U.S. patent application number 11/543575 was filed with the patent office on 2007-06-14 for stent with collagen.
Invention is credited to Stephen F. Badylak, Andrew W. Buirge, Paul H. Burmeister, Paul J. Buscemi.
Application Number | 20070135906 11/543575 |
Document ID | / |
Family ID | 26928790 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135906 |
Kind Code |
A1 |
Badylak; Stephen F. ; et
al. |
June 14, 2007 |
Stent with collagen
Abstract
Collagen applied to a vascular stem for increasing the
biocompatability of the stent on implantation find method of
treatment.
Inventors: |
Badylak; Stephen F.; (West
Lafayette, IN) ; Buirge; Andrew W.; (Minneapolis,
MN) ; Buscemi; Paul J.; (Long Lake, MN) ;
Burmeister; Paul H.; (Maple Grove, MN) |
Correspondence
Address: |
BARNES & THORNBURG LLP
11 SOUTH MERIDIAN
INDIANAPOLIS
IN
46204
US
|
Family ID: |
26928790 |
Appl. No.: |
11/543575 |
Filed: |
October 5, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11368587 |
Mar 6, 2006 |
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11543575 |
Oct 5, 2006 |
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11205682 |
Aug 17, 2005 |
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11368587 |
Mar 6, 2006 |
|
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11001281 |
Dec 1, 2004 |
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11205682 |
Aug 17, 2005 |
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|
09116734 |
Jul 16, 1998 |
|
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|
11001281 |
Dec 1, 2004 |
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08960276 |
Oct 29, 1997 |
6391052 |
|
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09116734 |
Jul 16, 1998 |
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08429308 |
Apr 26, 1995 |
5693085 |
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08960276 |
Oct 29, 1997 |
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08350223 |
Dec 6, 1994 |
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08429308 |
Apr 26, 1995 |
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08235300 |
Apr 29, 1994 |
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08350223 |
Dec 6, 1994 |
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Current U.S.
Class: |
623/1.44 |
Current CPC
Class: |
A61F 2/885 20130101;
A61F 2002/075 20130101; A61F 2220/005 20130101; A61F 2002/072
20130101; Y10S 623/917 20130101; A61F 2220/0075 20130101; A61M
25/0045 20130101; A61F 2/07 20130101; A61F 2/89 20130101; A61F
2002/9583 20130101; A61F 2/0022 20130101; A61F 2/90 20130101; A61F
2220/0091 20130101; A61F 2220/0058 20130101; A61F 2210/0076
20130101; A61F 2/915 20130101; A61F 2002/828 20130101; A61M 29/02
20130101; A61F 2250/0067 20130101; A61F 2/91 20130101; A61F 2/958
20130101; A61F 2002/91558 20130101; A61L 31/10 20130101; A61F
2220/0025 20130101; A61F 2/95 20130101; A61F 2002/91541 20130101;
A61F 2/86 20130101; A61L 31/10 20130101; C08L 89/06 20130101 |
Class at
Publication: |
623/001.44 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. In combination, a vascular prostheses comprised of an expandable
support framework, the expandable support framework, the expandable
support framework, comprising a stent, which has an expanded state
having a first diameter and a compressed state having a second
diameter, the second diameter being smaller the first diameter, and
is capable of being positioned at a targeted position within a
lumen transluminally when the stent is in its compressed state, and
a covering sleeve of a collagen material, the support framework and
the covering sleeve being substantially the same length and
substantially overlapping, and wherein the sleeve of collagen
material is in sheet form and is oriented with respect to the
longitudinal dimension of the stent such that the stretch
properties of the collagen are on a bias with respect thereto.
2. The combination of claim 1 wherein the collagen material covers
the stent inside and out.
3. The combination of claim 2 wherein the collagen is in the form
of an outer sleeve and an inner sleeve.
4. The combination of claim 1 wherein the collagen material is
comprised of collagen per se.
5. The combination of claim 1 wherein the collagen material is
comprised of collagen on a support.
6. The combination of claim 5 wherein the support is a fabric.
7. The combination of claim 1 wherein the framework is a stent of
variable diameter.
8. The combination of claim 7 wherein the stent is of the
self-expanding type.
9. The combination of claim 1 wherein the sleeve has elastic
properties.
10. The combination of claim 1 wherein the sleeve is sized large
with respect to the framework at least before implantation.
11. The combination of claim 1 wherein the collagen includes added
agent.
12. The combination of claim 11 wherein the agent is heparin.
13. The combination of claim 1 including a multi-layer arrangement
of Type I and Type IV collagen material on the outside of the
stent.
14. The combination of claim 13 wherein the Type TV is the
outermost layer.
15. The combination of claim 14 wherein the Type IV is SIS.
16. In combination, a vascular expandable stent and a layer of
collagen material in the form of a sleeve overlying the stent, the
layer of collagen material being substantially the same length and
substantially overlapping the stent so that when the combination is
inserted within a vascular lumen, the layer of collagen material is
positioned between the stent and the vascular wall of the lumen,
and wherein the sleeve of collagen material is in sheet form and is
oriented with respect to the longitudinal dimension of the stent
such that the stretch properties of the collagen are on a bias with
respect thereto.
17. In combination, a vascular prostheses comprised of a generally
cylindrical expandable support stent, which has an expanded state
having a first diameter and a compressed state having a second
diameter, the second diameter being smaller than the first
diameter, and is capable of being positioned at a targeted position
within a lumen transluminally when the stent is in its compressed
state, and an inner luminal liner comprising collagen material,
wherein the collagen liner is in sheet form and is oriented with
respect to the longitudinal dimension of the stent such that the
stretch properties of the collagen are on a bias with respect
thereto.
18. The combination of claim 17 wherein the collagen material
comprises a bilayer arrangement.
19. The combination of claim 18 wherein one of the layers in the
bilayer is a polymeric material.
20. The combination of claim 19 wherein the bilayer liner is
comprised at least two types of collagen material.
21. The combination of claim 20 wherein the collagen material
includes Type I and Type IV layers.
22. The combination of claim 21 wherein the Type IV is SIS.
23. The combination of claim 22 wherein the Type IV is the
innermost layer and the Type I layer includes a drug.
24. The combination of claim 17 wherein the stent is of variable
diameter.
25. The combination of claim 24 wherein the stent is of the
self-expanding type.
26. The combination of claim 17 wherein the liner has cuffs at
either end which overlap the ends of the stent.
27. The combination of claim 17 wherein the collagen includes an
added agent.
28. The combination of claim 27 wherein the agent is heparin.
29. The combination of claim 17 wherein the stent has wall openings
and the liner is perforated.
30. The combination of claim 29 wherein the perforations are about
10-60 microns in diameter.
31. The combination of claim 17 including SIS collagen material on
the outside of the stent.
32. In combination, a vascular prosthesis comprised of an
expandable stent, which has an expanded state having a first
diameter and a compressed state having a second diameter, the
second diameter being smaller than the first diameter, and is
capable of being positioned at a targeted position within a lumen
transluminally when the stent is in its compressed state, and inner
and outer layer of SIS collagen material positioned on the stent,
wherein at least one of the layers of collagen is in sheet form and
is oriented with respect to the longitudinal dimension of the stent
such that the stretch properties of the collagen are on a bias with
respect thereto.
33. In combination, a vascular prosthesis comprised of an
expandable stent, which is expandable from a first cylindrical
position to a second cylindrical position and is capable of being
positioned at a targeted position within a lumen transluminally
when the stent is in its compressed state, a collagen coating on
the stent and a collagen sleeve on the outside of the stent,
wherein the sleeve of collagen is in sheet form and is oriented
with respect to the longitudinal dimension of the stent such that
the stretch properties of the collagen are on a bias with respect
thereto.
34. The combination of claim 33 wherein the sleeve is SIS and the
coating is Type I or Type TV.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a Continuation of application Ser. No.
11/368,587, filed Mar. 6, 2006, which is a Continuation of
application Ser. No. 11/205,682, filed Aug. 17, 2005, which is a
Continuation of application Ser. No. 11/001,281, filed Dec. 01,
2004, which is a Continuation of application Ser. No. 09/116,734,
filed Jul. 16, 1998, which is a Continuation of application Ser.
No. 08/960,276, filed Oct. 29, 1997, now U.S. Pat. No. 6,391,052
which is a Continuation of application Ser. No. 08/429,308, filed
Apr. 26, 1995, now U.S. Pat. No. 5,693,085 which is a
Continuation-in-part of application Ser. No. 08/350,223, filed Dec.
6, 1994, now abandoned, which application is a Continuation-in-part
of application Ser. No. 08/235,300, filed Apr. 29, 1994, now
abandoned, each of the disclosures of which are hereby incorporated
by reference.
BACKGROUND OF THE INVENTION
[0002] This invention relates to vascular prostheses of improved
biocompatability and more specifically to stents in combination
with a collagen material. Such a combination provides an
endovascular stent which protects the vascular wall and forms a
non-thrombogenic cushion for the stent in the vascular lumen.
[0003] It also relates to stents in combination with a collagen
liner material. Such a combination provides an endoluminal stent
which engages the luminal wall and in the case of vascular
applications, forms a non-thrombogenic surface as well as providing
for the growth of endothelial cells, as well as a reservoir or
point of attachment for therapeutic agents in any application.
[0004] It also relates to combinations of both of the foregoing
arrangements.
[0005] Broadly, it relates to stents associated with an outer
covering of collagen material and/or a luminal liner of same. It
also relates to a method of applying collagen to the interior of a
vessel or the like as a liner by using a stent.
[0006] Stents are generally tubular in configuration, are open
ended, and are radially expandable between a generally unexpanded
insertion diameter and an expanded implantation diameter which is
greater than the unexpanded insertion diameter. Such intravascular
implants are used for maintaining vascular patency in humans and
animals.
[0007] Stents are typically placed or implanted by a mechanical
transluminal procedure. One common procedure for implanting a stent
is to first open the region of the vessels with a balloon catheter
and then place the stent in a position that bridges the treated
portion of the vessel by means of a placement catheter.
[0008] Prior art patents refer to the construction and design of
stents as well as apparatus for positioning stents within a vessel.
In general, for example, such patents disclose a technique for
positioning an elongated cylindrical stent at a region of an
aneurysm, stenosis or the like. The stent expands as necessary to
an implanted configuration after insertion with the aid of a
catheter.
[0009] Specifically, U.S. Pat. No. 4,733,665 to Palmaz which issued
Mar. 29, 1988, discloses a number of stent configurations for
implantation with the aid of a catheter. The catheter includes
means for mounting and retaining the stent, preferably on an
inflatable portion of the catheter. The stent is implanted by
positioning it within the blood vessel and monitoring its position
on a viewing monitor. Once the stent is properly positioned, the
catheter is expanded and the stent separated from the catheter
body. The catheter can then be withdrawn from the subject, leaving
the stent in place within the blood vessel. U.S. Pat. No. 4,950,227
to Savin et al., which issued on Aug. 21, 1990 is similar.
[0010] Another similar U.S. Pat. No. 5,019,090 discloses a
generally cylindrical stent and a technique for implanting it using
a deflated balloon catheter to position the stent within a vessel.
Once the stent is properly positioned the balloon is inflated to
press the stent against the inner wall linings of the vessel. The
balloon is then deflated and withdrawn from the vessel, leaving the
stent in place.
[0011] A patent to Dotter, U.S. Pat. No. 4,503,569 which issued
Mar. 12, 1985 discloses a spring stent which expands to an
implanted configuration with a change in temperature. The spring
stent is implanted in a coiled orientation and heated to cause the
spring to expand due to the characteristics of the shape memory
alloy from which the stent is made. Similarly, U.S. Pat. No.
4,512,338 to Balko et al., which issued Apr. 23, 1985, discloses a
shape memory alloy stent and method for its delivery and use other
kinds of self-expanding stents are known in the art.
[0012] The delivery and expansion of the stent of the invention is
the same as that already known in the art and practiced with the
stent of FIGS. 1 and 6. U.S. Pat. No. 5,195,984 to Schatz, issued
Mar. 23, 1993, describes a typical balloon expansion procedure for
an expandable stent. This patent is incorporated in its entirety
herein by reference. That patent describes a catheter having an
expandable inflatable portion associated therewith. In a
conventional manner, the catheter and stent are delivered to a
desired location within a body passageway at which it is desired to
expand the stent for implantation. Fluoroscopy, and or other
conventional techniques may be utilized to insure that the catheter
and graft are delivered to the desired location. The stent is then
controllably expanded and deformed by controllably expanding the
expandable inflatable portion of catheter, typically a balloon. As
a result the stent is deformed radially outwardly into contact with
the walls of the body passageway. In this regard, the expandable
inflatable portion of the catheter may be a convention angioplasty
balloon as is already known in the art. After the desired expansion
and deformation of the stent has been accomplished, the angioplasty
balloon may be deflated and the catheter removed in a conventional
manner from the passageway.
[0013] Also, this invention is useful in self-expanding stents such
as those disclosed in U.S. Pat. Nos. 4,732,152 and 4,848,343, both
of which are incorporated herein by reference.
[0014] All of the above-identified patents are incorporated herein
by reference.
SUMMARY OF THE INVENTION
[0015] In one preferred form a metal or other stent is delivered
for vascular implantation with a covering sleeve of collagen
material. If the stent is of the variable diameter type, the sleeve
may be stretched into place or otherwise positioned between the
stent and the vascular wall when the stent is seated or deployed. A
drug or other agent such as heparin or the like may be included in
the collagen for release after stent deployment.
[0016] In another preferred form a metal or other stent is
delivered for vascular implantation with a luminal liner of
collagen material. A drug or other agent such as heparin or the
like may be included in the collagen as a surface treatment or for
release after stent deployment.
[0017] In yet another preferred form, a stent is provided with both
an inner collagen liner and outer collagen coating.
BRIEF DESCRIPTION OF THE FIGURES
[0018] FIG. 1 shows a stent and covering sleeve combination being
formed according to the invention.
[0019] FIG. 2 is a fragmentary showing of collagen with a fabric
support.
[0020] FIG. 3 shows an example of another self-expanding stent
configuration useful in the invention.
[0021] FIG. 4 shows another stent configuration useful in the
invention.
[0022] FIGS. 5 and 6 show a flexible stent configuration which may
incorporate a covering sleeve according to the invention.
[0023] FIG. 7 is similar to FIG. 1, showing a combination being
formed including an internal liner and an external sleeve for a
stent, according to the invention.
[0024] FIG. 8 is a showing of an alternate mode of manufacture of
the invention by molding the collagen to the stent.
[0025] FIG. 9 shows a stent and an internal liner sleeve
combination being formed according to the invention.
[0026] FIG. 10 shows a bilayer collagen material in schematic and
fragmentary form.
[0027] FIGS. 11, 12, and 13 are schematic longitudinal
cross-sectional views of a stent carrying inner and outer layers of
collagen material.
[0028] FIG. 14 is a showing of an alternate stent/liner
arrangement.
[0029] FIG. 15 shows an optional technique for forming the
stent/liner arrangement by molding.
[0030] FIGS. 16, 17, and 18, schematically show the stretch of a
collagen stent being oriented on a bias with respect to a
stent.
[0031] FIGS. 19 and 20 show a coated stent, FIG. 20 being a
cross-sectional view of FIG. 19.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0032] Referring now to FIG. 1, a tubular metal stent generally
indicated at 10 is shown being combined with a covering sleeve of
collagen material generally indicated at 12 to provide the
combination stent/sleeve generally indicated at 14 for the purpose
of vascular implantation.
[0033] Stent 10 is of the type, typically of a metal such as for
example stainless steel, nitinol, superelastic alloys and other
metals or a suitable polymeric plastic and may be of a fixed
diameter or of a variable diameter, the latter being more preferred
and well known in the art. The variable diameter type are usually
either balloon expandable or self-expanding, both of which are also
known in the art. Examples of the former type are shown in U.S.
Pat. No. 4,733,665, U.S. Pat. No. 4,739,762 and U.S. Pat. No.
4,776,337, all of which are incorporated herein by reference. The
latter type is preferred for the purposes of this invention at
present, i.e., self-expanding, particularly those made of Nitinol
an example of which is discussed in the U.S. Pat. Nos. 4,503,569
and 4,512,338, also incorporated herein by reference. Also, for
example, useful stents are shown in co-pending application Ser. No.
08/246,320 filed May 19, 1994 entitled "Improved Tissue Supporting
Devices". The content of this application is incorporated herein by
reference.
[0034] In any event, generally a stent provides a supporting
framework structure which may take many forms. Typically stents are
open or perforate and may be comprised of a network of struts or
wire-like structure. Stent 10 is comprised of struts.
[0035] Collagen sleeve 12 shown in FIG. 1 may be comprised of
collagen per se or it 12a may be carried on a support 12b as shown
in FIG. 2, support 12b being of DACRON.RTM. fabric or the like as
is known and disclosed for example in U.S. Pat. Nos. 5,256,418,
5,201,764 and 5,197,977, the entire content of which are all
incorporated herein by reference, particularly those portions which
relate to the formation of collagen tubes. The Support 12b may be a
fabric, woven or braided, and may also be of polyester,
polyethylene, polyurethane or PTFE. The term "collagen material" is
used herein to refer to both supported and unsupported collagen for
the sleeve element of this invention.
[0036] The preferred collagen at present appears, for the purposes
of this invention, to be that composed of bovine or porcine Type I
or Type IV collagen and combinations thereof in bilayer sheet-like
form. The collagen may also be made of Type III or combinations of
any of the various types. U.S. Pat. Nos. 4,837,379; 4,902,508;
4,950,483; 4,956,178; 5,106,949; 5,110,064; 5,256,418; 5,275,826;
5,281,422 and 5,024,841 relate to collagen compositions and
production useful in this invention and are incorporated herein by
reference. Collagen can be extracted from various structural
tissues as is known in the art and reformed into sheets or tubes
and dried onto a stent. Generally, the thickness of these sheets or
tubes will range from about 5 to 200 microns. One preferred
collagen at present is that disclosed in U.S. Pat. No. 4,902,508
coated as described in U.S. Pat. No. 5,275,826 to provide bilayer
SIS as described further hereinbelow. Another preferred collagen is
that described as a "collagen construct" in U.S. Pat. No.
5,256,418, particularly in which the permeable substrate is also
collagen.
[0037] Cells of the blood vessel wall synthesize and secrete
several kinds of macromolecules forming extracellular matrix. The
components of this matrix comprise several large proteins that may
be synthetically constructed to form films, tubes or multilayer
sheets or other constructs. Among these biological components are
collagens of several types, elastin, glycosaminoglycans (GAGS),
fibronectin and laminin. Collagens are three chain glycoproteins
with molecular weights of about 300,000. Elastin is an insoluble
nonpolar amine acid rich crosslinked protein. The GAGs are linear
chain polysaccharides with various negative charges with various
molecular weights ranging from thousands to millions. Included in
the GAGs are heparin and heparin sulfate, dermatin sulfate and
chondroitin sulfate. Fibronectin is a 440,000 MW 2-chain adhesive
glycoprotein that acts as a substrate for many cell types and in
cell-cell interactions. Laminin is a 2 chain glycoprotein of MW
about 850,000 and acts as a basement membrane structure for
cellular-molecular interactions. Each of these macromolecules may
be combined in a multitude of combinations to form composites.
These are all natural materials that serve specific functions and
are exposed to blood under normal repair conditions. It is
therefore expected that, if a covering sleeve for a stent were made
of these macromolecules and used in the course of intervention,
repair of a blood vessel would proceed more naturally than if a
similar device were constructed of synthetic polymers such as
polyethylene, polyteraphthalate or polyurethanes. Such materials
are also referred to herein generally as "collagen". The term
"collagen" herein thus refers to not only the specific class of
macromolecules known as collagen but those natural materials that
normally or naturally form membranes with collagen such as laminin,
keratin, glycosaminoglycans, proteoglycans, pure carbohydrates,
fibrin, fibronectin, hyaluronic acid or the like, and other natural
materials that come into contact with collagen that can be made
into film, including albumin, globulins, and other blood borne
proteins. Tubular films made from any combination of the above
materials will provide substantially the same purpose as that of
pure collagen.
[0038] The interaction of blood with the differing membrane
components described above determines subsequent reactions in the
repair of blood vasculature. The initial thrombus formation
adhesion and activation of platelets and the initial events related
to intimal hyperplasia such as damage to the internal elastic
lamina are among those events. These events are natural components
of the repair process. Normally these events do not hamper the flow
conditions of blood except in the cases of severe trauma.
Microthrombi constantly form and disperse on blood vessel surfaces
so it would be advantageous to form stent or graft coverings of
materials that are accustomed to having thrombus form so that
subsequent lysis reactions of those thrombi can proceed in a
natural and unobtrusive manner. A sleeve or liner made of these
macromolecular components forming a protective layer will prove
advantageous when used with stents. Metal or polymeric stents which
will provide mechanical stability to the arterial wall to hold up
dissected tissue may also be used to hold a sleeve comprised of
collagen.
[0039] Nevertheless, because anything not formed in the body as a
natural component may elicit extreme and unexpected responses as
blood vessel closure due to thrombus formation or spasm and because
damage to blood vessels by the act of insertion itself of a device
may be extreme and unduly injurious to the blood vessel surface, it
is prudent to protect against such events. The materials described
above are capable of being manipulated to become hydrophilic or
hydrophobic with thicknesses ranging from about 5 to several
hundred microns. They can be made water soluble, insoluble and with
various porosities. They can also be constructed to have regions of
various hydrophilicity and porosity. Porosity control is well
known.
[0040] As such, stent sleeves or liners constructed of these
materials can be used for reservoirs for pharmaceutical agents and
the like. Hydrophilic drugs such as heparin or hirudin to protect
against coagulation or hydrophobic drugs such as prostaglandins or
aspirin and vitamin E may be used to protect against platelet
activation. Vitamin E and other anti oxidants such as sodium
ascorbate, phendies, carbazoles, and tocotrienols may be used to
protect against oxidation. Most preferably, the collagen material
will include a quantity of drug material such as heparin which may
be incorporated into the collagen in known manner for release after
placement of the stent. Generally, the drug materials may include
the known antithrombic agents, antibacterial and/or antimicrobial
agents, antifungal agents and the like.
[0041] During the formation process of the sleeve or sheet, various
components may be added to the solution prior to drying or may be
added separately after formation of the device. Heparin may be
directly added to the forming solution as may be aspirin.
Benzaalkonium heparin, a modified form of heparin which makes it
more hydrophobic may be used to coat the formed device or film from
a solution of alcohol. Prostaglandins PGI2 or PGE2 may be added
from a solution of propanol or propanol/methylene chloride onto a
collagen sleeve formed from an aqueous base. Vitamin E may be added
from even less polar solutions as chloroform. RGD peptide,
thrombomodulin, TPA (Tissue Plasminogen Activator) and Urokinase
are examples of bioactive proteins which may be added. Gene therapy
agents such as antiplatelet and antibody fragments, for example
GB2B3A may be included. Other agents could be similarly added. The
term "agents" is used herein to include all such additives.
[0042] Vitamin E is a known antioxidant. It is used in polymers and
as a drug. It could also be used in biodegradable stents for
multiple purposes. In those polymeric type stents that require some
form of energy as heat or light to be delivered it could serve to
protect the polymers therein against unwanted oxidation caused by
the energy source. Also, because tissue damage is caused by
oxidation originating from cellular components as macrophages and
neutrophils, Vitamin E could serve to protect the tissue as it
leached from implanted devices. It could also serve to protect the
polymer during extrusion or heat forming as pressing films. It
could also serve to plasticize the material in place of using other
non FDA approved materials. It is therefore contemplated that
Vitamin E may also be used in combination with the stent or
collagen material or the like in this invention for several
purposes.
[0043] A primary result of the use of a collagen sleeve made of
natural components is that cellular regrowth of endothelium will
take place onto a natural substrate that is essentially undamaged
and uniform and protects against tissue flaps and exposure of
necrotic or arthrosclerotic tissue to blood. In this regard, the
sleeve provides biological protection.
[0044] Metal stents are known to sometimes physically damage tissue
upon expansion. A sleeve made of a biological material is naturally
soft by comparison to the metals or polymers used to construct
stents. A sleeve comprised of collagen may be made sufficiently
thick and durable so that it will prevent or at a minimum reduce
any damage caused by the struts or other elements of any of the
metal stents to the remaining healthy endothelium and the internal
elastic lamina. The porosity of the sleeve may permit diffusion of
essential fluid components from the blood to the surviving tissue
below. In this regard, the benefit of the biological tissue
protection by the sleeve and the physical protection provided are
additive.
[0045] Both the biological and physical advantages as described
herein can not be provided by synthetic sleeves as Dacron or
PTFE.
[0046] In the case of a fixed diameter stent, the sleeve may be
fitted to the stent rather closely for ease of vascular placement.
However, in the case of variable diameter stents, the sleeve being
somewhat elastic will fit the constricted stent and stretch with it
upon deployment or it may be relatively loose fitting to
accommodate the expanded stent upon deployment without any
additional stress. Alternatively and most preferably, the stent may
be expanded temporarily and the collagen placed thereon. The
collagen may then be hydrated and the stent contracted to its
unexpanded configuration. Then the collagen is dehydrated and it
fits tightly to the stent.
[0047] A sleeve or a liner may be made to be more elastic by
altering the crosslink density of the collagen. This can be
accomplished in a variety of ways. Collagen sleeves may be prepared
to have a very low crosslink density. The crosslink density may be
increased in a variety of ways, dehydration, radiation exposure or
heating are some examples of ways. Chemical agents which react with
the collagen, such as short chain dialdehydes or formaldehyde may
be employed to crosslink the collagen. The avoidance of the
aforementioned processes can assure a non-crosslinked structure and
result in somewhat elastic material. Crosslinking with the
appropriate reagents can also enhance the elasticity of the
collagen sleeve. Such reagents are the long chain difunctional
molecules C12 and higher such as polyether or aliphatic
dialdehydes, activated diesters such as N-hydroxy succinimide
esters and diacid chlorides. These active esters will react with
amines present on the collagen chains thus bridging them by a
flexible link which allows expansion without failure and tearing.
Also, with amine functionality protected as an amide, the
interchain, irreversible amide formation, which results from
dehydration, is prevented.
[0048] A variety of stent types may be used in the invention. Some
examples are shown in FIGS. 3-6. In FIG. 3 there is shown a braided
self-expanding stent generally designated 40. As is clear from the
Figure, stent 40 has a cylindrical configuration. The stent may be
manufactured in a braiding machine, wherein the stainless steel
monofilaments consist of a plurality of wires, each having a
thickness of, for example, 0.08 mm. FIG. 4 shows yet another stent
configuration 50 which may be used in this invention. Other
examples of this type of stent are disclosed in U.S. Pat. No.
4,655,771; U.S. Pat. No. 4,732,152; U.S. Pat. No. 4,954,126 and
U.S. Pat. No. 5,061,275; all of which are incorporated herein by
reference.
[0049] Referring now to FIGS. 5 and 6 an articulated stent 60 is
shown with three stent segments 62 and two interconnecting hinge
elements 64. Stent segments 62 are each made of individual wire
elements welded together. Hinges 64 may be made of biocompatible
spring material and may be of a smaller diameter than those used in
forming stent segments 62. Hinges 64 are welded at each end to
stent segments 62 using either laser or resistance welding
techniques. Hinges 64 are preferably both attached to the same side
of stent segments 62. Stent 60, shown in FIG. 5, may be installed
in an artery 66 with a sleeve 12 as shown in FIG. 6 and may be bent
as shown.
[0050] Other stent configurations and materials will be apparent to
those familiar with this art.
[0051] Collagen sleeves may be made to cover both sides of the
stent, inside and out so that its surfaces are entirely encompassed
by collagen.
[0052] An example of one such embodiment is shown in FIG. 7 which
comprises a tubular stent generally indicated at 10 combined with
an inner sleeve 13 of collagen material and an outer sleeve 12 of
collagen material which provide in combination a stent/sleeve
generally indicated at 15 for the purpose of vascular implantation.
In some cases, it is preferred that the collagen sleeve 13 be
joined to the interior surface of the stent by a suitable means
such as collagen gel which acts as an adhesive, particularly when
the stent is of the variable diameter type. Such gels are known in
the art.
EXAMPLE
Method For the Preparation of the Sleeve Stent of FIG. 7
[0053] 1. SIS sheet is stretched about 50% while allowed to air
dry.
[0054] 2. Dry SIS sheet is wrapped onto an inflated, standard
angioplasty balloon, moistening along the seam to ensure proper
adhesion.
[0055] 3. A tubular stent is then placed over the SIS.
[0056] 4. A second sheet of SIS is wrapped over the exterior of the
stent. This sheet may be wetted to facilitate handling. The SIS
which resides inside the stent may be wetted with a small amount of
distilled water immediately preceding this wrapping procedure
also.
[0057] 5. Open cell foam sheeting is then wrapped onto the outer
second layer of collagen, followed by a wrap of dialysis tubing.
This radial pressure insures continuous contact and adhesion
between the collagen layers.
[0058] 6. The entire construction is then immersed in water
momentarily to wet the collagen.
[0059] 7. The entire combination is then heated to about
40.degree.-70.degree. C. for about 0.5-3 hours, then cooled to room
temperature. The purpose of this heat treatment is to bond the
collagen layers together. It may optionally be accomplished by use
of a chemical cross-linking agent.
[0060] 8. The resultant device is liberated from the balloon after
the dialysis tubing and foam are removed. Any excess collagen
material is then trimmed from the ends of the covered stent.
[0061] A cast or molded version is shown being manufactured in FIG.
8 which includes a cylindrical mold 80 into which a cylindrical
stent 82 is placed on end. Preferably, mold 80 will be porous, such
as a porous ceramic, so as to allow water to be drawn through the
mold to facilitate set-up of the poured collagen. A collagen gel
solution 83 is then poured into mold 80 around stent 82 and inside
of stent 82 and allowed to set-up. Upon set-up, the stent embedded
in collagen is removed from the mold and a longitudinal hole may be
formed through the collagen inside the stent to provide a
longitudinal opening therethrough. Otherwise, a mandrel or mold
insert may be used for this purpose as well.
[0062] In other embodiments, the collagen material may be coated
onto the stent surfaces as desired by spraying or dip coating or an
electrophoretic technique or the like. The electrophoretic
technique is a preferred coating technique and may be accomplished,
for example, in a solution of acetic acid, acetone, water and
collagen with a metal stent as the cathode, at a potential of about
three volts. This process bears some resemblance to modern
electroplating, where positively charged metal ions are reduced to
their corresponding metal at the negatively charged cathode. In the
case of collagen, the biomolecule is dissolved or suspended in an
acidic solution. The acid imparts a positive charge to the protein,
collagen, and allows it to travel in an electrical field. By
attaching a metal object to the negative electrode of a power
source, and then immersing both the positive and negative
electrodes in the acidic collagen solution, a layer of collagen
will form on the negatively charged surface. The result is a coated
stent of the type shown in FIGS. 19 and 20 which will preferably
include openings in the coating coincident with the openings in the
stent.
EXAMPLE
Collagen Coated Stent (Type IV) Via Electrodeposition
[0063] A. A solution of Sigma type IV human collagen (50 mg) was
placed in a polypropylene tube with 3 ml water, 1 ml of acetic acid
and 2 ml of acetone. This mixture was homogenized to a viscous
solution via high shear mixing for ca. 3 minutes. The solution was
diluted with water, then filtered through a cotton plug. The
solution was allowed to stand for 1 hour to eliminate air
bubbles.
[0064] B. A cylindrical container was fashioned out of
polypropylene and charged with 1 ml of the above prepared solution
A. To this container was added a nitinol substrate attached to the
negative lead of a variable voltage power supply which was set at 3
volts. The positive electrode was furnished with a 0.010 inch
diameter wire which was placed ca. 4 mm from the substrate. The
power supply was turned on and gas evolution was immediately
evident on the surfaces of each electrode. This was maintained for
several minutes, then the electrodes were removed from the collagen
solution. An even gelatinous mass was evident on the substrate,
which contained several bubbles. Upon standing for 1 to 2 minutes,
the bubbles were gone, and the electrodes were once again placed in
the bath. After three additional minutes of treatment, the
substrate was withdrawn from the bath and allowed to dry. The
coating appeared to be continuous via visual inspection.
[0065] Another coating technique is shown in U.S. Pat. No.
5,275,826 which is incorporated herein by reference.
[0066] Referring now to FIG. 9, a tubular metal stent generally
indicated at 10 carries within it a cylindrical liner or inner
sleeve of collagen material generally indicated at 12 to provide a
combination stent/liner generally indicated at 14 for the purpose
of vascular implantation.
[0067] Stent 10, as already described hereinabove, is of any type,
typically a metal such as for example stainless steel, nitinol,
superelastic alloys and other metals or a suitable polymer or any
other suitable material and may be of a fixed diameter or of a
variable diameter, the latter being more preferred and well known
in the art. The content of this application is incorporated herein
by reference.
[0068] Collagen liner 12 as described hereinbefore, may be of
collagen per se or it may be applied directly to the stent or it
may be carried as 12c on a support 12d as shown in FIG. 10 for
application to a stent.
[0069] When the collagen liner is comprised of two different
materials which are joined together as shown in FIG. 10, it may be
referred to as a bilayer structure. When placed in a stent, layer
12c is placed luminally with layer 12d contacting the inner surface
of the stent. Layer 12d, which may be in contact with the vessel
wall through openings in the stent in such an arrangement, is
preferably strong and enables the inner luminal layer 12c itself to
have the structural integrity necessary to ensure ease of loading,
delivery and deployment. Layer 12c may for example be comprised of
a collagenous material in the range of 5 to 200 microns thick. Such
a biologically derived material may be harvested from a donor
source, cleaned of unwanted tissues and formed into the tube by
wrapping it around a mandrel and bonding the material to itself.
Synthetic materials may be used to comprise the support of layer
12d of the liner, however, vascular graft materials such as PTFE,
woven dacron, polyurethane and the like may also be used.
Resorbable polymers (PLLA, PGA, PDLLA, PHB, polyanhydrides) are
another choice for the support layer 12d of the liner 12. These
materials may be formed into a tube by extrusion, solvent casting,
injection molding, etc. or spinning into fibers and weaving into a
tubular structure. A tube of one of the aforementioned polymers may
also be constructed by a non-woven fiber technique.
[0070] The innermost or luminal side, i.e., layer 12c of the liner
serves a different function than the support layer 12d. The luminal
surface or layer 12c must be a substrate for the growth of
endothelial cells, as well as a reservoir for therapeutic agents.
Preferred material is fibular Type I collagen and/or porcine Type
IV collagen in the range of 5-200 microns thick, although fibrin
may also be used for this purpose. Highly hydrated materials, such
as cross linked hydrogels meet the drug holding requirement for the
luminal portion of the liner, examples of which are polyethers,
polyalcohols, polypyrollidones, polypeptides, polyacids and the
like. The layer 12 may also be a mixture of the above materials
with a drug binding, ionic or covalent, molecule. One such molecule
would be protamine, which effectively ionically binds heparin.
These polymers can also be treated with growth factors, such as RGD
peptides to promote endothelialization. The preferred method of
drug incorporation would involve the preparation of a solution of
the therapeutic agent and allowing the dehydrated luminal side of
the sleeve to swell with the solution. Upon evaporation of the
carrier solvent, the drug would be made to reside in the matrix
which comprises the inner layer of the liner, i.e., layer 12c. The
device may act as a sponge to soak-up a drug in solution and to
elute it from the stent upon implantation.
[0071] The term "collagen" or "collagen material" should also be
understood to include the material referred to as Small Intestine
Submucosa (SIS) which has particular use in this invention, alone
and in combination with other collagen material such as Type 1. SIS
is comprised of a bilayer structure in which one layer is
predominantly (stratum compactum) Type IV and the second layer is a
mixture of Type I (muscularis mucosa) and Type III material. It is
described in detail in U.S. Pat. Nos. 4,902,508; 4,956,178 and
5,281,422, all of which are incorporated herein by reference. The
luminal side of the SIS as used in preferred embodiments of this
invention are predominantly a Type IV collagen material.
[0072] As with other collagen material, SIS may be used herein with
or without a support layer such as a layer 12d as shown in FIG. 10.
It may also be used as the support layer 12c in combination with a
layer 12d of Type I collagen as shown in FIG. 10. SIS functions
well without a support layer because it is itself a multi-layer
structure.
[0073] In yet another embodiment, an SIS layer may be combined with
a Type I layer to provide a one-way flow structure with reservoir
arrangement as shown schematically in FIG. 11. In this arrangement,
a cylindrical wire mesh stent 10 carries a tubular bilayer liner
generally indicated at 12 comprised of two layers 12c and 12d.
Layer 12c contacts the inner surface of stent 10 and is a Type I
collagen material and may carry a drug or the like, acting as a
reservoir. Luminal layer 12d is SIS material and inherently
functions to allow flow of drug from layer 12c into the luminal
interior of the stent through the luminal layer 12d of stent 10 but
does not permit appreciable fluid flow into layer 12c from the
interior of the stent.
[0074] Variations of this FIG. 11 arrangement are shown in FIGS. 12
and 13. In FIG. 12, stent 10 carries an inner or luminal liner made
up of layers 12c and 12d as described for FIG. 11 and an outer
layer of the same combination to allow predominantly one-way flow
of drug to the luminal interior of the stent and to the surface
against which the stent rests when implanted.
[0075] In FIG. 13, stent 10 carries an exterior layer 12 of
unsupported SIS material and an inner liner comprised of layers 12c
and 12d as in FIGS. 11 and 12. Layer 12c is Type I material acting
as a drug reservoir as previously shown in FIGS. 11 and 12. Layer
12d is of SIS acting as the one-way flow-through for drugs and the
like from layer 12c, as before.
[0076] As pointed out hereinabove, cells of the blood vessel wall
synthesize and secrete several kinds of macromolecules forming
extracellular matrix. Each of these macromolecules may be combined
in a multitude of combinations to form composites. Such materials
as already pointed out, are referred to herein generally as
"collagen".
[0077] A primary result of the use of a collagen liner made of
natural components is that cellular regrowth of endothelium will
take place onto a natural surface that is essentially undamaged and
uniform. In this regard, the liner provides biological
protection.
[0078] The liner may be tightly fitted to the stent in much the
same way as described hereinabove with reference to the outer
sleeve arrangement.
[0079] The liner may be attached to the stent in a wide variety of
ways. The basic goal of attachment in the preferred form is to
provide a stent device in which the supporting stent framework is
substantially, if not completely, isolated from the blood flow by
the liner. This can be achieved by placing liner 12 in the inside
dimension of the stent 10 and cuffing the ends of the liner over
the ends of the stent as shown at 16 in FIG. 14. This is an
especially preferred arrangement. Cuffs 16 may either be under or
over the outer sleeve. Cuffs 16 may be sutured to the stent,
sutured from one cuff to the other, or otherwise bonded to the
stent or to the liner itself. The collagen material may be welded,
by the application of localized heat and pressure, or the
application of a concentrated solution of collagen material which
acts like glue.
[0080] The liner may also be attached to the stent by the use of
pledgets (not shown). The pledget (or small swatch of material) can
be placed on the outside of the stent. The liner, which resides on
the luminal or inner surface of the stent, may be bonded to the
pledget in a variety of ways. Among these are suturing, gluing and
heat welding. In the case of a combination of liner with outer
sleeve, these means of attachment may be used as well.
[0081] The liner may be placed in the stent via several methods.
The stent may be made porous or perforated, thus allowing the liner
material to act as a forming mandrel for a collagen sleeve. The
collagen may also be precipitated onto the stent. This method would
require the stent to be heated in a solution of collagen. The
collagen forms a matrix on the surface of the stent, then when
properly annealed, the collagen assumes a fibular, well organized
structure conducive for the attachment and growth of cells.
[0082] A technique is indicated in FIG. 15 in which the collagen 12
is cast inside the stent 10 in a manner similar to that described
in connection with FIG. 8. Upon set-up, the stent with a liner of
cast collagen is removed from the mold and a hole may be formed
through the collagen to provide a longitudinal opening
therethrough. Otherwise, a mandrel or mold insert (not shown) may
be used for this purpose also. Holes may also be formed through the
stent walls in the collagen if the stent is perforated or the
like.
[0083] The liner may be attached to the stent by any of several
design features which may be incorporated into the stent. By
providing the stent with hooks, or other similar topography (not
shown), the sleeve may be readily attached to the stent. The sleeve
material may be impaled on such barbs, thus securing the sleeve.
With hooks of the appropriate size, the collagen material may not
be perforated, but rather embedded in the holding topography.
[0084] As can be seen from the foregoing, the invention provides in
one embodiment a stent in which collagen liner material is placed
within and/or on the outside of the stent thereby reducing thrombus
formation and therapeutically treating the vessel when a suitable
agent is included in the collagen.
[0085] It is to be understood that the collagen material referred
to herein as layers may be in the form of sheets associated with
the stent or deposited thereon, i.e., as a coating.
[0086] Thus, the collagen material may be coated onto the stent
surfaces as desired by spraying or dip coating or electrodeposition
or the like or attached in other ways as described above. Such a
coating might be about 1-50 microns thick. A coated stent is shown
in FIG. 19, which will preferably be perforate as shown.
[0087] A collagen coated stent may also have a collagen sleeve over
the collagen coating or under the collagen coating. For example,
one may place a stent into a collagen sleeve, as shown in FIG. 1,
with an interference fit. The inside of the stent may then be
coated with collagen so that the stent and interior of the sleeve
are covered and bonded together. Preferably, in such an
arrangement, the sleeve will be SIS and the coating Type I or Type
IV. It is also possible in the case of an open-work stent such as
shown in FIG. 1 or 3, to coat the stent struts with collagen, place
a collagen sleeve either over or inside the stent, or both, and
then heat bond the sleeve and/or liner to the coating. This would
preferably be done with Type IV collagen, especially SIS or with
fibrin.
[0088] In some applications it may be desirable to include
perforations in the collagen for fluid movement through the
stent\collagen wall. Such an arrangement is readily obtained as
stents are generally open or perforate with respect to their
structure and perforations may be readily formed in a collagen
liner, the perforations extending through the stent openings.
Perforation in collagen liners of about 10-60 microns in diameter
have been found satisfactory. The distribution of the perforations
may be such as to be evenly spaced, such as at 30-60 micron spacing
and to occupy about one-half of the liner surface areas. This, of
course, may vary.
[0089] Lastly, there is a preferred orientation for placing
collagen on the stent when the collagen is used in the form of a
sheet which is wrapped around the stent or a tube inserted in the
stent. It has been discovered that sheet collagen has the ability
to stretch but that its stretchability is predominantly
unidirectional. That is, most of the stretch is exhibited in one
primary direction in a sheet. This is shown schematically by the
parallel arrows 100 in FIG. 16 for a sheet of collagen 110 which
typically shows little or no stretch in a direction normal to the
arrows.
[0090] It has been discovered that the collagen sheet, when used as
a sleeve or liner on a stent which undergoes expansion and/or
contraction, can be better accommodated if the collagen sheet is
associated with the stent on a "bias". This will be more fully
explained by reference to FIGS. 17 and 18. If a piece of collagen
sheet 110a is taken from sheet 110 in the orientations shown in
FIG. 17, it can be seen that the stretch direction indicated by the
arrows 100 is on a bias with respect to sheet 110a. In this case,
the bias is 45.degree. relative to the edges of sheet 110a. If
sheet 110a is oriented normally with respect to a stent 120 as
shown in FIG. 18, i.e., the edges of sheet 110a are normal to the
longitudinal dimension of stent 120, when sheet 110a is wrapped
around stent 120 to form a sleeve or rolled up (in direction shown
at 112 in FIG. 18) into a tube for insertion into stent 120 as a
liner, the stretch properties of sheet 110a will be on a bias with
respect to the longitudinal dimension of stent 120, in this case
the bias is 45.degree., which is a preferred bias. Other degrees of
bias are acceptable but 45.degree. is preferred.
[0091] It can be seen from the foregoing that due to the variable
dimensions in both diameter and length which occurs with stents,
such an arrangement better accommodates collagen sleeves and liners
to dimensional changes in both directions without disruption at
seams and without tears in the material.
[0092] One preferred type of stent for use in this invention is one
of the type disclosed in related application Ser. No. 08/246,320,
filed May 19, 1994, the entire content of which is incorporated
herein by reference.
[0093] FIGS. 19 and 20 show a coated stent generally indicated at
140, the collagen coating 142 being best seen in FIG. 20. Coating
142 is shown on both the inside and outside surfaces of the stent
although it may be on either as well.
[0094] It can be seen from the above that the invention also
provides a treatment method of implanting a stent in which collagen
material is placed between the stent and the vessel wall thereby
reducing thrombus formation and therapeutically treating the vessel
when a suitable agent is included in the collagen.
[0095] The above Examples and disclosure are intended to be
illustrative and not exhaustive. These examples and description
will suggest many variations and alternatives to one of ordinary
skill in this art. All these alternatives and variations are
intended to be included within the scope of the attached claims.
Those familiar with the art may recognize other equivalents to the
specific embodiments described herein which equivalents are also
intended to be encompassed by the claims attached hereto.
* * * * *