Note: Descriptions are shown in the official language in which they were submitted.
CA 02616781 2008-01-09
ENDOLUMINAL DEVICE EXHIBITING IMPROVED ENDOTHELIALIZATION
AND METHOD OF MANUFACTURE THEREOF
Background of the Invention
The present invention relates generally to implantable endoluminal medical
devices
which contact biological fluids and tissues on at least one surface of the
medical device.
More particularly, the present invention relates to endoluminal stents which
are implanted
into anatomical passageways using minimally invasive techniques. Endoluminal
stents are
frequently used post-angioplasty in order to provide a structural support for
a blood vessel
and reduce the incidence of restenosis following percutaneous balloon
angioplasty. A
principal example of the present invention are endovascular stents which are
introduced to a
site of disease or trauma within the body's vasculature from an introductory
location remote
I5 from the disease or trauma site using an introductory catheter, passed
through the vasculature
communicating between the remote introductory location and the disease or
trauma site, and
released from the introductory catheter at the disease or trauma site to
maintain patentency of
the blood vessel at the site of disease or trauma.
While the use of endoluminal stents has successfully decreased the rate of
restenosis
in angioplasty patients, it has been found that a significant restenosis rate
continues to exist
even with the use of endoluminal stents. It is generally believed that the
post-stenting
restenosis rate is due, in major part, to a failure of the endothelial layer
to regrow over the
stent and the incidence of smooth muscle cell-related neo-intimal growth on
the luminal
surfaces of the stent. Injury to the endothelium, the natural nonthrombogenic
lining of the
arterial lumen, is a significant factor contributing to restonisis at the
situs of a stent.
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Endothelial loss exposes thrombogenic arterial wall proteins, which, along
with the generally
thrombogenic nature of many prosthetic materials, such as stainless steel,
titanium, tantalum,
Nitinol, etc. customarily used in manufacturing stents, initiates platelet
deposition and
activation of the coagulation cascade, which results in thrombus formation,
ranging from
partial covering of the luminal surface of the stent to an occlusive thrombus.
Additionally,
endothelial loss at the site of the stent has been implicated in the
development of neointimal
hyperplasia at the stent situs. Accordingly, rapid re-endothelialization of
the arterial wall
with concomitant endothelialization of the body fluid or blood contacting
surfaces of the
implanted device, is considered critical for maintaining vasculature patency
and preventing
low-flow thrombosis.
At present, most endoluminal stents are manufactured of stainless steel, which
is
known to be thrombogenic. In order to reduce the thrombogenicity of the
stainless steel and
to maintain sufficient dimensional profiles for catheter delivery, most stents
minimize the
metal surface area which contacts blood, in order to minimize thrombus
formation after
implantation. Thus, in order to reduce the thrombogenic response to stent
implantation, as
well as reduce the formation of neointimal hyperplasia, it would be
advantageous to increase
the rate at which endothelial cells from endothelium proximal and distal to
the stent situs,
migrate onto and the endothelial coverage of the luminal surface of the stent
which is in
contact with blood flow through the vasculature.
The surface of a solid, homogeneous material can be conceptualized as having
unsaturated inter-atomic and intermolecular bonds forming a reactive plane
ready to interact
with the environment. In practice, a perfectly clean surface is unattainable
because of
immediate adsorption of airborne species, upon exposure to ambient air, of 0,
02, CO2, SO2,
NO, hydrocarbons and other more complex reactive molecules. Reaction with
oxygen
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CA 02616781 2008-01-09
implies the formation of oxides on a metal surface, a self-limiting process,
known as
passivation. An oxidized surface is also reactive with air, by adsorbing
simple, organic
airborne compounds. Assuming the existence of bulk material of homogeneous
subsurface
and surface composition, oxygen and hydrocarbons may adsorb homogeneously.
Therefore,
further exposure to another environment, such as the vascular compartment, may
be followed
by a uniform biological response.
Current metallic vascular devices, such as stents, are made from bulk metals
made by
conventional methods, and stent precursors, such as hypotubes, are made with
many steps
each of which introduce processing aides to the metals. For example, olefins
trapped by cold
drawing and transformed into carbides or elemental carbon deposit by heat
treatment,
typically yield large carbon rich areas in 316L stainless steel tubing
manufactured by cold
drawing process. The conventional stents have marked surface and subsurface
heterogeneity
resulting from manufacturing processes (friction material transfer from
tooling, inclusion of
lubricants, chemical segregation from heat treatments). This results in
formation of surface
and subsurface inclusions with chemical composition and, therefore, reactivity
different from
the bulk material. Oxidation, organic contamination, water and electrolytic
interaction,
protein adsorption and cellular interaction may, therefore, be altered on the
surface of such
inclusion spots. Unpredictable distribution of inclusions such as those
mentioned above
provide an unpredictable and uncontrolled heterogeneous surface available for
interaction
with plasma proteins and cells. Specifically, these inclusions interrupt the
regular distribution
pattern of surface free energy and electrostatic charges on the metal surface
that determine the
nature and extent of plasma protein interaction. Plasma proteins deposit
nonspecifically on
surfaces according to their relative affinity for polar or non-polar areas and
their
concentration in blood. A replacement process known as the Vroman effect,
Vroman L. The
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CA 02616781 2008-01-09
importance of surfaces in contact phase reactions, Seminars of Thrombosis and
Hemostasis
1987;13(1):79-85, determines a time-dependent sequential replacement of
predominant
proteins at an artificial surface, starting with albumin, following with IgG,
fibrinogen and
ending with high molecular weigh kininogen. Despite this variability, some of
the adsorbed
proteins have receptors available for cell attachment and therefore constitute
adhesive sites.
Examples are: fibrinogen glycoprotein receptor IIbia for platelets and
fibronectin RGD
sequence for many blood activated cells. Since the coverage of an artificial
surface with
endothelial cells is a favorable end-point in the healing process, to favor
endothelialization is
desirable in implantable vascular device manufacture.
Normally, endothelial cells (EC) migrate and proliferate to cover denuded
areas until
confluence is achieved. Migration, quantitatively more important than
proliferation, proceeds
under normal blood flow roughly at a rate of 25 m/hr or 2.5 times the
diameter of an EC,
which is nominally 10 m. EC migrate by a rolling motion of the cell membrane,
coordinated
by a complex system of intracellular filaments attached to clusters of cell
membrane
attachment, integrin receptors, specifically focal contact points. The
integrins within the
focal contact sites are expressed according to complex signaling mechanisms
and eventually
couple to specific amino acid sequences in substrate adhesion molecules (such
as RGD,
mentioned above). An EC has roughly 16-22% of its cell surface represented by
integrin
clusters Davies P.F., Robotewskyi A., Grieco M.L. Endothelial cell adhesion in
real time.
J.Clin.Invest.1993;91:2640-2652, Davies, P.F., R.obotewski, A., Griem, M.L. ,
Qualitiative
studies of endothelial cell adhesion, J.Clin.Invest.1994;93:2031-2038_ This is
a dynamic
process, which implies more than 50% remodeling in 30 minutes. The focal
adhesion
contacts vary in size and distribution, but 80% of them measure less than 6
m2, with the
majority of them being about I m2, and tend to elongate in the direction of
flow and
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concentrate at leading edges of the cell. Although the process of recognition
and signaling to
determine specific attachment receptor response to attachment sites is
incompletely
understood, regular availability of attachment sites, more likely than not,
would favorably
influence attachment and migration. Irregular or unpredictable distribution of
attachment
sites, that might occur as a result of various inclusions, with spacing equal
or smaller to one
whole cell length, is likely to determine alternating hostile and favorable
attachment
conditions along the path of a migrating cell. These conditions may vary from
optimal
attachment force and migration speed to insufficient holding strength to
sustain attachment,
resulting in cell slough under arterial flow conditions. Due to present
manufacturing
processes, current implantable vascular devices exhibit such variability in
surface
composition as determined by surface sensitive techniques such as atomic force
microscopy,
X-ray photoelectron spectroscopy and time of flight secondary ion-mass
spectroscopy.
There have been numerous attempts to increase endothelialization of implanted
stents,
including covering the stent with a polymeric material (U.S. Patent No.
5,897,911), imparting
a diamond-like carbon coating onto the stent (U.S. Patent No. 5,725,573),
covalently binding
hydrophobic moieties to a heparin molecule (U.S. Patent No. 5,955,588),
coating a scent with
a layer of blue to black zirconium oxide or zirconium nitride (U.S. Patent No.
5,649,951),
coating a stent with a layer of turbostratic carbon (U.S. Patent No.
5,387,247), coating the
tissue-contacting surface of a scent with a thin layer of a Group VB metal
(U.S. Patent No.
5,607,463), imparting a porous coating of titanium or of a titanium alloy,
such as Ti-Nb-Zr
alloy, onto the surface of a stent (U.S. Patent No. 5,690,670), coating the
stent, under
ultrasonic conditions, with a synthetic or biological, active or inactive
agent, such as heparin,
endothelium derived growth factor, vascular growth factors, silicone,
polyurethane, or
polytetrafluoroethylene, U.S. Patent No. 5,891,507), coating a stent with a
silane compound
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with vinyl functionality, then forming a graft polymer by polymerization with
the vinyl
groups of the silane compound (U.S. Patent No. 5,782,908), grafting monomers,
oligomers or
polymers onto the surface of a stent using infrared radiation, microwave
radiation or high
voltage polymerization to impart the property of the monomer, oligomer or
polymer to the
scent (U.S. Patent No. 5,932,299). Thus, the problems of thrombogenicity and
re-
endothelialization associated with stents have been addressed by the art in
various manners
which cover the stent with either a biologically active or an inactive
covering which is less
thrombogenic than the stent material and/or which has an increase capacity for
promoting re-
endothelialization of the stent situs. These solutions, however, all require
the use of existing
stents as substrates for surface derivatization or modi ication, and each of
the solutions result
in a biased or laminate structure built upon the stent substrate. These prior
art coated stents
are susceptible to delamination and/or cracking of the coating when mechanical
stresses of
transluminal catheter delivery and/or radial expansion in vivo. Moreover,
because these prior
art stents employ coatings applied to stents fabricated in accordance with
conventional stent
formation techniques, e.g., cold-forming metals, the underlying stent
substrate is
characterized by uncontrolled heterogeneities on the surface thereof. Thus,
coatings merely
are laid upon the heterogeneous stent surface, and inherently conform to the
heterogeneities
in the the stent surface and mirror these heterogeneities at the blood contact
surface of the
resulting coating. This is conceptually similar to adding a coat of fresh
paint over an old
coating of blistered paint, the fresh coating will conform to the blistering
and eventually,
itself, blister and delaminate from the underlying substrate.
The current invention entails creating materials specifically designed for
manufacture
of stents and other intravascular devices. Manufacture of stents and other
intravascular
devices is controlled to attain a regular, homogeneous atomic and molecular
pattern of
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CA 02616781 2008-01-09
distribution along their surface. This avoids the marked variations in surface
composition,
would create a predictable oxidation and organic adsorption pattern and would
have a
predictable interaction with water, electrolytes, proteins and cells.
Particularly, EC migration
would be supported by a homogeneous distribution of binding domains which
serve as
natural or implanted cell attachment sites, in order to promote unimpeded
migration and
attachment. Based on observed EC attachment mechanisms such binding domains
should
have a repeating pattern along the blood contact surface of no less than 1 .Lm
radius and 2
m border to border spacing between binding domains. Ideally, the inter-binding
domain
spacing is less than the nominal diameter of an endothelial cell in order to
ensure that at any
given time, a portion of an endothelial cell is in proximity to a binding
domain.
Summary of the Invention
In accordance with the present invention, there is provided an implantable
endolununal device which is fabricated from materials which present a blood
contact surface
which is substantially homogeneous in material constitution. More
particularly, the
present invention provides an endoluminal stent which is made of a material
having
controlled heterogeneities along the blood flow surface of the stent. The
heterogeneities
which are controlled in the present invention include: grain size, grain
phase, grain material
composition, stent-material composition, and surface topography at the blood
flow surface of
the stent. Additionally, the present invention provides methods of making an
endoluminal
stent having controlled heterogeneities in the stent material along the blood
flow surface of
the stent.
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Brief Description of the Figures
Figure 1 is a diagrammatic representation of controlled heterogeneities in the
inventive stent.
Figure 2 is a micrograph of uncontrolled heterogeneities present in prior art
stent
material.
Detailed Description of the Preferred Embodiments
Blood protein interaction with surfaces of endoluminal devices appears to be
an initial
step in a chain of events leading to tissue incorporation of the endovascular
device. The
present invention is based, in part, upon the relationship between surface
energy of the
material used to make the endoluminal device and protein adsorption at the
surface of the
endoluminal device. The present inventors have found that a relationship
exists between
surface free energy and protein adsorption on metals commonly used in
fabrication of
endoluminal devices. In addition, specific electrostatic forces resident on
the surface of metal
endoluminal stents have been found to influence blood interactions with the
stent surface and
the vascular wall.
In accordance with the present invention there is.provided a stent which is
fabricated
of a material having substantially homogeneous surface properties,
specifically surface
energy and electrostatic charge, across the blood contact surface of the
stent. Current
manufacturing methods for fabricating endoluminal stents fail to achieve the
desired material
properties of the present invention. As discussed above, stents are fabricated
from bulk
metals which are processed in a manner which introduces processing aides to
the metal.
Presently, stents are made from hypotubes formed from the bulk metals, by
machining a
series of slots or patterns into the hyptotube to accommodate radial expansion
into a stainless
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CA 02616781 2011-03-01
CA 2,616,781
Agent Ref. 62497/00021
steel metal tube, or by weaving wires into a mesh pattern. According to the
present invention, a
stent with a substantially homogeneous metal constitution, exhibiting
substantially homogeneous
surface properties is made by imparting a stent pattern, suitable for making
either a balloon
expandable or self expanding stent, onto a substrate and depositing stent-
forming metal onto the
stent pattern by a deposition methodology which yields a metal having
controlled
heterogeneities. Suitable deposition methodologies, as are known in the
microelectronic and
vacuum coating fabrication arts, are plasma deposition and physical vapor
deposition which are
utilized to impart a metal layer onto the stent pattern.
The present invention consists of a stent made of a bulk material having
controlled
heterogeneities on the luminal surface thereof. Heterogeneities are controlled
by fabricating the
bulk material of the stent to have defined grain sizes which yield areas or
sites along the surface
of the stent having optimal protein binding capability. The characteristically
desirable properties
of the inventive stent are: (a) optimum mechanical properties consistent with
or exceeding
regulatory approval criteria, (b) minimization of defects, such as cracking or
pin hole defects, (c)
a fatigue life of 400 MM cycles as measured by simulated accelerated testing,
(d) corrosion
resistance, (e) biocompatibility without having biologically significant
impurities in the material,
(f) a substantially non-frictional abluminal surface to facilitate atraumatic
vascular crossing and
tracking and compatible with transcatheter techniques for stent introduction,
(g) radiopaque at
selected sites and MRI compatible, (h) have an luminal surface which is
optimized for surface
energy and microtopography, (i) minimal manufacturing and material cost
consistent with
achieving the desired material properties, and (j) high process yields.
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Agent Ref. 62497/00021
In accordance with the present invention, the foregoing properties are
achieved by
fabricating a stent by the same metal deposition methodologies as are used and
standard in the
microelectronics and nano-fabrication vacuum coating arts. In accordance with
the present
invention, the preferred deposition methodologies include ion-beam assisted
evaporative
deposition and sputtering techniques. In ion beam-assisted evaporative
deposition it is preferable
to employ dual and simultaneous thermal electron beam evaporation with
simultaneous ion
bombardment of the substrate using an inert gas, such as argon, xenon,
nitrogen or neon.
Bombardment with an inert gas, such as argon ions serves to reduce void
content by increasing
the atomic packing density in the deposited material during deposition. The
reduced void content
in the deposited material allows the mechanical properties of that deposited
material to be similar
to the bulk material properties. Deposition rates up to 20 nm/sec are
achievable using ion beam-
assisted evaporative deposition techniques.
When sputtering techniques are employed, a 200 micron thick stainless steel
film may be
deposited within about four hours of deposition time. With the sputtering
technique, it is
preferable to employ a cylindrical sputtering target, a single circumferential
source which
concentrically surrounds the substrate which is held in a coaxial position
within the source.
Alternate deposition processes which may be employed to form the stent in
accordance with the
present invention are cathodic arc, laser ablation, and direct ion beam
deposition. When
employing vacuum deposition methodologies, the crystalline structure of the
deposited film
affects the mechanical properties of the deposited film. These mechanical
properties of the
deposited film may be modified by post-process treatment, such as by, for
example, annealing,
high pressure treatment or gas quenching.
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CA 02616781 2008-01-09
Materials to make the inventive stents are chosen for their biocompatibility,
mechanical properties, i.e., tensile strength, yield strength, and their ease
of deposition
include the following:
elemental titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium,
silver,
gold, silicon, magnesium, neobium, scandium, platinum, cobalt, palladium,
manganese,
molybdenum and alloys thereof, such as zirconium-titanium-tantalum alloys,
nitinol, and
stainless steel.
During deposition, the chamber pressure, the deposition pressure and the
partial
pressure of the process gases are controlled to optimize deposition of the
desired species onto
the substrate. As is known in the microelectronic fabrication, nano-
fabrication and vacuum
coating arts, both the reactive and non-reactive gases are controlled and the
inert or non-
reactive gaseous species introduced into the deposition chamber are typically
argon and
nitrogen. The substrate may be either stationary or moveable, either rotated
about its
longitudinal axis, or moved in an X-Y plane within the reactor to facilitate
deposition or
patterning of the deposited material onto the substrate. The deposited
material maybe
deposited either as a uniform solid film onto the substrate, or patterned by
(a) imparting either
a positive or negative pattern onto the substrate, such as by etching or
photolithography
techniques applied to the substrate surface to create a positive or negative
image of the
desired pattern or (b) using a mask or set of masks which are either
stationary or moveable
relative to the substrate to define the pattern applied to the substrate.
Patterning may be
employed to achieve complex finished geometries of the resultant scent, both
in the context
of spatial orientation of the pattern as well as the material thickness at
different regions of the
deposited film, such as by varying the wall thickness of the material over its
length to thicken
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sections at proximal and distal ends of the stent to prevent flaring of the
stent ends upon
radial expansion of the stent.
The stent may be removed from the substrate after stent formation by any of a
variety
of methods. For example, the substrate may be removed by chemical means, such
as etching
or dissolution, by ablation, by machining or by ultrasonic energy.
Alternatively, a sacrificial
layer of a material, such as carbon or aluminum, may be deposited intermediate
the substrate
and the stent and the sacrificial layer removed by melting, chemical means,
ablation,
machining or other suitable means to free the stent from the substrate.
The resulting stent may then be subjected to post-deposition processing to
modify the
crystalline structure, such as by annealing, or to modify the surface
topography, such as by
etching to affect and control the heterogeneities on the blood flow surface of
the stent.
Example 1: Stent Formation By Sputtering
A ceramic cylindrical substrate is introduced into a deposition chamber with
capabilities of glow discharge substrate cleaning and sputter deposition of
carbon and
stainless steel. The deposition chamber is evacuated to a pressure less than
or equal to 2 x 10-
7 Torr. Pre-cleaning of the substrate is conducted under vacuum by glow
discharge. The
substrate temperature is controlled to achieve a temperature between about 300
and 1100
degrees Centigrade. A bias voltage between -1000 and +1000 volts is applied to
the substrate
sufficient to cause energetic species arriving at the surface of the substrate
to have a
hyperthermal energy between 0.1 eV and about 700 eV, preferably between 5-50
eV. The
deposition sources are circumferential and are oriented to deposit from the
target
circumferentially about the substrate.
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During deposition, the deposition pressure is maintained between 0.1 and 10
mTorr.
A sacrificial carbon layer of substantially uniform thickness ( 5%) between
10 and 500
Angstroms is deposited circumferentially on the substrate. After depositing
the carbon layer,
a cylindrical film of stainless steel is deposited onto the sacrificial carbon
layer on the
cylindrical substrate at a deposition rate between about 10 to 100
microns/hour. After
formation of the stainless steel film, the substrate is removed from the
deposition chamber
and heated to volatilize the intermediate sacrificial carbon layer between the
substrate and the
film. After removing the carbon intermediate layer, the stainless steel film
is removed from
the substrate and exhibits material properties similar to the bulk stainless
steel target and
surface properties characterized by controlled heterogeneities in grain size,
material
composition and surface topography. A series of patterns are then machined
into the
resultant stainless steel film to form a stent by electrical discharge
machining (EDM) or laser
cutting the film.
Example 2: Stent Formation by Sputtering
The same operating conditions are followed as in Example 1, except that the
substrate
is tubular and selected to have a coefficient of thermal expansion different
than that of the
resultant stent. No intermediate layer of sacrificial carbon is deposited onto
the substrate,
and the outer surface of the substrate is etched with a pattern of recesses
defining a desired
stent pattern. The substrate is mounted onto a rotational jig within the
deposition chamber
and rotated at a uniform rate during deposition. Tantalum is used as the
target material and
deposited into the recesses of the substrate from a single stationary source.
After deposition,
the temperature of the substrate and the deposited stent are controlled to
impart diametric
differential in the substrate and stent and permit removal of the stent from
the substrate.
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Example 3: Stent Formation by Ion Beam-assisted Evaporative Deposition
A cylindrical substrate is introduced into a deposition chamber which has
capabilities
of: substrate rotation and precise positioning, glow discharge substrate
cleaning, ion beam-
assisted evaporative deposition, and cylindrical magnetron sputtering. The
deposition
sources are (a) dual electron beam evaporative sources placed adjacent one
another at the
base of the deposition chamber at a fixed distance from the substrate, these
are used with
simultaneous argon ion impingement onto the substrate from a controlled ion
beam source,
and (b) a cylindrical magnetron sputtering source with a carbon target capable
of
circumferentially coating a carbon sacrificial layer of substantially uniform
thickness of
between 10 and 200 Angstroms onto the substrate.
The substrate temperature is controlled to achieve a substrate temperature
between
about 300 and 1100 degrees Centigrade. The deposition chamber is evacuated to
a pressure
less than or equal to 2 x 10-7 Torr. A pre-cleaning of the substrate is
conducted under
vacuum by glow discharge. The substrate is rotated to ensure uniform cleaning
and
subsequent uniform deposition thickness. After cleaning the substrate is moved
into the
magnetron and coated with the carbon layer. The substrate is then moved into
position to
receive the stent-forming metal coating with simultaneous ion bombardment. One
electron
beam evaporation source contains titanium while the other source contains
nickel. The
evaporation rates of each of the titanium and nickel evaporation sources are
separately
controlled to form a nitinol alloy on the substrate as the stent-forming
metal.
Example 4: Planar Deposition of Stent.
The same operating conditions of Example 3 are followed, except that a planar
substrate is used. The deposition source is a single electron beam evaporation
source
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containing platinum and is used with simultaneous argon ion impingement onto
the substrate
from a controlled ion beam source.
The substrate temperature is controlled to achieve a substrate temperature
between
about 300 and 1100 degrees Centigrade. The deposition chamber is evacuated to
a pressure
less than or equal to 2 x 10'' Ton. A pre-cleaning of the substrate is
conducted under
vacuum by glow discharge. After cleaning the substrate is moved into position
within the
deposition chamber and coated with platinum from the electron beam evaporation
source
with simultaneous argon ion bombardment, with the electron beam evaporation
source
passing platinum through a pattern mask corresponding to a stent pattern which
is interposed
between the source and the substrate to pass a pattern of platinum onto the
substrate.
After deposition, the patterned stent is removed from the substrate and rolled
about a
forming substrate to a cylindrical shape and opposing ends of the planar stent
material are
brought into juxtaposition with one another and may be attached by laser
welding or left
uncoupled.
While the invention has been described with reference to its preferred
embodiments,
those of ordinary skill in the relevant arts will understand and appreciate
that the present
invention is not limited to the recited preferred embodiments, but that
various modifications
in material selection, deposition methodology, manner of controlling the
material
heterogeneities of the deposited stent material, and deposition process
parameters may be
employed without departing from the invention, which is to be limited only by
the claims
appended hereto.
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