U.S. patent application number 15/194117 was filed with the patent office on 2017-05-11 for methods of making medical devices.
The applicant listed for this patent is Advanced Bio Prosthetic Surfaces, Ltd., a wholly owned subsidiary of Palmaz Scientific, Inc.. Invention is credited to Christopher E. BANAS, Conor P. MULLENS, Daniel D. SIMS, Jeffrey N. STEINMETZ, Alexander Parker WOOD.
Application Number | 20170130322 15/194117 |
Document ID | / |
Family ID | 38322383 |
Filed Date | 2017-05-11 |
United States Patent
Application |
20170130322 |
Kind Code |
A1 |
SIMS; Daniel D. ; et
al. |
May 11, 2017 |
METHODS OF MAKING MEDICAL DEVICES
Abstract
A vacuum deposition substrate comprising at least one of a
plurality of patterned recesses, raises, or openings. The at least
one of a plurality of patterned recesses, raises, or openings
further define a geometry of a medical device.
Inventors: |
SIMS; Daniel D.; (Arvada,
CO) ; STEINMETZ; Jeffrey N.; (Arvada, CO) ;
MULLENS; Conor P.; (San Antonio, TX) ; WOOD;
Alexander Parker; (Marion, TX) ; BANAS; Christopher
E.; (Breckenridge, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Advanced Bio Prosthetic Surfaces, Ltd., a wholly owned subsidiary
of Palmaz Scientific, Inc. |
Fremont |
CA |
US |
|
|
Family ID: |
38322383 |
Appl. No.: |
15/194117 |
Filed: |
June 27, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14177978 |
Feb 11, 2014 |
9375330 |
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15194117 |
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13590613 |
Aug 21, 2012 |
8647700 |
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14177978 |
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12780689 |
May 14, 2010 |
8247020 |
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13590613 |
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11343993 |
Jan 31, 2006 |
7736687 |
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12780689 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
Y10T 156/1043 20150115;
A61F 2/91 20130101; A61F 2220/0058 20130101; A61F 2220/005
20130101; A61F 2250/0068 20130101; A61F 2002/91575 20130101; B29C
59/043 20130101; Y10T 156/10 20150115; A61F 2210/0076 20130101;
A61F 2240/001 20130101; A61F 2220/0075 20130101; A61F 2/915
20130101; A61F 2/07 20130101; B29C 59/04 20130101; C23C 14/24
20130101; A61F 2002/9155 20130101; A61F 2220/0041 20130101 |
International
Class: |
C23C 14/24 20060101
C23C014/24; A61F 2/07 20060101 A61F002/07; A61F 2/915 20060101
A61F002/915 |
Claims
1. A vacuum deposition substrate comprising at least one of a
plurality of patterned recesses, at least one of a plurality of
patterned raises, or at least at least one of a plurality of
patterned openings.
2. The vacuum deposition substrate of claim 1 wherein the at least
one of the plurality of patterned recesses or the at least one of a
plurality of patterned raises is configured to define a geometry of
a scaffold.
3. The vacuum deposition substrate of claim 1 wherein the vacuum
deposition substrate is tubular.
4. The vacuum deposition substrate of claim 1 wherein the at least
one of the plurality of patterned recesses or the at least one of a
plurality of patterned raises is configured to define a geometry of
a stent.
5. The vacuum deposition substrate of claim 1 wherein vacuum
deposition substrate is substantially planar.
6. The vacuum deposition substrate of claim 1 wherein the vacuum
deposition substrate is arcuate.
7. The vacuum deposition substrate of claim 1 further comprised of
a deoxygenated copper material.
8. The vacuum deposition substrate of claim 7 further comprised of
a titanium nitride coating on a surface.
9. The vacuum deposition substrate of claim 8 wherein the titanium
nitride coating is configured as a diffusion barrier to prevent
migration of copper into a deposited layer.
10. The vacuum deposition substrate of claim 1 further configured
to be rotated about a longitudinal axis, moved in an X-Y plane, or
planatarily or rotationally moved within a deposition chamber to
facilitate deposition or patterning of a deposited material onto
the vacuum deposition substrate.
11. The vacuum deposition substrate of claim 2 wherein the
patterned openings comprise a plurality of circular openings
passing through the vacuum deposition substrate.
12. The vacuum deposition substrate of claim 11 wherein the
plurality of circular openings is patterned in a regular array of
rows and columns with regular inter-opening spacing 165 between
adjacent openings.
13. The vacuum deposition substrate of claim 12 wherein a diameter
of each of the plurality of circular openings is about 19 .mu.m,
with an inter-opening spacing in each row and column of about 34
.mu.m on center.
14. The vacuum deposition substrate of claim 2 wherein the
patterned openings comprise an alternating slot pattern in which
the patterned openings are arrayed adjacent one another forming a
y-axis oriented array relative to the vacuum deposition substrate,
further wherein a second plurality of patterned openings are
arrayed adjacent one another forming an x-axis oriented array
relative to vacuum deposition substrate.
15. The vacuum deposition substrate of claim 14 inter-array wherein
the alternating slot pattern includes a spacing between the y-axis
oriented array and the x-axis oriented array of about 17 .mu.m,
further wherein each of the plurality of openings has a length of
about 153 .mu.m and a width of about 17 .mu.m.
16. The vacuum deposition substrate of claim 2 wherein the
patterned openings comprise an array of a plurality of
diamond-shaped openings passing through the vacuum deposition
substrate.
17. The vacuum deposition substrate of claim 16 wherein the
plurality of diamond-shaped openings includes a dimension
configured to permit cellular migration through the plurality of
diamond-shaped openings while preventing blood flow or seepage, and
passage of embolic material through the plurality of diamond-shaped
openings.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/177,978, filed Feb. 11, 2014, now U.S. Pat.
No. 9,375,330, issued Jun. 28, 2016, which is a continuation of
U.S. patent application Ser. No. 13/590,613, filed Aug. 21, 2012,
now U.S. Pat. No. 8,647,700, issued on Feb. 11, 2014, which is a
continuation of U.S. patent application Ser. No. 12/780,689, filed
May 14, 2010, now U.S. Pat. No. 8,247,020 issued on Aug. 21, 2012,
which is a continuation of U.S. patent application Ser. No.
11/343,993, filed Jan. 31, 2006, now U.S. Pat. No 7,736,687, issued
on Jun. 15, 2010, which is related to U.S. patent application Ser.
No. 10/289,974, filed Nov. 6, 2002, now U.S. Pat. No. 7,491,226,
issued on Feb. 17, 2009, which is a divisional application of U.S.
patent application Ser. No. 09/532,164 filed Mar. 20, 2000, now
U.S. Pat. No. 6,537,310, issued on Mar. 25, 2003, which is a
continuation-in-part of U.S. patent application Ser. No.
09/443,929, filed Nov. 19, 1999, now U.S. Pat. No. 6,379,383,
issued on Apr. 30, 2002, all incorporated by reference herein.
BACKGROUND OF THE INVENTION
[0002] The present invention relates generally to methods of
fabricating medical devices by vacuum deposition of device-forming
materials onto a suitable substrate. More particularly, the present
invention relates to methods of fabricating structural scaffolds,
coverings for scaffolds and covered scaffolds. The present
invention also pertains generally to implantable medical devices
and, more particularly, to implantable medical devices which are
capable of being implanted utilizing minimally-invasive delivery
techniques.
[0003] Conventional endoluminal stents and stent-grafts are
frequently used after a percutaneous transluminal angioplasty (PTA)
or percutaneous transluminal coronary angioplasty (PTCA) procedure
which dilitates an occluded, obstructed or diseased anatomical
passageway to provide structural support and maintain the patency
of the anatomical passageway. An example of this is the
post-angioplasty use of intravascular stents to provide a
structural support for a blood vessel and reduce the incidence of
restenosis. A principal, but non-limiting, example of the present
invention are covered intravascular stents which are introduced to
a site of disease or trauma within the body's vasculature from an
introductory location remote 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 patency of the blood
vessel at the site of disease or trauma. Covered stents are
delivered and deployed under similar circumstances and are utilized
to maintain patency of an anatomic passageway, for example, by
reducing restenosis following angioplasty, or when used to exclude
an aneurysm, such as in aortic aneurysm exclusion applications.
Embolic protection devices, which generally consist of a porous
flexible material coupled to an expansive structural scaffold, are
an example of alternative devices capable of being fabricated by
the present invention. For purposes of illustration only, and
without any intent to so limit the present invention, hereinafter
reference will be made to endoluminal stents and covered stents.
However, those of ordinary skill in the art will understand that
alternative types of medical devices which are susceptible of being
fabricated by the methods of the present invention.
[0004] While endoluminal stenting has successfully decreased the
rate of restenosis in angioplasty patients, it has been found that
a significant restenosis rate continues to exist in spite of the
use of endoluminal stents. It is generally believed that the
post-stenting restenosis rate is due, in major part, to the
non-regrowth of the endothelial layer over the stent and the
incidence of smooth muscle cell-related neointimal 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 restenosis at the situs of a
stent. 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.
[0005] Most endoluminal stents are manufactured of metals that fail
to promote redevelopment of a healthy endothelium and/or are known
to be thrombogenic. In order to increase the healing and promote
endothelialization, while maintaining sufficient dimensional
profiles for catheter delivery, most stents minimize the metal
surface area that contacts blood. 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 form endothelium
proximal and distal to the stent situs, migrate onto and provide
endothelial coverage of the luminal surface of the stent which is
in contact with blood flow through the vasculature.
[0006] Current covered stents are essentially endoluminal stents
with a discrete covering on either or both of the luminal and
abluminal surfaces of the stent that occludes the open spaces, or
interstices, between adjacent structural scaffold members of the
endoluminal stent. It is known in the art to fabricate stent-grafts
by covering the stent with endogenous vein or a synthetic material,
such as woven polyester known as DACRON, or with expanded
polytetrafluoroethylene. Additionally, it is known in the art to
cover the stent with a biological material, such as a xenograft or
collagen. A primary purpose for covering stents with grafts is to
reduce the thrombogenic effect of the stent material and prevent
embolic material from passing through stent interstices and into
the general circulation. However, the use of conventional graft
materials has not proven to be a complete solution to enhancing the
healing response of conventional stents.
[0007] U.S. Pat. No. 6,312,463 describes a variation of a
prosthesis in that the prosthesis includes a tubular element that
is a thin-walled sheet having temperature-activated shape memory
properties. The tubular element is supported by a support element
that includes a plurality of struts. The tubular element is
described as a thin-walled sheet preferably having of a
coiled-sheet configuration with overlapping inner and outer
sections.
[0008] Current metallic vascular devices, such as stents, are made
from bulk metals made by conventional methods, and stent
precursors, such as hypotubes, are made by many steps that
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 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 weight kininogen. Despite
this variability in surface adsorption specificity, some of the
adsorbed proteins have receptors available for cell attachment and
therefore constitute adhesive sites. Examples are: fibrinogen
glycoprotein receptor IIbIIIa 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, favoring endothelialization in device
design is desirable in implantable vascular device
manufacturing.
[0009] 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 .mu.m/hr or 2.5 times the
diameter of an EC, which is nominally 10 .mu.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 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.,
Griem M. L. Endothelial cell adhesion in real time. J. Clin.
Invest. 1993; 91:2640-2652, Davies, P. F., Robotewski, 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 .mu.m.sup.2, with the majority of them being about 1-2
.mu.m.sup.2, and tend to elongate in the direction of flow and
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.
[0010] There have been numerous attempts to increase
endothelialization of implanted stents, including covering the
stent with a polymeric material (U.S. Pat. No. 5,897,911),
imparting a diamond-like carbon coating onto the stent (U.S. Pat.
No. 5,725,573), covalently binding hydrophobic moieties to a
heparin molecule (U.S. Pat. No. 5,955,588), coating a stent with a
layer of blue to black zirconium oxide or zirconium nitride (U.S.
Pat. No. 5,649,951), coating a stent with a layer of turbostratic
carbon (U.S. Pat. No. 5,387,247), coating the tissue-contacting
surface of a stent with a thin layer of a Group VB metal (U.S. Pat.
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. Pat. 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. Pat. No. 5,891,507), coating a stent
with a silane compound with vinyl functionality, then forming a
graft polymer by polymerization with the vinyl groups of the silane
compound (U.S. Pat. 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 stent (U.S.
Pat. No. 5,932,299).
[0011] 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 neointimal 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 restenosis at the situs of a
stent. 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. The thrombus
formation can range from partial covering of the luminal surface of
the stent to a completely 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.
[0012] Although the problems of thrombogenicity and
re-endothelialization associated with stents have been contemplated
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 increased
capacity for promoting re-endothelialization of the stent situs,
the problems remain. These solutions require the use of existing
stents as substrates for surface derivatization or modification,
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 delaminating 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 topographical heterogeneities in 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, blister and
delaminate from the underlying substrate. Thus, topographical
heterogeneities are typically telegraphed through a surface
coating. Chemical heterogeneities, on the other hand, may not be
telegraphed through a surface coating but may be exposed due to
cracking or peeling of the adherent layer, depending upon the
particular chemical heterogeneity.
[0013] Heretofore, medical devices consisting of covered scaffolds
have been fabricated by separately forming the scaffold and the
cover, then joining the cover material to the supporting scaffold
such as by sutures, forming thermal joints, such as welds,
adhesives or the like.
[0014] Fabrication of covered scaffolds by depositing successive
layers of materials onto a substrate has, heretofore been unknown
in the art. Furthermore, the art still has a need for a covered
stent device in which a structural support, such as a stent,
defines openings which are subtended by a thin film layer, with
both the stent and the subtending thin film being formed, at least
in portions thereof, as a single, integral, monolithic structure
and fabricated of metals or of metal-like materials.
SUMMARY OF THE INVENTION
[0015] Alternative embodiments disclosed herein relate to medical
devices including both a structural scaffold member for support and
a thin film cover, preferably an integral cover, including
endoluminal grafts, covered stent devices including stent-grafts
and stent-graft-type devices, and embolic filters, each of which
are fabricated entirely of biocompatible metals or of biocompatible
materials which exhibit biological response and material
characteristics substantially the same as biocompatible metals,
referred to herein synonymously as "pseudometallic materials" or
"pseudometals", such as for example composite materials. Both the
structural scaffold member and thin film cover are fabricated of
biocompatible metals or of pseudometallic materials. Such devices
are delivered through anatomical passageways using minimally
invasive delivery techniques. In accordance with one embodiment,
the medical devices are fabricated by physical vapor deposition
processes in which the covering and the scaffold are integrally and
monolithically joined to one another during the deposition process.
In accordance with an alternative embodiment, the medical devices
are fabricated by electrochemical deposition of metals onto a
suitable substrate.
[0016] One embodiment is to provide methods for fabricating medical
devices by depositing device-forming materials onto a suitable
substrate to form a structural scaffold and a covering membrane or
film over the structural scaffold. In accordance with this
embodiment, both the structural scaffold and the covering membrane
are formed in operable association with one another on the
deposition substrate.
[0017] A further embodiment provides an implantable device which
consists of a microporous thin film covering comprised of a
metallic or pseudometallic material and an underlying structural
support made of a metallic or pseudometallic material, both formed
in conjunction with one another on a deposition substrate. The
microporous metallic or pseudometallic thin film covering is also
described in co-pending, commonly assigned U.S. Pat. No. 6,936,066,
issued Aug. 30, 2005, which is hereby expressly incorporated by
reference as describing the microporous thin film covering. While
both the microporous thin film covering and the underlying
structural support may be fabricated from many different materials,
in accordance with one embodiment, both the microporous thin film
covering and the underlying structural scaffold support are
fabricated from metallic or pseudometallic materials having shape
memory and/or superelastic properties. More preferably, the metal
used to fabricate both the microporous thin film covering and the
underlying structural support of inventive implantable endoluminal
graft is Nitinol. The underlying structural support, without the
microporous thin film covering, may be a stent, an embolic filter
scaffold or other type of medical scaffold. The underlying
structural support can assume any commonly known geometries in the
art that possess requisite hoop strength, circumferential
compliance or longitudinal flexibility for both endoluminal
delivery and/or acting as an in vivo prosthesis. In a preferred
embodiment, the structural support element adopts a geometry that
includes at least a pair of cylindrical elements and
interconnecting members that join adjacent cylindrical elements at
nearly identical angular points along the circumference of the
cylindrical elements.
[0018] In another embodiment, an implantable graft includes a
microporous thin film covering comprised of a metallic material
which has shape memory and/or pseudoelastic properties and a
structural support element underlying the microporous thin film
covering. "Pseudoelastic properties" is used herein to refer to the
ability of the metallic material to undergo "pseudoelastic
deformation". In a preferred aspect, the structural support element
has shape memory properties that allow the structural support
element to undergo a phase transition from martensite to austenite
phase at body temperature. During this phase transition, the
structural support element self-expands from an initial, delivery
diameter to an enlarged expanded diameter for its intended in vivo
use. The shape memory expansion of the structural support element
exerts a radially expansive force upon the microporous thin film
covering, thereby causing the microporous thin film to radially
expand with the structural support element. While the expansion of
the microporous thin film appears to be plastic, because the
microporous thin film is a shape memory material, the expansion is
actually fully recoverable above the transition temperature of the
material, and is, therefore, "pseudoplastic".
[0019] In still another embodiment, an implantable endoluminal
graft is comprised of a microporous thin film covering comprised of
a shape memory alloy having an austenite phase transition
temperature, A.sub.s, greater than 37.degree. C. and a structural
support element underlying the microporous thin film covering that
is comprised of a shape memory alloy that has an austenite phase
transition temperature less than 37.degree. C. Thus, in both the
delivery diameter and the implanted expanded diameter, the
microporous thin film remains in a martensite state, while the
structural element undergoes a phase transition from martensite to
austenite at body temperature.
[0020] Another embodiment is an implantable endoluminal graft
wherein the structural support element is monolithically connected
to the microporous thin film covering at least one point of contact
between the microporous thin film covering and the structural
support element.
[0021] Preferably, the at least one point of contact is located at
either near a proximal end or distal end of the microporous thin
film covering and corresponding end of the structural support
element. Even more preferably, the at least one point of contact is
located at near a distal end of the microporous thin film covering
and structural support element.
[0022] In another embodiment, the implantable endoluminal graft
includes a microporous thin film covering comprised of a uniform
pattern of openings throughout the surface of the microporous thin
film covering. The openings can be selected from common geometric
shapes including a circle, triangle, ellipsoid, diamond, star,
clover, rectangle, square, or straight or curved lines.
[0023] The structural scaffold member may consist of any type of
structural scaffold member.
[0024] In accordance with the several embodiments, the structural
support member may be selected from the group of stents, embolic
protection filter supports, valvular prostheses, septal occluders,
vascular occluders, shunts or the like. In accordance with an
embodiment, the structural scaffold support is preferably generally
tubular in configuration, and has an inner or luminal wall surface
and an outer or abluminal wall surface and a central lumen passing
along the longitudinal axis of the structural support member and is
comprises of a plurality of interconnected expansive structural
scaffold members. The structural support member may be comprised of
a wide variety of geometric configurations and constructions, as
are known in the art. For example, the structural support member
may assume a balloon expandable slotted configuration of U.S. Pat.
Nos. 4,733,665, 4,739,762, 4,776,337 or 5,102,417 or the structural
support member may be configured as a plurality of self-expanding
interwoven wire members or it may assume any of the wall geometries
disclosed in Serruys, P. W., Kutryk, M. J. B., Handbook of Coronary
Stents, 3.sup.rd Ed. (2000). Each of the structural support member
designs, structural support member materials, structural support
member material characteristics, e.g., balloon expandable,
self-expanding by spring tension of the material, self-expanding by
shape memory properties of the structural support member material,
or self-expanding by superelastic properties of the structural
support member material are well known to one of ordinary skill in
the art and may be used with the implantable graft of one
embodiment.
[0025] An aspect of one embodiment is a method for creating
materials specifically designed for manufacture of grafts, stents,
covered stents, stent-grafts, embolic filters or other medical
devices capable of delivery by minimally invasive techniques.
According to one embodiment, the manufacture of the materials used
to form the medical devices is controlled to attain a regular,
homogeneous atomic and molecular pattern of distribution along
their surfaces. This avoids the marked variations in surface
composition, creating predictable oxidation and organic adsorption
patterns and has predictable interactions with water, electrolytes,
proteins and cells. Particularly, EC migration is supported by a
homogeneous distribution of binding domains that 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 about a 1 .mu.m
radius and about a 2 .mu.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.
[0026] In accordance with one particular embodiment, there is
provided a covered stent device in which there is at least one of a
plurality of structural scaffold members that provides a primary
means of structural support for the covered stent device. The
plurality of structural scaffold members is spaced apart to form
open regions or interstices between adjacent structural scaffold
members. In one embodiment, a web of material, that is the same or
similar to the material which forms the plurality of structural
scaffold members, subtends the interstices or open regions between
adjacent structural scaffold members. The web may be formed within
all or a portion of the interstitial area or open regions between
the plurality of structural support members. Both the plurality of
interconnected structural scaffold members and the web may be
formed of initially substantially planar materials or of initially
substantially cylindrical materials.
[0027] Still another embodiment provides a method of fabricating
the medical device which entails depositing a first layer of
device-forming material onto a substrate having a at least one of a
plurality of patterned recesses defining the geometry of the
structural scaffold, then planarizing the deposited first layer to
the surface of the substrate, such that only the device-forming
material in the recesses remains, then depositing a second layer of
device-forming material onto the substrate and the first layer,
then patterning a plurality of openings in the second layer, then
removing the substrate from the deposited and patterned second
layer and first layer of device-forming material to provide the
formed medical device.
[0028] A further aspect of one embodiment provides a method of
fabricating a medical device which includes the step of disposing a
structural scaffold, such as a stent or an expansible framework for
an embolic filter, onto a substrate, vacuum depositing a
sacrificial material onto the structural scaffold and the
substrate, planarizing the sacrificial material to an outer surface
of the structural scaffold, depositing a cover material onto the
planarized sacrificial material and the structural scaffold,
patterning openings in deposited cover material, and removing the
sacrificial material and the substrate to release the formed
medical device.
[0029] Devices, such as covered stents, drug-eluting stents,
embolic filters, supported grafts, shunts, or the like may be made
by any of the methods disclosed herein. Common to such devices,
there is provided a cover member or graft formed as a discrete thin
sheet or tube of biocompatible metal or metal-like materials. A
plurality of openings are formed which pass transversely through
the cover member. The plurality of openings may be random or may be
patterned. The size of each of the plurality of openings may be
such as to permit cellular migration through each opening, without
permitting fluid flow there through, but various cells or proteins
may freely pass through the plurality of openings to promote device
healing in vivo. Alternatively, for example as in the case of
embolic filter, blood must pass through and therefore the size of
each of the openings will be larger to accommodate blood flow
therethrough.
[0030] In accordance with another embodiment, there is provided an
implantable endoluminal device that is fabricated from materials
that present a blood or tissue contact surface that is
substantially homogeneous in material constitution. More
particularly, the present invention provides an endoluminal graft,
stent, stent-graft and web-stent that are made of a material having
controlled heterogeneities along the blood flow or
tissue-contacting surface of the stent.
BRIEF DESCRIPTION OF THE FIGURES
[0031] FIG. 1 is process diagram illustrating a first embodiment of
the method of the present invention.
[0032] FIGS. 2A-2H are sequential cross-sectional fragmentary views
illustrating device formation in accordance with the first
embodiment.
[0033] FIG. 3 is a diagrammatic representation of a gravure
calendaring die engaged upon a substrate creating a corresponding
pattern in the substrate.
[0034] FIG. 4 is a perspective view of a gravure embossed substrate
having a recessed pattern corresponding to a stent geometry.
[0035] FIGS. 5A-5E are sequential cross-sectional fragmentary views
illustrating device formation in accordance with a second
embodiment.
[0036] FIG. 6 is a process diagram illustrating the second
embodiment of the method of making.
[0037] FIGS. 7A-7E are sequential cross-sectional views
illustrating a third embodiment of an inventive covered stent made
in accordance with the second embodiment of the method of
making.
[0038] FIGS. 8A-8G are sequential fragmentary cross-sectional views
illustrating a fourth embodiment of a covered stent suitable for
drug eluting applications made by the method of the making.
[0039] FIG. 9 is a photographic top plan view of a web-stent in
accordance with one embodiment.
[0040] FIG. 10 is a perspective view of a preferred embodiment of
the web-stent.
[0041] FIG. 11 is a perspective view of a stent-graft in accordance
with one embodiment.
[0042] FIG. 12 is a perspective view of an alternative embodiment
of the inventive stent-graft.
[0043] FIG. 13 is a cross-sectional view taken along line 13-13 of
FIG. 12.
[0044] FIG. 14 is a cross-sectional view illustrating a pair of
support members and a section of interstitial web between adjacent
supporting members.
[0045] FIG. 15 is a cross-sectional view illustrating a pair of
support members and a section of interstitial web between adjacent
supporting members in accordance with an alternative
embodiment.
[0046] FIG. 16A is a top-plan view of a graft or web region with a
plurality of openings passing there through.
[0047] FIG. 16B is a top plan view of an alternative embodiment of
a graft or web region with a plurality of openings passing there
through.
[0048] FIG. 16C is a top plan view of a third embodiment of a graft
or web region with a plurality of openings passing there
through.
[0049] FIG. 17A is a transverse cross-sectional view of a first
embodiment of a graft member in accordance with one embodiment; and
17B is a transverse cross-sectional view of a second embodiment of
a graft member in accordance with one embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0050] According to the present invention, alternative embodiments
of a method for fabricating medical devices are disclosed and
taught. Additionally, metallic or pseudometallic medical devices
made by the inventive methods are disclosed and taught. While the
invention is described with reference to certain preferred
embodiments and examples, these are exemplary and are not meant to
limit the scope of the invention.
[0051] Additionally, medical devices fabricated by the inventive
methods are provided which preferably have surfaces thereof having
heterogeneities which are controlled during the fabrication process
by controlling the conditions of fabrication. The inventive medical
devices may be made utilizing a pre-fabricated scaffold or cover,
or a vacuum deposited scaffold or cover, either of which may
originate in either a planar or cylindrical conformation. Where a
scaffold is provided, either from a pre-fabricated scaffold or by
vacuum deposition formation, the cover may be added to the scaffold
by vacuum deposition. Alternatively, where a cover is provided,
either by pre-fabrication or by vacuum deposition formation, then a
scaffold may be added either by vacuum deposition or by imparting a
pattern of support members to the film by removing at least some
regions of the film to create thinner regions in the starting film
and defining relatively thinner and thicker film regions, such as
thinner web regions between adjacent structural scaffold members
formed by thicker film regions and/or relatively thinner graft
regions. An additive methodology may include vacuum deposition or
lamination of a pattern of support members upon the planar or
cylindrical film. A subtractive methodology includes etching
unwanted regions of material by masking regions to form the
structural scaffold members and expose unmasked regions to the
etchant. Additionally, in order to improve in vivo healing, it is
advantageous to impart openings passing through the web or the
graft. The openings are preferably produced during the process of
forming the web or the graft. The openings in the web or the graft
may be formed by conventional methods such as photolithographic
processes, by masking and etching techniques, by mechanical means,
such as laser ablation, EDM, or micromachining, etc. Suitable
deposition methodologies, as are known in the microelectronic and
vacuum coating fabrication arts and incorporated herein by
reference, are plasma deposition and physical vapor deposition
which are utilized to impart a metal layer onto the stent
pattern.
[0052] The implantable endoluminal devices are formed from at least
one structural scaffold member, that serves as a scaffold and
provides the requisite support for the device, and a metallic or
pseudometallic thin film cover that covers at least a portion of
the structural scaffold member. A plurality of openings are formed
in the cover to impart flexibility and compliance to the cover,
while serving to filter embolic material and permitting transmural
cellular growth for implantable devices. The implantable
endoluminal devices have sufficient longitudinal flexibility to
traverse tortuous anatomical pathways without risk of injury and
are deployable at a remote situs with the structural scaffold
member providing support for the thin film cover to retain it
either in a deployed position, such as in the case of an embolic
filter, or affixed against a vascular wall or aneurysmal thrombus,
such as in the case of a covered stent or supported graft.
[0053] Suitable deposition methodologies, as are known in the
microelectronic and vacuum coating fabrication arts and
incorporated herein by reference, are plasma deposition and
physical vapor deposition. Of particular relevance are commonly
assigned, published U.S. Patent Publication Nos. 2003/0028246 and
2003/0059640, which are hereby incorporated by reference and teach
physical vapor deposition methods for fabricating metallic and
pseudometallic materials suitable for fabricating medical
devices.
[0054] In accordance with another aspect of the inventive medical
device, it is contemplated that more than one cover members are
employed, with an outer diameter of a first cover member being
smaller than the inner diameter of a cover member, such that the
first cover member is concentrically engageable within a lumen of
the second cover member. Both the first and second cover members
have a pattern of a plurality of openings passing there through.
The first and second cover members are positioned concentrically
with respect to one another, with the plurality of patterned
openings being positioned out of phase relative to one another such
as to create a tortuous cellular migration pathway through the wall
of the concentrically engaged first and second cover members. In
order to facilitate cellular migration through and healing of the
first and second cover members in vivo, it is preferable to provide
additional cellular migration pathways that communicate between the
plurality of openings in the first and second cover members. These
additional cellular migration pathways may be imparted as 1) a
plurality of projections formed on either the luminal surface of
the second cover or the abluminal surface of the first cover, or
both, which serve as spacers and act to maintain an annular opening
between the first and second cover members that permits cellular
migration and cellular communication between the plurality of
openings in the first and second graft members, or 2) a plurality
of microgrooves, which may be random, radial, helical, or
longitudinal relative to the longitudinal axis of the first and
second cover members, the plurality of microgrooves being of a
sufficient size to facilitate cellular migration and propagation
along the groove without permitting fluid flow there through, the
microgrooves serve as cellular migration conduits between the
plurality of openings in the first and second graft members.
Methods for forming such microgrooves and their utilization in
promoting endothelialization are described more fully in
commonly-assigned U.S. Pat. No. 6,190,404 issued Feb. 20, 2001 and
in U.S. Patent Application Publication No. 20020017503 published
Feb. 14, 2002, both of which are hereby expressly incorporated by
reference.
[0055] A covered scaffold device in accordance with one embodiment
may be forming or joining a cover member with a structural scaffold
support member. Either or both of the cover member and the
structural scaffold support member may be formed in accordance with
the inventive methods or may be provided as pre-fabricated
materials. A covered scaffold may be formed by first forming, such
as by vacuum deposition methods or by etching a pre-existing
material blank, a graft member as a contiguous thin sheet or tube
which projects outwardly from at least one aspect of the plurality
of structural scaffold members. The thin sheet is then everted over
the structural scaffold members and brought into a position
adjacent a terminal portion of the plurality of structural scaffold
members such that it covers one or both of the putative luminal or
abluminal surfaces of the plurality of structural scaffold members.
The graft member is then mechanically joined at an opposing end,
i.e., the putative proximal or the putative distal end of the
plurality of structural scaffold members.
[0056] In accordance with one of the embodiments, there is provided
a covered scaffold-supported device, termed a "web-stent" in which
scaffold members provide a primary means of structural support for
the webbed-stent device. The scaffold members may be arranged in
any manner as is known in the art of stent or embolic filter
fabrication, e.g., single element forming a circle or ellipse, a
single or plural elements which form a tubular diamond-like or
undulating pattern, in which adjacent structural scaffold members
are spaced apart forming open regions or interstices between
adjacent structural scaffold members. In one embodiment, the
interstices or open regions between adjacent structural scaffold
members are subtended by a cover material that is the same material
or a material exhibiting similar biological and mechanical response
as the material that forms the plurality of structural scaffold
members. This cover may be formed within all or a portion of the
interstitial area or open regions between the plurality of
structural scaffold members and may either be integrally part of or
connected to one or more structural scaffold members, or may
overlay or may underlay a structural scaffold member.
[0057] Where a device is being fabricated, the thickness of the
deposited or pre-fabricated starting film may be less than that
where a web-stent is being formed, due to the absence of structural
scaffold members in the graft member. However, where a stent-graft
or a web-stent is being fabricated, structural scaffold members may
be formed by alternative methods. The structural scaffold members
may be formed by additive techniques by applying a pattern of
structural scaffold members onto a film, such as by vacuum
deposition techniques or conventional metal forming techniques,
such as laminating or casting. Conversely, the structural scaffold
members may be provided first, either by a deposition methodology
or as a pre-fabricated structural scaffold; then the cover added to
the scaffold by deposition or mechanical affixation. Subtractive or
selective removal techniques may alternatively be employed to
remove material from patterned regions on a film, such as by
etching a pattern of interstitial regions between adjacent
structural scaffold members until a thinner film is created which
forms the web subtending the plurality of structural scaffold
members. Where a pre-existing stent is employed as the structural
scaffold members, obviously, the structural scaffold members do not
need to be fabricated or formed.
[0058] In accordance with several embodiments, the graft, the
plurality of structural scaffold members and the web are fabricated
of the same or similar metals or metal-like materials. In order to
improve healing response, it is preferable that the materials
employed have substantially homogenous surface profiles at the
blood or tissue contact surfaces thereof. A substantially
homogeneous surface profile is achieved by controlling
heterogeneities along the blood or tissue-contacting surface of the
material. The heterogeneities that are controlled in accordance
with an embodiment that include: grain size, grain phase, grain
material composition, stent-material composition, and surface
topography at the blood flow surface of the stent. Additionally,
the embodiments provide methods of making endoluminal devices
having controlled heterogeneities in the device material along the
blood flow or tissue-contacting surface of the device. Material
heterogeneities are preferably controlled by using conventional
methods of vacuum deposition of materials onto a substrate.
[0059] 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 O, O.sub.2, CO.sub.2, SO.sub.2,
NO, hydrocarbons and other more complex reactive molecules.
Reaction with oxygen 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.
[0060] In accordance with an aspect of the embodiments, there is
provided a vacuum deposited device that is fabricated of a material
having surface material heterogeneities controlled during
deposition of the material. Current manufacturing methods for
fabricating endoluminal stents fail to achieve the desired material
properties. As discussed above, stents are fabricated from bulk
metals that are processed in a manner that incorporates processing
aides to the base metal. Presently, stents are made from hypotubes
formed from bulk metals, by machining a series of slots or patterns
into the hypotube to accommodate radial expansion, or by weaving
wires into a mesh pattern.
[0061] The embodiments consists of a medical device, such as a
scaffold supported cover or graft, which is made of a bulk material
having controlled heterogeneities on a surface thereof.
[0062] Heterogeneities are controlled by fabricating the bulk
material of the stent to have defined grain sizes that 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)
controlling discontinuities, such as cracking or pinholes, (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 MM compatible, (h) have a 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.
[0063] Controlling the surface profile of an endoluminal device is
significant because blood protein interactions with surfaces of
endoluminal devices appear to be the initial step in a chain of
events leading to tissue incorporation of the intravascular device.
The embodiments are 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.
[0064] In accordance with a preferred embodiment, the inventive
devices have surface profiles which are achieved by fabricating the
devices by the same metal deposition methodologies as are used and
standard in the microelectronic and nanofabrication vacuum coating
arts, and which are hereby incorporated by reference. In accordance
with a preferred embodiment, 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 material being
deposited using an inert gas, such as argon, xenon, nitrogen or
neon. Bombardment with inert gas ions during deposition serves to
reduce void content by increasing the atomic packing density in the
deposited material. 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.
[0065] When sputtering techniques are employed in accordance with
the methods of making the shape memory nickel-titanium alloys have
been deposited having thicknesses between 0.5 .mu.m and 200 .mu.m
which exhibit shape memory properties without the need for
post-deposition annealing to shape-set the deposited material. With
the sputtering technique, it is preferable to employ a cylindrical
sputtering target, a single circumferential source that
concentrically surrounds the substrate that is held in a coaxial
position within the source.
[0066] Alternate deposition processes which may be employed to form
the stent in accordance with several embodiments which include
cathodic arc, laser ablation, and direct ion beam deposition. In
the metal fabrication arts, 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.
[0067] Materials to make the inventive graft, stent-graft and
web-stent are chosen for their biocompatibility, mechanical
properties, i.e., tensile strength, yield strength, and their ease
of deposition include, without limitation, the following: elemental
titanium, vanadium, aluminum, nickel, tantalum, zirconium,
chromium, silver, gold, silicon, magnesium, niobium, scandium,
platinum, cobalt, palladium, manganese, molybdenum and alloys
thereof, such as zirconium-titanium-tantalum alloys, cobalt
chromium alloy, nickel-titanium alloy and stainless steel.
[0068] During deposition various deposition conditions, such as the
chamber pressure, the deposition pressure, the partial pressure of
the process gases, the target temperature, voltage bias, target
composition, and the deposition rate are controlled to optimize
deposition of the desired species onto the substrate and yield
desired physical and mechanical properties to the deposited
material. As is known in the microelectronic fabrication,
nanofabrication 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,
moved in an X-Y plane, planatarily or rotationally moved within
the-deposition chamber to facilitate deposition or patterning of
the deposited material onto the substrate. The deposited material
may be 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 structural supports, web-regions or graft, both in
the context of spatial orientation of patterns of regions of
relative thickness and thinness, such as by varying the thickness
of the film over its length to impart different mechanical
characteristics under different delivery, deployment or in vivo
environmental conditions.
[0069] The device may be removed from the substrate after device
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,
aluminum or organic based materials, such as photoresists, 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.
[0070] Those of ordinary skill in the art, will understand and
appreciate that alternative methods of removing material from areas
that form relatively thinner regions of the device may be employed.
For example, in addition to chemical etching, relatively thinner
regions may be formed by removing bulk material by ion milling,
laser ablation, EDM, laser machine, electron beam lithography,
reactive ion etching, sputtering or equivalent methods which are
capable of reducing the thickness of the material in either the
graft region or the interstitial web region between the structural
scaffold members. Alternatively, the structural scaffold members
may be added to the defined interstitial web or graft regions to
form the device, or the interstitial web or graft regions may be
added to pre-existing structural scaffold members. Additive methods
that may be employed include conventional metal forming techniques,
including laminating, plating, or casting.
[0071] Similarly, a wide variety of initial bulk material
configurations may be employed, including a substantially planar
sheet substrate, an arcuate substrate or a tubular substrate, which
is then processed by either subtractive or additive techniques
discussed above.
[0072] By forming the structural scaffold members, the interstitial
web and/or the graft of an integral, monolithic material, both the
circumferential or hoop strength of the resultant device, as well
as the longitudinal or columnar strength of the device are enhanced
over conventional stent-graft devices. Additional advantages of the
embodiments, depending upon fabrication methods, may include:
controlled homogeneity and/or heterogeneity of the material used to
form the device by deposition methodologies, enhanced ability to
control dimensional and mechanical characteristics of the device,
the ability to fabricate complex device conformations, ability to
pattern and control the porosity of the web and/or graft regions,
and a monolithic one-piece construction of a device which yields a
minimized device profile and cross-sectional area. The devices of
the alternative embodiments have relatively thicker and thinner
regions, in which the thinner regions permit radial collapse of the
device for endoluminal delivery. The inventive device exhibits
superior column strength that permits smaller introducer size and
more readily facilitates deployment of the device.
[0073] In accordance with a preferred embodiment, the cover regions
of the inventive devices have a plurality of openings which pass
through the thickness of the cover material. Each of the plurality
of openings is dimensioned to permit cellular migration through the
opening without permitting blood leakage or seepage through the
plurality of openings and to exclude embolic material from passing
into the general circulation. Alternative, such as in the case of
an embolic filter, the openings will be of sufficient size to
permit blood flow therethrough but capture embolic material. The
plurality of openings may be random or may be patterned. However,
in order to control the effective porosity of the device, it is
desirable to impart a pattern of openings in the material used to
fabricate the inventive device.
[0074] With particular reference to FIG. 1, a first preferred
embodiment of the inventive method 10 is illustrated. A substrate
suitable for use in vacuum deposition is provided 12, and the
substrate is patterned 14 with a pattern corresponding to a desired
scaffold geometry. The pattern may be provided by any suitable
method, such as etching 15, embossing using an embossing die or
gravure calendaring 16. The scaffold may be formed by depositing a
first material onto the patterned substrate 18 and into the
patterning, then planarized 20 to the upper or outer surface of the
substrate, leaving the first material layer present in the pattern
of the substrate 18. In accordance with the preferred embodiments,
the first material layer is preferably a biocompatible material,
such as stainless steel or a shape memory material, such as
nickel-titanium alloy or cobalt-chromium alloy; the material is
preferably vacuum deposited by sputtering, but may also be
deposited by evaporation, ion bombardment, chemical vapor
deposition or electrochemical deposition. If desired, the formed
scaffold may be removed from the substrate 22 and prepared for use
as a medical scaffold material either alone or with a separately
formed cover material. However, in accordance with the inventive
method 10, it is preferred that the planarized substrate and
deposited first material resident in the pattern on the substrate
be cleaned, such as by glow discharge cleaning 24, then a second
material be deposited onto the planarized first material and the
substrate 26. A plurality of openings are then created which pass
through the second material 28, preferably in regions which do not
overly a scaffold member. At this point, the substrate may be
removed from the formed device 30, such as by selective chemical
etching.
[0075] FIGS. 2A-2H sequentially depict device formation by the
foregoing described method 10. First a substrate 40 is provided
which is suitable for vacuum deposition. In accordance with a most
preferred embodiment, the substrate 40 is preferably a deoxygenated
copper material which may have a titanium nitride coating on a
surface thereof as a diffusion barrier to prevent migration of
minute amounts of copper into the deposited layer. A patterning
member 50, which may either by an embossing die or gravure plate,
having pattern-forming regions 52 corresponding to a desired
pattern for the scaffold, is engaged with the substrate 40 to
create substrate pattern regions 42 in or on the substrate 40.
Those skilled in the art will understand and appreciate that the
pattern-forming regions 52 on the patterning member may correspond
to either a positive or negative of the desired pattern for the
scaffold, and hence, either consist of raised projections emanating
from the surface of the patterning member 50 or consist of recesses
formed in the surface of the patterning member 50. Depending upon
whether the patterning member 50 is provided with a positive or
negative pattern of the desired scaffold geometry, the
corresponding negative or positive pattern of substrate pattern
regions 42 will be formed in or on the substrate 40. For purposes
of illustration only, patterning member 50 and pattern-forming
regions 52 are shown as a positive pattern corresponding to the
scaffold geometry.
[0076] Once the patterned substrate 40 is formed, a
scaffold-forming material 44 is vacuum deposited onto the substrate
40. Scaffold-forming material 44 conforms to the substrate pattern
regions 42 as shown in FIG. 2D. Where the substrate pattern regions
42 are recesses, as depicted in FIGS. 2B-2E, the scaffold-forming
material 44 is preferably planarized to the surface of the
substrate 40, leaving the scaffold-forming material 44 present only
in the substrate pattern regions 42 and not on interstitial regions
45 between the scaffold 46 or on other regions of the substrate 40.
At this point, the scaffold forming material 44 conforms to the
desired scaffold geometry and the formed scaffold 46 may be
released from the substrate 40, such as by selectively chemically
etching the substrate 40. On the other hand, where the substrate
pattern regions 42 are raised projections, interstitial regions 45
between adjacent members of the scaffold 46 may be removed by
mechanical or thermal methods, such as laser ablation or electrical
discharge machining (EDM).
[0077] In accordance with one embodiment, however, and as
illustrated in FIGS. 2G and 2H, rather than removing the formed
scaffold 46 from the substrate 40, it is desirable to leave the
formed scaffold 46 in the substrate as depicted in FIG. 2E and
vacuum deposit a cover material 48 onto the scaffold 46 and the
substrate 40. In this manner, the deposited cover material 48 is
deposited over both the scaffold 46 and the interstitial regions 45
on the substrate 40.
[0078] After the cover material 48 and the scaffold 46 are formed,
and preferably while they remain on the substrate 40 for ease of
handling, a plurality of openings 49 are formed which pass through
the thickness of the cover material 48 in the interstitial regions
45. It is desirable, though not required, that the openings 49 are
not formed in the cover material 48 in those areas which overlie
the scaffold 46 so as not to impinge upon the scaffold 46. After
the plurality of openings 49 are formed, the substrate 40 is
selectively removed from the formed device, such as by selective
chemical etching.
[0079] In accordance with the preferred embodiments, both the first
material for the scaffold 46 and the cover material 48 are formed
of biocompatible metals or pseudometals. The plurality of openings
49 may be random or may be patterned. It is preferable that the
size of each of the plurality of openings 49 be such so as to
exclude friable embolic material from passing through the openings
49, as well as to permit endothelialization to aid in healing of
implantable devices.
[0080] In accordance with a further embodiment, a method for making
a drug eluting device 105 is shown in FIGS. 8A-8G. The method for
making a drug eluting device 105 entails substantially identical
processing as formation of a covered scaffold described above with
reference to FIGS. 1 and 2. A substrate 40 is patterned and layered
with a scaffold-forming material 46 and a cover forming layer 48 is
then deposited onto the scaffold-forming material 46. However in
accordance with the method for making a drug eluting device 105,
instead of removing the substrate from the formed covered scaffold,
a second scaffold 110 is disposed on the cover-forming material 48,
followed by deposition of a sacrificial material 112 onto the
second scaffold 110 and the cover-forming material 48. The
sacrificial material 112 is preferably planarized to expose upper
surfaces of the second scaffold-forming material 110, then a second
cover-forming material 114 is deposited onto the sacrificial
material 112 and the second scaffold-forming material 110. A
plurality of openings 116 may then be formed through the second
cover-forming material 114, preferably in regions which do not
overlie the second scaffold-forming material 110. The plurality of
openings 116 may also be formed through the first cover-forming
material 48 at the same time as those being formed through the
second cover-forming material 114. The sacrificial material 112,
may then be removed through the plurality of openings 116, such as
by selective chemical etching, to leave a void plenum 120
intermediate the cover-forming material 48 and the second
cover-forming material 114, which are maintained in spaced apart
relationship by the second scaffold-forming material 110. The
substrate 40 may be removed, preferably by selective chemical
etching.
[0081] A pharmacologically active agent may then be loaded into the
void plenums 120 by known methods, with known carriers or
excipients, and with known matrices. Local or localized delivery of
drug or drug combinations may be utilized to treat a wide variety
of conditions utilizing any number of medical devices, or to
enhance the function and/or life of the device. Accordingly, in
addition to the embodiments described herein, therapeutic or
pharmaceutical agents may be added to any component of the device,
including within the void plenums 120, during fabrication to treat
any number of conditions. In addition, therapeutic or
pharmaceutical agents may be applied to the device, such as in the
form of a drug or drug eluting layer, or surface treatment after
the device has been formed. In a preferred embodiment, the
therapeutic and pharmaceutical agents may include any one or more
of the following: antiproliferative/antimitotic agents including
natural products such as vinca alkaloids (i.e. vinblastine,
vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins
(i.e. etoposide, teniposide), antibiotics (dactinomycin
(actinomycin D) daunorubicin, doxorubicin and idarubicin),
anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin)
and mitomycin, enzymes (L-asparaginase which systemically
metabolizes L-asparagine and deprives cells which do not have the
capacity to synthesize their own asparagine); antiplatelet agents
such as G(GP) 111.sub.b/111.sub.a inhibitors and vitronectin
receptor antagonists; antiproliferative/antimitotic alkylating
agents such as nitrogen mustards (mechlorethamine, cyclophosphamide
and analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and analogs,
streptozocin), trazenes--dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid
analogs (methotrexate), pyrimidine analogs (fluorouracil,
floxuridine, and cytarabine), purine analogs and related inhibitors
(mercaptopurine, thioguanine, pentostatin and
2-chlorodeoxyadenosine {cladribine}); platinum coordination
complexes (cisplatin, carboplatin), procarbazine, hydroxyurea,
mitotane, aminoglutethimide; hormones (i.e. estrogen);
anticoagulants (heparin, synthetic heparin salts and other
inhibitors of thrombin); fibrinolytic agents (such as tissue
plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel, abciximab; antimigratory;
antisecretory (breveldin); anti-inflammatory:
[0082] such as adrenocortical steroids (cortisol, cortisone,
fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone,
triamcinolone, betamethasone, and dexamethasone), non-steroidal
agents (salicylic acid derivatives i.e. aspirin; para-aminophenol
derivatives i.e. acetaminophen; indole and indene acetic acids
(indomethacin, sulindac, and etodalac), heteroaryl acetic acids
(tolmetin, diclofenac, and ketorolac), arylpropionic acids
(ibuprofen and derivatives), anthranilic acids (mefenamic acid, and
meclofenamic acid), enolic acids (piroxicam, tenoxicam,
phenylbutazone, and oxyphenthatrazone), nabumetone, gold compounds
(auranofin, aurothioglucose, gold sodium thiomalate);
immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus
(rapamycin), azathioprine, mycophenolate mofetil); angiogenic
agents: vascular endothelial growth factor (VEGF), fibroblast
growth factor (FGF); angiotensin receptor blockers; nitric oxide
donors; anti-sense oligonucleotides and combinations thereof; cell
cycle inhibitors, mTOR inhibitors, and growth factor receptor
signal transduction kinase inhibitors; retenoids; cyclin/CDK
inhibitors; HMG co-enzyme reductase inhibitors (statins); and
protease inhibitors.
[0083] For such drugs the ideal pharmacokinetic profile will be one
wherein the drug concentration reached therapeutic levels without
exceeding the maximum tolerable dose and maintains these
concentrations for extended periods of time until the desired
therapeutic effect is reached. One of the ways such a profile can
be achieved in an ideal case scenario would be by encapsulating the
drug in a polymer matrix. The technology of polymeric drug delivery
has been studied in details over the past 30 years and numerous
excellent reviews are readily available to those skilled in the
art. Polymeric drug delivery offers several advantages, including,
for example: (1) Localized delivery of drug: The product can be
implanted directly at the site where drug action is needed and
hence systemic exposure of the drug can be reduced. This becomes
especially important for toxic drugs which are related to various
systemic side effects (such as the chemotherapeutic drugs). (2)
Sustained delivery of drugs: The drug encapsulated is released over
extended periods and hence eliminates the need for multiple
injections. This feature can improve patient compliance especially
for drugs for chronic indications, requiring frequent injections
(such as for deficiency of certain proteins); (3) Stabilization of
the drug: The polymer can protect the drug from the physiological
environment and hence improve its stability in vivo. This
particular feature makes this technology attractive for the
delivery of labile drugs such as proteins.
[0084] The drug may be released from the polymer matrix either by
diffusion out of the polymer matrix or by degradation of the
polymer matrix of a combination of diffusion and degradation
mechanisms. Polymer degradation may occur by enzymatic means,
hydrolysis of a combination of these two. Hydrolysis, in turn, may
be mediated by bulk erosion or by surface erosion of the polymer
matrix. For a given drug, the release kinetics from the polymer
matrix are predominantly governed by three factors, namely, the
type of polymer, polymer morphology and the excipients present in
the system.
[0085] The polymer could be non-degradable or degradable. A major
disadvantage with non-degradable polymers is that a surgery may be
required to harvest these polymers out of the body once they are
depleted of the drug. Degradable polymers on the other hand do not
require surgical intervention and hence are preferred for drug
delivery applications. However, since they degrade to smaller
absorbable molecules, it is important to make sure that the
polymers are non-toxic in nature. Commonly employed polymers
include, for example, polylactide (PLA), poly(lactide-co-glycolide)
(PLGA), Poly(urethanes), Poly(siloxanes) or silicones, Poly(methyl
methacrylate), Poly(vinyl alcohol), Poly(ethylene), Poly(vinyl
pyrrolidone) and the specific polymers Poly(2-hydroxy ethyl
methacrylate), Poly(N-vinyl pyrrolidone), Poly(methyl
methacrylate), Poly(vinyl alcohol). Poly(acrylic acid).
Polyacrylamide. Poly(ethylene-co-vinyl acetate). Poly(ethylene
glycol). Poly(methacrylic acid).
[0086] Degradation of lactide based polymers and in general all
hydrolytically degradable polymers, depends on the following
properties: (1) chemical composition: The rate of degradation of
polymers depends on the type of degradable bonds present on the
polymer. In general, the rate of degradation of different chemical
bonds follows as Anhydride>Esters>Amides; (2) crystallinity:
generally, the higher the crystallinity of a polymer, the slower is
its rate of degradation; and (3) hydrophilicity: if the polymer has
a lot of hydrophobic groups present on it, then it is likely to
degrade slower than a polymer which is hydrophilic in nature.
Polylactides are known to be more hydrophobic as compared to PLGA
and take a longer time to degrade.
[0087] Among the polylactides, DL-PLA, which is a polymer of D and
L-lactide, degrades faster than L-PLA, which is a homopolymer of
L-lactide, presumably due to lesser crystallinity. Similarly, the
more hydrophobic end-capped PLGA polymers degrade faster than the
carboxyl-ended PLGA. Some new polymers showing promise as
drug-delivery mechanisms include polyothroesters, polyphosphazenes,
polyanhydrides and polyphosphoesters.
[0088] Morphology of the polymer matrix also plays an important
role in governing the release characteristics of the encapsulated
drug. The polymer matrix could be formulated as either
micro/nano-spheres, gel, film or an extruded shape (such as
cylinder, rod etc). The shape of the extruded polymer can be
important to the drug release kinetics. For example, it has been
shown that zero order drug release can be achieved using a
hemispherical polymer form. Polymer microspheres are the most
popular form due to manufacturing advantages as well as ease of
administration (injectability by suspending in a vehicle). Polymer
microspheres can be manufactured by using various techniques such
as spray drying, solvent evaporation, etc. The type of technique
used affects factors such as porosity, size distribution and
surface morphology of the microspheres and may subsequently affect
the performance of the drug delivery product.
[0089] Polymeric drug delivery products can be formulated with
excipients added to the polymer matrix. The main objective of
having excipients in the polymer matrix could be either to modulate
the drug release, or to stabilize the drug or to modulate the
polymer degradation kinetics. By incorporating basic salts as
excipients in polymeric microspheres, the stability of the
incorporated protein can be improved. It has been shown that these
basic salts also slow the degradation of the polymer. Similarly,
hydrophilic excipients can accelerate the release of drugs, though
they may also increase the initial burst effect.
[0090] FIG. 3 depicts a prototypical system for imparting a
scaffold pattern onto a cylindrical or tubular substrate 40. The
resulting substrate 40 having the scaffold pattern 42 is shown in
FIG. 4. An die 50 which carries a pattern 52 corresponding to the
desired geometry of the scaffold 46 is provided. The substrate 40
is placed on a pair of cylindrical rollers 55, which impart a
rotary movement 57 to the substrate 40 along its longitudinal axis.
Contacting the die 50 with the surface of the substrate under
pressure, causes the transfer of the pattern 52 from the die 50 to
impart the corresponding pattern 42 on the substrate 40. While
pattern 52 is shown as a positive pattern and, corresponding
pattern 42 is shown as a negative pattern, pattern 52 and its
corresponding pattern 42 may be negative-positive or
positive-negative, as desired, depending upon the desired manner of
fabricating the medical device. Where die 50 is an embossing die,
it will be necessary that substrate 40 be fabricated of a material
capable of being deformed under pressure to precisely accept and
retain an embossed pattern in the surface thereof. Where die 50 is
a gravure die, the pattern 52 is typically etched into the surface
of the die 50, then a lithographic material is applied to the
pattern 52 and transferred to the substrate 40. Gravure processes
are typically used in photolithography to pattern the substrate
40.
[0091] FIGS. 5A-E and 6 illustrates an alternate embodiment of the
inventive method 70 of making a covered scaffold device 60. Unlike
method 10, according to method 70 a substrate is selected at step
72, then a pre-existing scaffold 64 is mounted onto a deposition
substrate 62 at step 74. In this manner, the substrate 62 does not
require patterning and a first step of depositing a
scaffold-forming material is, similarly, not required. Once the
scaffold 64 is mounted on the deposition substrate 62, a
sacrificial material 66 is deposited over the scaffold 64 and the
substrate 62 at step 76. The sacrificial material 66 is then
planarized at step 78 to expose at least a top surface of the
scaffold 64, while leaving remaining regions of the sacrificial
material 66 covering the substrate 62 in interstitial regions of
the scaffold 64. It is preferable to clean the planarized
sacrificial material and exposed scaffold surface, such as by glow
discharge cleaning, at step 80, before further processing. A cover
material 68 is then deposited onto the exposed surfaces of the
scaffold 64 and the sacrificial material 66 at step 82. Then, a
plurality of openings are formed at step 84, through the deposited
cover material 68 and into the sacrificial material 66, preferably
in regions of the cover material 68 which do not overlay the
scaffold 64 members. Finally, the substrate and the sacrificial
material are removed at step 86, such as by selective chemical
etching, to release the formed covered scaffold in FIG. 5E having a
cover member 68 integrally joined to the scaffold 64.
[0092] FIGS. 7A-E illustrate another alternative embodiment in
which there is illustrated a method 90 for fabricating an inventive
covered scaffold device consisting of a scaffold 94 and a cover 100
in which the cover 100 is integrally formed to only sections 96 of
the scaffold 94. Covered scaffold device 91 is preferably
fabricated by either forming the scaffold 94 as depicted in FIGS.
2A-2F, or by engaging a pre-existing scaffold 94 onto a deposition
substrate 92 as depicted in FIG. 7A. A sacrificial material 98 is
then deposited onto the scaffold 94 and substrate 92 as illustrated
in FIG. 7B. The sacrificial material 98 is then planarized or
otherwise removed to expose only portions 96 of the underlying
scaffold 94. In accordance with a preferred embodiment, the
scaffold 94 is a stent and the exposed portions 96 are situated at
proximal and/or distal ends of the stent. By exposing only portions
96 of the scaffold 94 underlying the sacrificial material 98, other
portions of the scaffold 94 remain covered by the sacrificial
material 98. Subsequent deposition of a cover material 100 onto the
exposed scaffold 94 portions 96 and the sacrificial material 98,
integrally joins the exposed portions 96 of the scaffold 94 with
the cover material, while the sacrificial material 98 maintains
separation between the remaining regions of scaffold 94 underlying
the sacrificial material 98 and the cover material 100, as
illustrated in FIG. 7D. A plurality of openings 102 are formed in
the cover material 100, preferably in those regions in which the
cover material 100 overlays the sacrificial material 98, so as not
to impinge upon or damage the underlying scaffold portions 96. It
is anticipated, however, that the plurality of openings 100 may,
however, be patterned on top of the scaffold 96 patterned where
sacrificial material 98 is between the scaffold and cover material,
and may patterned where the cover material 100 is directly on top
of the scaffold 96 if the scaffold surface is sufficiently large
without deleterious effects to the scaffold. After removal of the
substrate 92 and the sacrificial material 98, the cover material
100 remains integrally joined only to the scaffold 94 portions 96,
while remaining regions of the scaffold 94 are unjoined to the
cover material 100 creating an open region 104 between the scaffold
94 and the cover material 100 which serves as a slip plane for
expansion and relative movement of the scaffold 94 and the cover
material 100.
[0093] The alternative embodiments comprise a medical device
fabricated of a bulk material having controlled heterogeneities on
a blood or tissue contacting surface thereof. Heterogeneities are
controlled by fabricating the bulk material of the stent to have
defined grain sizes that 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) controlling discontinuities, such
as cracking or pinholes, (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 MM
compatible, (h) have a 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.
[0094] Controlling the surface profile of an endoluminal device is
significant because blood protein interactions with surfaces of
endoluminal devices appear to be the initial step in a chain of
events leading to tissue incorporation of the intravascular device.
The alternative embodiments are 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.
[0095] In accordance with a preferred embodiment, the inventive
grafts, stent-grafts and web-stents have surface profiles which are
achieved by fabricating the graft, stent-graft and web-stent by the
same metal deposition methodologies as are used and standard in the
microelectronic and nano-fabrication vacuum coating arts, and which
are hereby incorporated by reference. In accordance with a
preferred embodiment, 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 material being
deposited using an inert gas, such as argon, xenon, nitrogen or
neon. Bombardment with inert gas ions during deposition serves to
reduce void content by increasing the atomic packing density in the
deposited material. 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.
[0096] 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 that concentrically surrounds the substrate that is held in
a coaxial position within the source.
[0097] Alternate deposition processes which may be employed to form
the stent in accordance with the alternative embodiments are
cathodic arc, laser ablation, and direct ion beam deposition. As
known in the metal fabrication arts, 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.
[0098] Materials to make the inventive graft, stent-graft and
web-stent are chosen for their biocompatibility, mechanical
properties, i.e., tensile strength, yield strength, and their ease
of deposition include, without limitation, the following: elemental
titanium, vanadium, aluminum, nickel, tantalum, zirconium,
chromium, silver, gold, silicon, magnesium, niobium, scandium,
platinum, cobalt, palladium, manganese, molybdenum and alloys
thereof, such as zirconium-titanium-tantalum alloys, nitinol, and
stainless steel.
[0099] During deposition, the deposition process parameters, such
as chamber pressure, deposition pressure, partial pressure of the
process gases, the target temperature, bias voltage, substrate or
source movement relative to the target, and power 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, moved in an X-Y plane, planatarily or
rotationally moved within the deposition chamber to facilitate
deposition or patterning of the deposited material onto the
substrate. The deposited material may be 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 structural
supports, web-regions or graft, both in the context of spatial
orientation of patterns of regions of relative thickness and
thinness, such as by varying the thickness of the film over its
length to impart different mechanical characteristics under
different delivery, deployment or in vivo environmental
conditions.
[0100] The device may be removed from the substrate after device
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,
aluminum or organic based materials, such as photoresists, 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.
[0101] The resulting device 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 expose a heterogeneous surface of the device.
[0102] FIGS. 9 and 10 illustrate a web-stent 121 in accordance with
one embodiment. The web-stent 121 is formed of a material blank,
which has been either pre-manufactured or has been vacuum deposited
as a planar or cylindrical film. The web-stent 121 is formed by
masking regions of the material blank which are to form a plurality
of structural scaffold members 122, and then etching the unmasked
regions which then form interstitial webs 124 which subtend
interstitial regions between adjacent structural scaffold members
122. The interstitial webs 124 are etched to a material thickness
that is less than the thickness of the plurality of structural
scaffold members 122. It is preferable to impart a plurality of
openings in the interstitial webs 124 in order to permit
endothelialization of the luminal surface 126 of the interstitial
webs 124. The openings may be imparted as a random pattern or as a
regular pattern in the interstitial web 124, as will be discussed
hereinafter.
[0103] With reference to FIG. 11 there is depicted a covered
scaffold 130 in accordance with one embodiment. Covered scaffold
130 is formed either from a tubular or planar material blank, which
is etched to form the plurality of structural scaffold members 132
and interstitial regions 134 between the structural scaffold
members 132. In addition, either or both a proximal 136 or a distal
138 cover region of the scaffold are provided and project outwardly
from terminal structural scaffold members 132. The proximal graft
region 136 and the distal graft region 138 are preferably etched to
a reduced thickness of less than the thickness of the structural
scaffold members, and are made with openings passing there through
which promote cellular migration and exclude embolic material.
[0104] Under certain applications it may be useful to employ the
covered scaffold 130 with either or both of the proximal 136 or
distal 138 graft regions projecting outwardly from the structural
supports 132 (FIG. 11).
[0105] An alternative embodiment is illustrated in FIGS. 12 and 13.
The alternative embodiment of the covered scaffold 130 involves
covering the luminal and/or abluminal surfaces of a plurality of
structural supports 132 with a luminal cover 136a and an abluminal
cover 138a. The luminal cover 136a may initially be formed as the
proximal graft region 136 in FIG. 11 and be luminally inverted 139
and passed into the lumen defined by the structural scaffold
members 132. The abluminal cover 138a may initially be formed as
the distal cover region 138 in FIG. 11 and be abluminally everted
137 over the structural scaffold members 132. Alternatively, the
luminal cover 136a and the abluminal cover 138a may be formed as
either pre-fabricated discrete cover members made of biocompatible
metal or metal-like materials that engaged about the plurality of
structural scaffold members 132. Portions of each of the abluminal
cover 138a and the luminal cover 136a are mechanically joined to
the plurality of structural scaffold members 132 or to one another,
thereby effectively encapsulating the plurality of structural
scaffold members 132 between the luminal cover 136a and the
abluminal cover 138a. It is preferable that opposing free ends of
each of the abluminal cover 138a and luminal cover 136a be joined
to and co-terminus with a terminal portion of the plurality of
structural scaffold members 132. Joining may be by mechanical
means, such as welding, suturing, adhesive bonding, soldering,
thermobonding, riveting, crimping, or dovetailing, or by
deposition, such as by vacuum deposition, chemical vapor deposition
or electrochemical deposition. In accordance with an alternate
embodiment, the interstitial regions may be subtended by a web 134,
as discussed hereinabove, with reference to FIGS. 9 and 10.
[0106] Those of ordinary skill in the art, will understand and
appreciate that alternative methods of removing material from areas
that form relatively thinner regions of the stent, web-stent or
stent-graft may be employed. For example, in addition to chemical
etching, relatively thinner regions may be formed by removing bulk
material by ion milling, laser ablation, EDM, laser machine,
electron beam lithography, reactive ion etching, sputtering or
equivalent methods which are capable of reducing the thickness of
the material in either the graft region or the interstitial web
region between the structural scaffold members. Alternatively, the
structural scaffold members may be added to the defined
interstitial web or graft regions to form the device, or the
interstitial web or graft regions may be added to pre-existing
structural scaffold members. Additive methods that may be employed
include conventional metal forming techniques, including
laminating, plating, or casting.
[0107] Similarly, a wide variety of initial bulk material
configurations may be employed, including a substantially planar
sheet substrate, an arcuate substrate or a tubular substrate, which
is then processed by either subtractive or additive techniques
discussed above.
[0108] By forming the structural scaffold members, the interstitial
web and/or the graft of an integral, monolithic material, both the
circumferential or hoop strength of the resultant device, as well
as the longitudinal or columnar strength of the device are enhanced
over conventional stent-graft devices. Additional advantages of the
alternative embodiments, depending upon fabrication methods, may
include: controlled homogeneity and/or heterogeneity of the
material used to form the device by deposition methodologies,
enhanced ability to control dimensional and mechanical
characteristics of the device, the ability to fabricate complex
device conformations, ability to pattern and control the porosity
of the web and/or graft regions, and a monolithic one-piece
construction of a device which yields a minimized device profile
and cross-sectional area. The devices of the alternative
embodiments have relatively thicker and thinner regions, in which
the thinner regions permit radial collapse of the device for
endoluminal delivery. The inventive device exhibits superior column
strength that permits smaller introducer size and more readily
facilitates deployment of the device.
[0109] As illustrated in FIGS. 14 and 15, the web and/or cover
regions, 144, 154 between adjacent structural scaffold members 142,
152 may be co-planar with either the luminal or abluminal surface
of the structural scaffold members 142, or may be positioned
intermediate the luminal 151 and abluminal 156 surfaces of the
structural scaffold members 152.
[0110] In accordance with a preferred embodiment, the web regions
of the inventive web-stent, the graft regions of the inventive
stent-graft and the inventive graft have a plurality of openings
which pass through the thickness of the material used to fabricated
the inventive devices. Each of the plurality of openings is
dimensioned to permit cellular migration through the opening
without permitting blood leakage or seepage through the plurality
of openings. The plurality of openings may be random or may be
patterned. However, in order to control the effective porosity of
the device, it is desirable to impart a pattern of openings in the
material used to fabricate the inventive device.
[0111] FIGS. 16A-16C depict several non-limiting examples of
patterned openings in a section of material used to make the
inventive covered scaffold devices in accordance with one
embodiment. FIG. 16A depicts a material 160 with a plurality of
circular openings 164 passing through the material substrate 162.
The plurality of circular openings is patterned in a regular array
of rows and columns with regular inter-opening spacing 165 between
adjacent openings. In the particular embodiment illustrated the
diameter of each of the plurality of openings is about 19 .mu.m,
with an inter-opening spacing in each row and column of about 34
.mu.m on center. The thickness of the material 162 is preferably
between about 0.5 .mu.m and about 10 .mu.m. FIG. 16B illustrates
another example of a pattern of a plurality of openings useful in
the alternative embodiments. The material 162 has a plurality of
openings 166 and 167 passing there through. The pattern of the
plurality of openings 166 and 167 is an alternating slot pattern in
which the plurality of openings 166 are arrayed adjacent one
another forming a y-axis oriented array 168 relative to the
material 162, while a plurality of openings 167 are arrayed
adjacent one another forming an x-axis oriented array 169 relative
to the material 162. The y-axis-oriented array 168 and the
x-axis-oriented array 169 are then positioned adjacent one and
other in the material 162. In this particular example, the
inter-array spacing between the y-axis-oriented array 168 and the
x-axis-oriented array 169 is about 17 .mu.m, while each of the
plurality of openings has a length of about 153 .mu.m and a width
of about 17 .mu.m. An alternative design for the plurality of
openings 167 and 168 is to orient all of the openings such that
each slot opening has a longitudinal axis oriented along a common
axis as the other slot openings. In this manner, the openings 167
and 168 may all be oriented along either the longitudinal axis or
circumferential axis of the cover material 160. Finally, FIG. 16C
illustrates a material 160 in which the material substrate 162 has
a regular array of a plurality of diamond-shaped openings 163
passing through the material substrate 162. As with the alternative
embodiments exemplified in FIGS. 16A and 16B, the dimension of the
plurality of diamond-shaped openings 163 is of sufficient size to
permit cellular migration through the openings 163, while
preventing blood flow or seepage, and the passage of embolic
material through the plurality of openings 163.
[0112] FIGS. 17A and 17B illustrate alternate preferred embodiments
of graft 170 and graft 180 in accordance with one embodiment. Graft
170 consists generally of concentrically positioned luminal graft
member 174 and abluminal graft member 172 and an interfacial region
176 where the luminal surface of the abluminal graft member 172 and
the abluminal surface of the luminal graft member 74 are in
immediate juxtaposition with one another. Both the luminal 174 and
the abluminal 172 graft members are fabricated in accordance with
the methodologies described above, and are provided with a
plurality of patterned openings 173 in the abluminal graft member
172 and a plurality of patterned openings 175 in the luminal graft
member 174.
[0113] The plurality of patterned openings 173 and 175 are
positioned out of phase relative to one another. By positioning the
plurality of patterned openings 173 and 175 in an out-of-phase
relationship, there is no continuous opening that passes through
the interfacial region 76 which would permit blood flow or seepage
from the lumen of the graft. However, in order to permit cellular
migration from the abluminal surface of the graft to the lumen of
the graft, the interfacial region 176 should have microroughness
[not shown] which is oriented either randomly or selectively, such
as helically or circumferential, about the interfacial region 176.
The microroughness preferably has a peak-to-valley depth of between
about 5 .mu.m to about 65 .mu.m most preferably between about 10
.mu.m to 15 .mu.m, may be either on the luminal surface of the
abluminal graft 172 or on the abluminal surface of the luminal
graft 174, or both. The microroughness spans the surface area
region between adjacent pairs of openings 173, 175, and the
microroughness depth permits cellular migration across the surfaces
between adjacent openings 173 and 175. The microroughness is not
large enough to permit fluid passage through the inter-opening
regions at the interface 176 between the luminal graft 174 and the
abluminal graft 172. This property of permitting cellular growth is
similar to the difference between the porosity of expanded
polytetrafluoroethylene grafts which do not require pre-clotting,
and the much larger porosity of polyester or DACRON grafts which
require pre-clotting to prevent fluid seepage there from.
[0114] FIG. 17B illustrates an alternative embodiment of the
inventive graft 180 in which an abluminal graft member 182 is
concentrically positioned about a luminal graft member 184.
[0115] Each of the abluminal graft member 182 and the luminal graft
member 184 having a plurality of patterned openings 183, 185,
respectively, passing there through. As with the embodiment
depicted in FIG. 17A, the plurality of patterned openings 183 and
185 are positioned in an out-of-phase relationship to one another
in order to prevent forming a continuous opening between the
luminal and abluminal surfaces of the graft 180. However, unlike
the embodiment in FIG. 17A, there is no corresponding interfacial
region 176. Rather, an annular open region 187 is positioned
intermediate the luminal graft member 184 and the abluminal graft
member 182. The annular open region 187 is created by providing a
plurality of microprojections 186 that project either radially
inward from the luminal surface of the abluminal graft member 182
or radially outward from the abluminal surface of the luminal graft
member 184. The plurality of microprojections 186 may also comprise
a scaffold member interdisposed between the concentric graft
members 184, 182. The plurality of microprojections 186 or scaffold
member act as spacers which abut the opposing surface of either the
luminal graft member 184 or the abluminal graft member 182 which
bound the annular open region 187. The height of the
microprojections 186 and, therefore, the size of the annular open
region 187, are dimensioned such that cells may migrate through the
annular open region 187, while blood flow or seepage will not occur
between the lumen and the abluminal surface of the graft 180.
[0116] According to a specific aspect of the graft embodiment, the
size of the plurality of openings in the luminal graft member 174,
184 may be different than the size of the plurality of openings in
the abluminal graft member 172, 182. For example, the plurality of
openings in the abluminal graft member 172, 182 preferably have a
larger size than the plurality of openings in the luminal graft
member 174, 184, while still retaining the out-of-phase
relationship between the plurality of openings in the luminal 174,
184 and the abluminal 172, 182 graft members. Where circular
openings are provided, it is preferable that the luminal 172, 182
and the abluminal 174, 184 graft members have openings having
diameters of between about 5 .mu.m and 100 .mu.m.
[0117] Additionally, a third member may be interposed between the
luminal 174, 184 and the abluminal 182, 172 graft members. The
third member will preferably have a very fine plurality of
openings, such as on the order of between 2-10 .mu.m and permits
use of a higher porosity in the luminal and abluminal grafts,
without the need to maintain an out-of-phase relationship between
the openings in the luminal 174, 184 and the abluminal 172, 182
graft members.
[0118] The following examples are provided in order to illustrate
the alternative embodiments of the invention, and are not intended
to limit the scope of the invention.
EXAMPLE 1
Stent-Graft Formation
[0119] A self-expanding nickel-titanium stent was expanded and
concentrically engaged about a 1.77 mm diameter copper substrate.
The stent-substrate assembly was introduced into a sputter
deposition chamber with a copper target. Copper was sputter
deposited onto the stent-substrate assembly while the substrate was
rotated. A negative voltage bias was applied. Deposition was
allowed to run for about 4.5 hours to deposit a 300 .mu.m thick
film of copper. The deposition chamber was quenched with
nitrogen.
[0120] The copper layer is planarized to expose the upper surfaces
of the stent while leaving the copper layer present in interstices
of the stent. The copper coated stent-substrate assembly was then
introduced into a sputter deposition reactor and cleaned by glow
discharge cleaning, a nickel-titanium target was employed to
sputter deposit a 15 .mu.m layer of NiTi onto the stent-substrate
assembly during a 3.0 hour deposition run in the presence of a
negative bias voltage. The reactor chamber was quenched with cold
argon.
[0121] The NiTi coated stent-substrate was then placed into a
nitric acid bath to selectively etch the copper substrate and the
sacrificial copper from the stent and NiTi coating. It was found
that the NiTi coating and the stent were well-adhered to each
other.
EXAMPLE 2
Covered Stent Formation
[0122] A self-expanding nickel-titanium stent or a balloon
expandable stainless steel stent having proximal and distal welding
pad extensions is concentrically engaged onto a cylindrical copper
substrate such that the outer diameter of the stent is between 5-10
.mu.m less than the desired inner diameter of the cover to be
deposited. The stent-substrate assembly is introduced into a
sputter deposition reactor and copper is sputter deposited onto the
stent-substrate assembly to a thickness at least equal to the
thickness of the stent struts. The copper coated stent-substrate
assembly is then removed from the sputter deposition reactor and
mechanically polished such that the upper surfaces of the proximal
and distal welding pad extensions are exposed, but a copper layer
having a thickness between about 5-20 .mu.m remains on the
remainder of the stent and substrate. The assembly is then
re-loaded into the sputter deposition reactor and back sputtered
(such as by glow discharge) to remove oxide formed on the proximal
and distal weld-pads, then NiTi is sputter deposited onto the
assembly to a thickness of 4.5 .mu.m covering the proximal and
distal welding pad extensions of the stent, and the copper layer. A
pattern of openings are formed through the NiTi film layer
overlaying the copper film and those areas of the NiTi film
overlaying the proximal and distal welding pad extensions. The
assembly may then be introduced into a holding catheter and etched
in a nitric acid etchant to remove the copper substrate and copper
deposited layer.
EXAMPLE 3
Electrochemical Formation of Stent Patterned Substrate
[0123] A balloon expandable stainless steel stent was obtained and
expanded to approximately a 3 mm inner diameter. Copper was plated
onto the stent using a H.sub.2O/Cu.sub.3(SO.sub.4).sub.2/glycerol
solution with 1.5V applied for 30 seconds. The plating was burned
and removed with a hot nitric acid solution. The surface was
activated by applying -6.0V in the
H.sub.2O/Cu.sub.3(SO.sub.4).sub.2/glycerol solution. The plated
stent was sonicated in water to remove copper dust. The plated
stent was then plated for 20 min. at 1.3V in the same
H.sub.2O/Cu.sub.3(SO.sub.4).sub.2/glycerol solution. The copper
layer was continuous over the surface of the stent, but flaked upon
manual manipulation of the stent. The activation step was repeated
for 5 seconds using 6.0V for cleaning and activation. The stent was
left submerged in solution and plated at -1.0V for 10 seconds
forming a very thin layer with improved adhesion to the stainless
steel. The plated stent was capable of manual manipulation,
crimping and re-expansion, with the adherent copper film remaining
substantially continuous and adherent.
EXAMPLE 4
Method for Forming Monolithic Covered Stent
[0124] A tubular copper substrate was obtained. A negative imprint
of a desired stent pattern was imparted onto the copper substrate
either using the embossing die or a gravure calendaring roller
having the desired stent pattern. The negative stent pattern is
transferred onto the tubular copper substrate as a recessed pattern
within the surface of the copper substrate by physically pressing
the positive stent pattern onto the surface. Nitinol was then
sputter deposited onto the copper substrate with the embossed stent
pattern. After sputter deposition of the nitinol, the surface of
the copper substrate plus deposited nitinol was planarized. The
surface was subjected to glow discharge to clean the surface. A
thin layer of nitinol was deposited onto the cleaned surface to
form a thin film nitinol cover. The copper elements were chemically
removed to release the stent with thin film nitinol cover. The
stent and nitinol cover complex forming a substantially monolithic
device.
EXAMPLE 5
Alternative Method for Forming Monolithic Covered Stent
[0125] A nitinol stent was fitted over a copper mandrel. A thin
film of copper, approximately 300 .mu.m in thickness, was deposited
onto the copper mandrel fitted with the nitinol stent. The surface
was planarized so that the nitinol stent was exposed and the
surface was level, including surface between the nitinol and copper
portions. The covered mandrel was subjected to glow discharge to
clean the surface. After cleaning, a thin film nitinol cover was
deposited onto the planarized and cleaned surface. The copper
portions were removed, e.g., chemically etching copper, to result
in a stent covered with a thin film nitinol cover. The overall
structure has substantially monolithic characteristics.
EXAMPLE 6
Alternative Method for Forming Monolithic Covered Stent
[0126] A copper mandrel is obtained having a recessed stent pattern
on its surface. A stent having the corresponding stent pattern is
engaged into the recessed stent pattern in the mandrel so that the
top surface of the stent is substantially co-planar with the
non-recessed portions of the substrate's surface. The copper
mandrel plus the fitted stent was subjected to glow discharge and
the surface was cleaned. A continuous nitinol cover is vacuum
deposited onto the stent and copper mandrel. The copper mandrel is
removed by etching in a nitric acid etchant with the stent and
formed NiTi film cover being adherent to the stent. The overall
structure has substantially monolithic characteristics.
EXAMPLE 7
Method for Forming Stent having Multiple Microporous Covers
[0127] Iliac leg stent segments were glued to a 1/2 inch copper
mandrel with 1/4 inch adaptors at the ends covered with Kapton
tape. The copper mandrel having circular grooves to index segments.
Low Ap covers (20.degree. C. to 30.degree. C.) 2.9 .mu.m
diameter.times.4.5 .mu.m were expanded and slid over the stent
segments, a second cover fitting over a first cover. The two covers
used were 2147/S3 and 2152/S3, both having the pattern R505. The
stent with two covers was welded with about 3000 welds throughout
the whole surface of the stent. After welding the covers onto the
stent, the combination was dipped in acetone to remove the glue.
The copper parts were then etched away.
EXAMPLE 8
Alternative Method for Forming Stent having Multiple Microporous
Covers
[0128] Iliac leg stent segments were glued to a 1/2 inch copper
mandrel with circular grooves to index segments. Low Ap covers
(20.degree. to 30.degree. C.) 2.9 .mu.m diameter.times.4.5 .mu.m
was expanded and slid over 22 mm section of the leg stent, while a
1/2 inch.times.7 .mu.m R106 circumferential section, approximately
70 mm in length, was slid over the 12.7 mm leg stent section. A
second cover was then expanded and slid over the first cover. The
covers used were 2150/S3, 2148/S3 and 2166/S3. The stent with two
covers was welded with about 3000 welds throughout the whole
surface of the stent. After welding the covers onto the stent, the
combination was dipped in acetone to remove the glue. The copper
components were then etched in a nitric acid etchant.
[0129] 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.
* * * * *