymer occlusion coils, the
coils
are loaded by mews of a pusher wire. The coils may be attached to~ the distal
end of the pusher via a cleavable joint (e.g., a joint that is severable by
heat,
electrolysis, electrodynamic activation or other means) or a mechanical joint
that
permits the coil to be detached from the distal end of the pusher wire by
mechanical manipulation. Alternatively, the coils may be free and detached
from
the pusher wire, simply pushed through the catheter and expelled from the
distal
end of the catheter.
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Many alterations and modifications may be made by those having ordinary
skill in the art without departing from the spirit and scope of the invention.
Therefore, it must be understood that the illustrated embodiment has been set
forth only for the purposes of example and that it should not be taken as
limiting
5 the invention as defined by the following claims.
The words used in this spec~cation to describe the invention and its
various embodiments are to be understood not only in the sense of their
commonly defined meanings, but to include by special definition in this
specification structure, material or acts beyond the scope of the commonly
10 defined meanings. Thus if an element can be understood in the context of
this
specification as including more than one meaning, then its use in a claim must
be
understood as being generic to all possible meanings supported by the
specification and by the word itself.
The definitions of the words or elements of the following claims are,
therefore, defined in this specification to include not only the combination
of
elements which are literally set forth, but all equivalent structure, material
or acts
for performing substantially the same function in substantially the same way
to
obtain substantially the same result. In this sense it is therefore
contemplated
that an equivalent substitution of two or more elements may be made for any
one
of the elements in the claims below or that a single element may be
substituted
for two or more elements in a claim.
Insubstantial changes from the claimed subject matter as viewed by a
person with ordinary skill in the art, now known or later devised, are
expressly
contemplated as being equivalently within the scope of the claims. Therefore,
obvious substitutions now or later known to one with ordinary skill in the art
are
defined to be within the scope of the defined elements.
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The claims are thus to be understood to include what is specifically
illustrated and described above, what is conceptionally equivalent, what can
be
obviously substituted and also what essentially incorporates the essential
idea of
the invention.
