Note: Descriptions are shown in the official language in which they were submitted.
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STENT COVER
TECHNICAL FIELD
The present invention relates to stents and to methods for reducing the
occurrence of restenosis, and particularly restenosis due to intimal
hyperplasia, in the
course of the use of such stems. In a related aspect, the invention relates to
coatings
and covers for use on stents. In a further related aspect, the invention
relates to
methods of preparing and methods of using coated or covered stems.
BACKGROUND OF THE INVENTION
A number of improvements and advances have been made in recent years in
the technique of percutaneous transluminal coronary angioplasty ("PTCA"}. In
turn,
intravascular stent implantation has arisen to address the need to treat
abrupt vessel
closure and prevent restenosis after angioplasty. Coronary stents represent
the first
major breakthrough in interventional cardiology since the introduction of
balloon
angioplasty in the 1970s. Before the use of stents, 30% to 40% of patients who
had a
coronary interventional procedure were likely to experience restenosis.
Restenosis
rates have dropped from 10% to 20% of all stented procedures in recent
clinical
studies, prompting rapid adoption of coronary stents among the interventional
cardiology community.
The cardiovascular stent market reached an approximate level $2 billion in
annual sales by the year 1998, with further growth expected. See L.
Haimovitch,
Cardiovascular Device Update 4(11):1-5, November 1998. The companies having
stems in development or already marketed include Johnson & Johnson
Interventional
Systems / Cordis, Medtronic, Pfizer/Schneider and Arterial Vascular
Engineering,
along with AngioDynamics, Biotronik, Boston Scientific Corporation, C.R. Bard,
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Cook, Inc., Devon Medical, Global Therapeutics, Guidant Corporation, and
Progressive Angioplasty Systems.
Restenosis, however, continues to pose a problem for cardiologists.
Restenosis is typically viewed as involving two components - recoil (collapse
of the
artery after it's been opened) and the proliferative response (development of
scar
tissue). While stents prevent recoil, they are not presently able to inhibit
scar
formation. In fact, through unavoidable injury to the vessel surface, stems
may
actually increase the formation of scar tissue. A number of approaches have
been
suggested for tackling the problem of restenosis, including the use of
coronary
radiation to inhibit proliferation.
See, for instance, Donald F. Phillips, JAMA, Medical News & Perspectives -
May I, 1996 , "New Ideas on Pathology of Restenosis", which describes the
manner
in which the long-term benefits of PTCA, as a means of treating coronary
artery
disease, remain tempered by restenosis, which develops in 30% to SO% of
patients
within 6 months after the procedure is done. The prevailing view is that the
angioplasty procedure damages the coronary wall, leading to platelet
activation, which
causes vascular smooth muscle cells to proliferate and migrate to the damaged
area of
the vessel where they accumulate. This creates an extracellular matrix that
forms an
intimal lesion, resulting in the loss of lumen cross-sectional area, thus
impeding blood
flow. The Phillips article goes on to suggest that the elimination of
restenosis may
require a combined approach, including a mechanical device to resist geometric
remodeling and a pharmacologic agent to inhibit cellular proliferation.
Along these lines, a variety of approaches have been described for preventing
cell ingrowth and intimal hyperplasia, including modifications to the stent
design
itself, as well as the use of coatings and coverings. In particular, a variety
of
approaches and materials have been described for use in covering stents.
Fouere (WO
9$16172), for instance, discloses a balloon-expandable stent which can also be
bent in
the center to fit straight or curved vessels. The stmt includes a laser-
machined thin
metal tube with radially-expandable mesh at ends and central zigzag links,
with a
biocompatible covering. The covering is described as being a flexible
synthetic
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material such a polyurethane, silicone rubber or polyester, in order to
prevent
endothelium with penetration through the mesh and into the tube.
Chu et al. (International Patent Application No. WO 9800090, assigned to
Baxter) describe a tubular stented graft, alternately used in radially compact
and
radially expanded configurations having first and second diameters
respectively. The
stent graft includes a continuous, tubular polytetrafluoroethylene covering
formed on
a stmt comprising lateral openings in the stmt when the stmt is at the
radially
expanded diameter. The polytetrafluoroethylene covering includes a tubular
outer
layer formed of expanded, sintered polytetrafluoroethylene. The outer layer is
about
the outer surface of the stmt so that the stent is captured between the outer
layer and a
tubular base graft, formed of expanded sintered polytetrafluoroethylene.
Solovay, in U.S. Patent No. 5769884 (assigned to Cordis), describes a
controlled porosity endovascular implant for damaged or stenosed blood vessel.
The
implant includes a stent having an expandable frame structure and a stent
covering
with two regions having different porosities.
Buirge et al. (LTS Patent No. 5693085, assigned to Scimed Life Systems)
describes a vascular prosthesis that includes a stmt with a collagen sleeve,
with the
collagen in biased stretch orientation to the stent. The patent includes a
combination
of a vascular prosthesis comprising an expandable support framework stmt , and
a
covering sleeve and/or liner of a collagen material.
Finally, House et al. (US Patent No. 5620763, assigned to Gore & Assoc.)
describes a thin-walled, porous, seamless plastic tube for use as an
intraluminal
vascular graft or as covering for intraluminal stent. The tube may have a wall
thickness ranging from less than 0.1 mm to less than 0.06 mm, preferably about
0.2
mm. Also claimed is a tube formed by two layers of 0.05 mm thick membrane with
a
0.013 thick non-porous layer of fluorinated ethylene propylene therebetween.
The
PTFE layers are oriented with their fibrils disposed perpendicularly, and the
tube
formed as hereinbefore described.
The use of stent covers is generally limited by a variety of considerations,
including the need to find a cover material that is sufficiently
biocompatible. Such
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materials should also be sufficiently thin, so as not to add undue size to the
already-
limited stmt, yet strong enough for its intended purpose. The ability to
achieve a thin
material, however, is often tempered by the accompanying lack of strength or
integrity.
A limited number of biological materials have also been used as well, or
proposed for use as stmt covers. See, for instance, H.B. Lin et al.
Proceedings of the
24'" Annual Meeting of the Society for Biomaterials, April 22-26, 1998, and
Vanderwalde et al., Stent-Graft (SG) with Bovine Pericardium (BP):Acute
Results in
Porcine Coronary Arteries, TCT-14 (abstract) American J. Cardiol., pp SS-6S,
October, 1998. The Vanderwalde et al. work is said to employ a "thin BP"
obtained
by "special processing". The abstract itself provides little detail, and
speaks only of a
process that includes obtaining pericardium and suturing it into a tube that
is then
positioned onto a stent, and attached to the stent using sutures. There is no
mention of
the tissue being treated in any manner, or of the formed tube being closely
adapted to
the constricted size of the stent. The abstract implies that the tube is
simply formed
with a diameter sufficient to accommodate the expanded diameter of the stent,
and is
then retained in place on the constricted stent by the sutures described. Nor
is there
any indication of the actual thickness of the "thin" material, or the manner
in which
the "special processing" may have been used to achieve such a material.
Assuming it
can be determined that such processing involved peeling the pericardium, in
the
hydrated state, a comparative example herein shows that such a method provides
an
inferior combination of absolute thickness, uniformity of thickness, strength,
and
consistency of results for use in commercial applications.
What is clearly needed, therefore, are materials and methods for reducing or
eliminating intimal hyperplasia that provide an optimal combination of such
properties as efficacy, adaptability to-various stent designs, availability
and cost.
With regard to the use of biological tissues for such purposes, what is
particularly
needed are materials that provide these and other features, together with an
improved
combination of absolute thickness, as well as consistency and uniformity in
thickness.
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SUMMARY OF THE INVENTION
The present invention provides a stent cover adapted to act as a barrier
between an expandable vascular stent and the vascular surface. The stmt cover
is
adapted to be placed over a stmt (e.g., an expandable metallic stent) that is
deployed
percutaneously within a mammalian vein or artery. The stmt cover functions to
increase the patency rate of the vein or artery after stent placement, and to
decrease
the incidence and/or extent of intimal hyperplasia, as compared to an
identical stmt
lacking such a cover.
In another aspect, the present invention provides a stent cover comprising a
natural tissue dimensioned and adapted to be placed over an expandable stent
and to
be expanded in situ, upon expansion of the stent, in a manner that permits the
cover to
maintain its integrity and decrease the incidence and/or extent of intimal
hyperplasia,
as compared to a stmt lacking the cover. The stent cover also provides an
improved
combination of absolute thickness, uniformity of thickness and physical
characteristics (e.g., strength) as compared to a pericardium cover prepared
by other
routes.
The stmt cover can be formed (e.g., crimped) to assume substantially the
shape of the constricted stent, and thereafter expanded, upon expansion of the
stent, to
assume the shape and diameter of the expanded stent as well. Preferably, the
expansion is largely achieved by physical means, as opposed to elasticity of
the
material itself, e.g., by crimping the cover onto the constricted stent and
permitting it
become uncrimped as the stent is expanded. Optionally, however, the material
can
contribute an element of elasticity as well, particularly in its expanded
form, for
instance, to accommodate slight variations in size, and to form a more
intimate fit.
In a preferred embodiment, the natural tissue is a strong tissue of mammalian
origin and is either itself sufficiently thin and biocompatible for its
intended purpose,
or can be rendered so in the manner described herein. The word "thin", and
inflections thereof, as used in describing a stent cover of this invention,
refers to a
tissue that imparts negligible additional size to the stmt upon insertion, or
when
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expanded, such that the stent can be delivered in a normal fashion and with
undue
trauma or damage to the vessel. Many, if not all, stmt covers described
previously,
tend to be unduly thick, or lack uniformity, when used in this respect.
By comparison, Applicants have discovered that natural tissues can be
obtained and/or prepared to be sufficiently thin. In a preferred embodiment,
for
instance, Applicants have discovered that even bovine pericardium can be
prepared in
a particularly thin and uniform fashion, e.g., by a method that involves at
least one,
and preferably two or three, "dry peeling" steps as described herein (as
opposed to a
single peeling in the wet or hydrated state). A preferred method of the
present
invention is a mufti-step method that includes, first, carefully "dry peeling"
the
vacuum dried tissue, e.g., to a thickness of about 100 microns or more (and
preferably
between about 150 microns to 250 microns thickness), followed by a second step
in
which the tissue is rehydrated and then air dried to provide a compact tissue,
having a
f nal thickness of about one-third the thickness of the dry-peeled tissue,
that is,
between about 50 microns and about 100 microns in thickness. In other words,
air
drying the tissue serves to compact it to on the order of about one-fourth to
one-half,
and preferably about one-third of its thickness. This can be compared with a
thickness of about 200 microns to about 250 microns, which is typically the
smallest
thickness that can be achieved by a single peeling of the tissue in its
hydrated state.
Moreover, peeling in the dry state permits the manufacturer to make multiple
peels of
the tissue, as compared to the single peel typically permitted using hydrated
tissue.
In a further preferred embodiment Applicants include yet another step in the
processing of pericardium. This step includes treating the tissue with a
disinfecting
agent, e.g., sodium hydroxide, in order to further lessen the already minimal
possibility of bovine spongiform encephalitis (BSE) infection. Such treatment
is not
only effective as an treatment effective to reduce/eliminate BSE infectivity
when used
in this manner, but moreover, that a tissue thus treated provides improved or
comparable properties as compared to untreated tissues.
Particularly preferred tissues are selected from the group consisting of
mammalian arteries (e.g., human umbilical arteries), and fibro-serous and
serous
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membranes, including fibro-serous membranes such as pericardium (e.g., bovine
pericardium) and serous membranes such as peritoneum (e.g., porcine
peritoneum).
Such tissues are preferably obtained, prepared, and/or treated in a manner
that renders
the tissues biocompatible, e.g., substantially nonantigenic. By the term
"substantially
nonantigenic" it is meant that the tissue does not elicit an antigenic or
other
physiological response on the part of the host, to an extent that would render
the cover
unsuitable for its intended use. A stent cover of this invention can either be
permanent (that is, present for so long as the stent itself remains in place),
or
temporary (e.g., removable or biodegradable over a period of weeks, months or
years).
Optionally, in turn, such tissues can also be decellularized and/or cross-
linked.
A cover of the present invention can be provided in any suitable form, e.g.,
as
flat or textured sheets, strips or in tubular form. Preferred covers are
either naturally
occurring or prepared (e.g., sutured and/or sealed) to be tubular in shape.
Particularly
preferred covers are provided in a seamless tubular configuration, e.g., using
mammalian vessels such as human umbilical arteries or veins.
A stent cover of this invention is also sufficiently expandible to permit it
to be
placed upon a stent prior to implantation, and once implanted, to expand with
the stmt
in order to provide a sufficient barrier to intimal hyperplasia. Expandability
can be
achieved in any suitable fashion, e.g., by the use of a tissue having
sufficient elasticity
to permit it to be stretched and placed over the unexpanded stent, and to then
maintain
its integrity by itself expanding upon expansion of the stent itself. In
another, and
preferred embodiment, the tissue can be positioned upon the stent by crimping,
or
otherwise conforming it to the outer dimensions of the unexpended stent. Once
positioned within the vein or artery, the combination of hydration and/or
stent
expansion permit the cover to become uncrimped, and return to substantially
its
original dimensions. Such a cover is therefore provided with dimensions
sufficient to
permit it to stay in position upon an expanded stent of predetermined
configuration
and dimensions.
In a further preferred embodiment, a stent cover of this invention is thin,
e.g.,
sufficiently thin to permit it to be temporarily and reversibly crimped or
folded onto a
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stent, and to then return to substantially its original dimensions upon
expansion of the
stent in situ. For instance, a particularly preferred cover of the present
invention is
provided in the form of a cylinder of tissue constructed from thin bovine
pericardium
which is crimped into an expandable stent cover, and there crosslinked.
Crosslinking
at that point provides a number of benefits, including biocompatability and
permanence in situ, as well as facilitating the ability of the cover to retain
its crimped
configuration. In other words, in such an embodiment, the overlapping or
crimped
portions of tissue are themselves crosslinked to other portions of tissue.
This
crosslinking is of sufficient strength to improve the stability of the crimps
during
storage and insertion, while also permitting the crimps to become unfolded in
situ
upon expansion of the stmt. Applicants have developed a method for providing
bovine pericardium that is particularly thin, as compared to the original
tissue, yet
surprisingly maintains most or all of its other desired properties, such as
strength,
integrity, and biocompatability.
In another aspect, the invention provides a combination comprising a stmt
covered with a natural, optionally treated, tissue of the type described
herein. In yet
another aspect, the invention provides a method of fabricating a stmt cover,
and a
cover prepared by such a method, as well as a kit comprising a stent and a
cover, as
described herein, adapted to be positioned on the stent, as well as a covered
stent
prepared using such a kit. In a further aspect, the invention provides a
method of
using a stent having a cover as described herein, as well as an artery having
an
expanded covered stent positioned therein.
DETAILED DESCRIPTION
Tissues suitable for use as a stmt cover of the present invention provide an
optimal combination of such properties as availability, biocompatability,
strength, the
ability to be easily fabricated and used.
Tissues can be obtained from any suitable source, e.g., from mammalian
tissues such as arteries as well as serous and fibro-serous membranes. In a
particularly preferred embodiment, the tissue source is selected from the
group
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consisting of bovine pericardium, human umbilical tissue (e.g., artery) and
porcine
peritoneum. Tissues are preferably fixed, e.g., by crosslinking, in order to
improve
their biocompatability. Suitable crosslinking agents include, for instance,
aldehydes
such as glutaraldehyde, epoxides, isocyanates, carbodiimides, isothiocyanates,
glycidalethers, and acyl azides. Tissues can be fixed at any suitable point,
e.g., prior
to or after being cleaned, formed, or positioned upon a stent or mandrel. In a
preferred embodiment, for instance using pericardium, the tissue is
crosslinked after it
has been positioned and crimped onto the stem itself, or a suitable mandrel
(e.g., one
dimensioned to permit the cover to be removed and placed onto a stent of
choice).
In one particularly prefer ed embodiment, the cover is formed from bovine
pericardium, in a method as described herein, to provide the tissue with an
optimal
combination of biocompatability, thickness, and other physical and
physiological
properties.
Tissues useful as stmt covers of this invention provide an optimal combination
of chemical, physical and physiological (e.g., immunological) properties for
use as
stent covers. In a preferred sense, the tissues provide an optimal combination
of such
properties as suture retention, shrink temperature, circumferential tensile
strength, and
tensile strength, as each are determined and described herein. For instance,
with
regard to suture retention, particularly preferred tissues provide between
about 10 g to
about 200 g, and more preferably between about 30 g and about 150 g, suture
retention. With regard to shrink temperature, preferred tissues provide shrink
temperatures between about 70 C and 90 C, and preferably between about 80 and
about 90 C. With regard to circumferential tensile strength, preferred tissues
provide
between about 0.2 N/mm to about 0.5 N/mm, and more preferably between about
0.3
N/mm and about 0.4 (N/mm). Finally, preferred tissues provide tensile
strengths of
between about 5 MPa and about 15 MPa, and more preferably between about 7 MPa
and about 12 MPa.
Stent covers of the present invention can be fabricated in any suitable shape
or
configuration, and in any suitable dimensions for their intended use. For
instance, the
tissue can be provided and packaged in flat (e.g., sheet or tape-like) or
tubular form,
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with either or both major surfaces thereof being optionally textured or
modified (e.g.,
by the covalent attachment, entrapment, and/or adsorption of biologically
active
factors, lubricious agents, antimicrobial agents, and the like).
See, for instance, M. Valente, et al., "Detoxified Glutaraldehyde Cross-linked
Pericardium: Tissue Preservation and Mineralization Mitigation in a
Subcutaneous
Rat Model", (J. Heart Valve Dis. 1998 May;7(3):283-91), and C. Stacchino et
al.,
"Detoxification Process for Glutaraldehyde-treated Bovine Pericardium:
Biological,
Chemical and Mechanical Characterization", J Heart Valve Dis 1998 Mar;7(2):190-
4,
the disclosures of each of which are incorporated herein by reference. These
articles
describe the manner in which glutaraldehyde promotes calcification by the
action of
toxic aldehyde group residuals from cross-linking. The authors have found that
post-
fixation treatment with homocysteic acid (HA), besides bonding aldehyde groups
and
neutralizing toxicity, can enhance biocompatibility due to the strongly
electronegative
sulfonic group. Moreover, the tissue can be provided with markings or other
suitable
means to indicate its preferred orientation or direction.
The present stent covers can also be provided to have any desired dimensions,
in both their constricted (e.g., crimped) and expanded (e.g., unconstricted)
form.
Suitable covers, for instance, can be provided having an overall length of
between
about 5 mm and about 50 mm, preferably between about 10 mm and about 30 mm,
and a maximum (e.g., swelled or unconstricted) diameter range between about 1
mm
and about 10 mm, preferably between about 2 mm and about 5 mm. Such covers are
also able to be constricted (e.g., by crimping or shrinking) to a diameter of
between
about'h mm and about 5 mm, and preferably of between about 1 mm and about 3
mm. Particularly preferred are thin covers, e.g., those having an average
maximum
wall thickness of between about 20 microns and about 80 microns, and
preferably
between about 40 and about 60 microns
When used in tubular form, for instance, the stem cover can be either seamless
or seamed, and is typically adapted to be positioned over a stent of a
particular size or
size range. The stent cover can be positioned upon the stmt in any suitable
manner as
well, e.g., it can be stretched so as to allow the cover to be expanded,
placed over the
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stent, and allowed to return toward its original dimensions. Tissues can be
formed
into tubes, for instance, by sealing a flat tissue in a cylindrical form,
e.g., by the use of
sutures, or in a sutureless fashion as by the use of an adhesive.
Alternatively, or in addition, the stent cover can be crimped (and optionally
secured or dried) onto the stent, to be uncrimped in situ at the time of use,
by
expansion of the stent itself. Other optional techniques for applying the
tissue cover
include wrapping the tissue (e.g., when provided in the form of sheets or
strips), and
unrolling a tissue provided in a donut-like rolled configuration.
Covers of this invention can be adapted for use with any suitable stent,
including presently available stents such as those available from
AngioDynamics
("AngioStent), AVE ("Micro Stenf~, Biotronik ("Biotronik Stent"), Boston
Scientific/Medinol and Boston Scientific/SciMed ("IVIR"), Cook ("GRI"), C.R.
Bard
("Angiomed" and "X-Trode"), Global Therapeutics ("Freedom" and "Freedom
Force"), GuidantlACS ("Multi-Link"), Johnson & Johnson/Cordis ("Palmaz-
Schatz",
"Crown", "Crossflex"), Medtronic ("Witkor" and "BeStent"), Medtronic/Instent
("CardioCoil"), Pfizer/Schneider ("Wallstent"), and Progressive Angioplasty
Systems/ACT ("AT-One").
Such stents tend to be either self deployed (1VIR, Angiomed, Cardiocol and
WallStent brands) or deployed by balloon (as in the remaining designs
specified
above), and prepared of materials that include platinum/iridium (AngioStent),
tantalum/silicon carbide (Biotronik), stainless steel (1~TIR/Medinol, X-Trode,
Freedom
and Freedom Force, Multi-Link, Palmaz Schatz, Crown, Crossflex, BeStent
brands),
nitinol (1VIR/SciMed, Angiomed, Cardiocoil, ACT-One brands), tantalum (Cordis
and
Wiktor brands, and multialloys (WallStent). The stents can be provided to have
a
variety of designs, including those selected from the group consisting of
single wire
sinusoidals with longitudinal spines, geometric struts, slotted tubes with
articulations,
flexible coils, flexible coils with flat struts and an axial spine, coils,
single wire
_ fishbones, multiple links with articulations, slotted tubes with spiral
articulations,
sinusoidal helical coils, single wire sinusoidal helicies, sinusoidal helical
coils,
serpentine meshes, spiral coils, multiple wire brails, and slotted tubes with
single
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articulations. See, for example "Market Pulse, Table 3 at www.med-
device.com/tablethree.html, the disclosure of which is incorporated herein by
reference.
In one preferred method, a tubular pericardium stent cover is provided by a
method that involves both treating the tissue with an agent to
reduct/eliminate BSE
infectivity and at least one "dry peel" step, the overall method including the
steps of
1) obtaining pericardium from a suitable (e.g., USDA-approved) source,
2) cleaning the tissue and optionally, and preferably, treating it in order to
reduce/eliminate potential BSE infectivity,
3) drying the tissue, e.g., by vacuum,
4) peeling off one or more layers of the tissue, in the dry state, to provide
a tissue of desired thickness, and optionally air drying the peeled tissue in
order to
permit it to become further compact and thin,
5) optionally, forming the peeled tissue into tubular form (e.g., by
adhering and/or suturing abutting or overlapping surfaces),
6) positioning the tissue on a mandrel or stent and moistening it in order
to facilitate its crimping and forming,
7) optionally crossIinking the tissue in its crimped configuration,
8) optionally attaching the cover to the stent, e.g., by the use of one or
more sutures, and
9) sterilizing and packaging the cover itself and/or the covered stent.
The invention will be further described by reference to the following non-
limiting examples.
EXAMPLES
TEST PROCEDURES
Unless otherwise indicated, the various materials described herein were tested
for physical integrity by standard tests using the general methods described
below.
These tests were performed on the ChemDyne MC1000 (Columbia Labs, Inc.)
tensile
testing system. Suture retention were tested according to ~
for Ca_rdiovascula_r impla_n_ts-Vascular pro h from the Association for the
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Advancement of Medical Instrumentation (1994). Shrink temperature,
circumferential tensile strength and suture retention were measured to test
the physical
integrity of the stent covers.
oisyre Content
Moisture content was analyzed on a Mettler Toledo HG53 Halogen Moisture
Analyzer. A temperature setting of 200°C was used. Results are
recorded in a
moisture content. Moisture content is determined after vacuum drying and after
air
drying.
Suture Retention
The suture retention test determines the force necessary to pull a suture from
the prosthesis. Suture retention was performed using 5-0 Prolene suture. The
needle
was placed into the tissue with a 2 mm bite below the edge of the tissue. The
suture is
pulled at a constant force moving up at 100 mm/min, sampling at 20 Hz. Suture
retention was performed on the ChemDyne MC1000 (Columbia Labs, Inc.) tensile
testing system. Suture retention was tested according to American_ National
Sta-n-dard
for Ca_rdiovascula_r im~a~nts-Vascular pro he ec from the Association for the
Advancement of Medical Instrumentation (1994).
VL1V1717 UHLi111
Stress-strain was performed on the ChemDyne MC1000 (Columbia Labs, Inc.)
tensile testing system. The stress-strain test gives unidirectional tensile
properties
such as tensile strength, strain at break, and Young's Modules.
Shrink Tem~;rature
Shrink temperature is the temperature at which the collagen denatures. The
shrink temperature was measured using a 30 gram preload in a bath of water at
steadily increasing temperature. The shrink temperature was calculated by
using the
knee method. The shrink temperature is dependent upon the cross-linking agent
used.
C'm'rcumferential Te~ile Stren~h
Circumferential tensile strength was measured with the cover in its tubular
form. One 3 mm segment was placed onto two rounded pins. It was then stretched
at
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SOmm/min until the break point was reached. Circumferential tensile strength
was
defined as the peak load divided by twice the lengthin N/mm, force/2*L.
Measurements were also made in terms of displacement vs. force.
EXAMPLE 1
Human Umbilical Cord Arterv ("HUCA"1 Stent Cover
A cylinder of tissue is constructed from human umbilical cord artery which is
crimped into an expandable stent cover.
Cleaned fresh human umbilical cord arteries (HUCA) were obtained from
hospital wards, rinsed with water and stored frozen until use. The tissues
were rinsed
in ultra-filtered deionized (LJFDI) water and placed into 2L of UFDI water
which was
changed each day Monday through Friday for 2 weeks. Arteries were isolated
from
the cord by inserting a 2 mm diameter mandrel into the arteries and carefully
stripping
away the rest of the cord. Excess tissue was gently removed from the arteries.
Arteries prepared in this manner were stored in 70% ethanol at 4 C until
further
processing.
Once isolated from the surrounding tissue, the HUCA were placed onto 3mm
to 4mm diameter polyflorotetraethylene (PTFE) mandrels. Once positioned on the
mandrels, the HUCA stent covers were fixed by placing them into a solution
containing 0.25% glutaraldehyde (Electron Microscopy Sciences,) 0.9% NaCI
(Fisher,) and 0.02% sodium bicarbonate (Sigma) at pH 7.4-8.4 for 48 hours. The
tissues were then removed from the PTFE mandrels and placed into UFDI water.
The fixed tissues were cut into 30 mm segments, and a 2mm cross-section was
taken from one end to be used for wall thickness measurement. The segments
were
then placed onto 1.5 mm diameter PTFE mandrels. The tissue was carefully
dampened and crimped onto the smaller mandrels using a rolling motion on a low
lint
cloth. Each crimp was very small, almost undetectable, giving the. appearance
of a
congruent surface on the 1.5 mm mandrels. Once the crimping was complete, the
covers were air dried and sterilized by placing them into a solution of 70%
EtOH and
1% propylene oxide for 2 weeks, after which they were placed into a 1%
propylene
oxide storage solution.
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Results are provided in TABLE 1 below. These results are consistent with data
on human umbilical cord vein cross-linked in 1% glutaraldehyde.
The present stent cover can be placed over a stent in the operating mom or in
conjunction with a stent prior to packaging. The stent cover is designed to be
expandable over the stent, by crimping and drying the tissue. Once crimped,
the
tissue can be stretched in situ and will return close to the original
uncrimped
conformation. This is beneficial, giving a close fit onto the stent. This stmt
cover,
made from human umbilical cord artery, is extremely thin, adding less than
200pm of
thickness to the stmt diameter. Applicant's experience with arterial and
vascular
prostheses formed of glutaraldehyde cmss-linked tissue would indicate that no
tissue-
blood surface related problems are expected. The water content of the dry
tissue is
preferably about 5% to about 10% by weight based on the weight of the tissue.
TABLE 1
Test Results
of HUCA
Stent Cover
Test ParametersSuture RetentionShrink TemperatureCircumferential Tensile
(g) (C) Strength
(N/mm)
Mean 41.9 81.8 0.403
St. Dev. 20.3 1.7 0.177
No. of Samples5 _ I 6 _ ~ 5
EXAMPLE 2a
A cylinder of tissue is constructed from thin bovine pericardium which is
crimped into an expandable stent cover.
Bovine pericardium was obtained in the US from USDA-inspected healthy
cows, minimum age 12 months. Fresh pericardium was obtained from and sent
through a series of three saline rinses, followed by a final ice cold water
rinse. Excess
liquid was squeezed out of the tissues, and they were stored at 0 C to 4 C
overnight
for processing the following day. Tissue was then used fresh or stored at -
20C.
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Pericardium was then stripped of extraneous tissue and cut into 10 cm x 10 cm
squares for further processing.
The tissue was placed into 1M NaOH for 1 hour, using 200 ml of 1M NaOH
per pericardial sac. After 1 hour the tissue was rinsed in IJFDI water and
placed into a
SOmM citrate buffer, 200 ml buffer per sac. Buffer was changed every hour for
3
hours. Once the tissue was at a pH of 6.5-7.5 it was placed in a water bath
over night.
The tissue was then placed in wire mesh racks and vacuum dried until the
tissue had a water content of less than 15% moisture. Tissue was dried in a
Virtis
Genesis vacuum dryer at 11 S mTorr. The tissue was trimmed on each side and
the
shiny side was peeled down to a thickness of less than 250 pm.
The tissue was wetted with UFDI (ultrafiltered deionized) water and placed
shiny side down onto a clean transparency film or other very smooth surface.
When
allowed to air dry the tissue had a moisture content of less than 18% water
and had
become compacted, in the course of drying, to a final thickness of less than
100 Vim.
The various tests described above were performed, the results of which are
provided in TABLES 2a and 2b below, and were consistent with other
glutaraldehyde
crosslinked BioVascular, Inc. pericardium products. The exemplified method
includes peeling the pericardium tissue while it is dry and then re-hydrating
it and air-
drying it. These steps allow for the tissue to be much thinner than if it were
not
peeled. In addition to the thinness of the tissue, the tissue also retains the
strong
physical characteristics of bovine pericardium.
Pericardium tissue prepared as described above was cut 30 rnm long and 16
mm wide, to make a 4 mm diameter tube (30 mm long) with a 2 to 3mm overlap for
adhering and of varying diameters with 2 mm overlap for adhering. A gelatin
suspension was made using porcine gelatin granules (Sigma) and 0.1 % acetic
acid
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solution (Aldrich.) The tissue was positioned shiny side up against a PTFE
mandrel
and each edge was coated with the gelatin suspension. Tissue edges were
adhered
together by gently rolling the mandrel and the covers were set to dry.
Once the tubes were dry, they were removed from the PTFE mandrels and
placed onto a 1.5 mm diameter PTFE mandrels. The tissue was carefully dampened
and crimped onto the smaller mandrels using a rolling motion on a low lint
cloth.
Each crimp was very small, almost undetectable, giving the appearance of a
congruent
surface on the 1.5 mm mandrels. Once the crimping was complete, the covers
were
air dried.
Dried crimped stent covers were placed into a 0.25% glutaraldehyde (Electron
Microscopy Sciences,) 0.9% NaCI (Fisher,) 0.02% sodium bicarbonate (Sigma) at
pH
7.4-8.4 for 48 hours. After fixation, the covers were rinsed with deionized
water and
placed into 70% EtOH and I% proplyene oxide solution for 2 weeks and then into
a
1 % propylene oxide storage solution.
TABLE 2a
Test Results
of BP Stent
Cover
Test ParametersSuture RetentionShrink TemperatureCircumferential Tensile
(g) (C) Strength
(N/mm)
Mean 64.7 83.8 0.33
St. Dev. 29.7 1.3 0.23
No. of Samples6 6 5
TABLE 2b
Stress-Strain
Test Results
of BP (Sheet
Form) Used
For Stent
Cover
Test ParametersThicknessTensile StrengthStrain at Young's Modulus
(mm) (MPa) Break {MPa)
(%)
Mean 0.088 9.6 16.7 43.8
St. Dev. 0.030 2.9 4.1 17.1
No. of Samples6 6 6 6
A thin bovine pericardium stmt cover, prepared in this manner, can be placed
over a stem in the operating room. The present stent cover is designed to be
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expandable over the stent, e.g., by crimping the tissue prior to
glutaraldehyde fixation.
Once crosslinked, the tissue can be stretched and will return to the original
crimped
conformation. This is beneficial, giving a close fit onto the stmt. This stent
cover,
made of peeled bovine pericardium, is extremely thin, adding less than 200pm
of
S thickness to the stent diameter.
COMPARATIVE EXAMPLE 2b
Bovine pericardium was peeled in its hydrated ("wet") state in order to test
its
physical properties and compare them to those described for the dry-peeled
pericardium described in Example 2a.
Hydrated pericardium was prepared in the following manner:
1 ) Fresh bovine pericardium was obtained in the same manner as
described above,
I 5 2) The pericardium was peeled by grasping one edge of one corner of a
rectangular piece of tissue (approximately 10 cm by 6 cm) with a forceps and
grasping
the other edge of the same corner with another forceps, and gently pulling the
tissue
apart.
3) The peeled tissue was placed into a solution of 0.25% glutaraldehyde,
0.9% NaCI and 0.02% sodium bicarbonate, in order to crosslink the tissue for
42
hours at room temperature. Tissue was approximately 100 to 400 microns thick
after
crosslinking.
4) Physical parameters were determined and are summarized in TABLE
2c below.
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TABLE 2c
Stress-Strain
Test Results
of Wet Peeled
Bovine Pericardium
Test ParametersThicknessTensile StrengthStrain at Young's Modulus
(mm) (MPa) Break (MPa)
(%)
Mean 0.23 6.1 34.5 9.2
St. Dev. 0.09 3.7 24.9 7.5
No. of Samples6 6 6 6
It can be seen that the physical characteristics of the dry-peeled pericardium
are significantly better, on balance, than those of the wet-peeled tissue,
particularly in
terms of thickness and strength (e.g., Young's Modulus).
EXAMPLE 3
A cylinder of tissue was constructed from porcine peritoneum and crimped
into the form of an expandable stmt cover.
Cleaned fresh porcine peritoneum was obtained from 2 week old pigs. The
tissue was taken from the inferior area of the peritoneal cavity, rinsed in
deionized
water and stored in 50% ethanol for shipment.
The tissue was rinsed in ultra-filtered deionized (IJFDI) water and cleaned of
extraneous fatty tissue and edges trimmed. The tissue was then placed into a
2:1
solution of ethyl acetate and methanol (Fisher} for 48 hours. Tissue was then
rinsed in
LJFDI water for at least 24 hours. Shiny sides were placed into LTFDI water
and then
placed shiny side down on a transparency film to air dry in a class 10,000
clean room
environment. The tissue was cut 2.5 cm long and l6mm wide to make 4 mm
diameter
tubes. A gelatin suspension was made using gelatin granules (Sigma) and 0.1 %
acetic
acid solution (Aldrich.) The tissue was positioned shiny side up against a
PTFE
mandrel and each edge was coated with gelatin suspension. Tissue edges were
adhered together by gently rolling the mandrel. The covers were set to dry.
Once the 4 mm tubes were dry, they were removed from the PTFE mandrels
and placed onto a 1.5 mm diameter PTFE mandrels. The tissue was carefully
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dampened and crimped onto the smaller mandrels using a rolling motion on a low
lint
cloth. Each crimp was very small, almost undetectable, giving the appearance
of a
congruent surface on the 1.5 mm mandrels. Once the crimping was complete, the
covers were air dried. Dried crimped stent covers were placed into a 0.25%
glutaraldehyde (Electron Microscopy Sciences,) 0.9% NaCI (Fisher,) 0.02%
sodium
bicarbonate (Sigma) at pH 7.4-8.4 for 48-72 hours. After fixation, the covers
were
rinsed with saline and placed into 70% EtOH and 1 % propylene oxide solution
for 2
weeks and then into a 1 % propylene oxide storage solution.
Results of these tests are provided in TABLE 3 below, and were consistent
with other glutaraldehyde cross-linked BioVascular, Inc. products.
__.T~~3
Test Results
of PP Steut
Cover
Test ParametersSuture RetentionShrink TemperatureCircumferential
(g) (C) Tensile
Strength
(N/mm)
Mean 126.3 88.9 0.362
St. Dev. 83.4 0.8 0.172
No. of Samples10 4 5
A stent cover has been developed which can be placed over a stmt in the
operating room. The stent cover has been designed to be expandable over the
stmt.
The tissue is crimped prior to going into glutaraldehyde crosslinking
solution. Once
crosslinked, the tissue can be stretched and will return to the original
crimped
conformation. This is beneficial, giving a close fit onto the stmt. This stent
cover,
made porcine peritoneum, is extremely thin, adding less than 200pm of
thickness to
the stent diameter.
