U.S. patent application number 11/435508 was filed with the patent office on 2006-12-07 for medical device including remodelable material attached to frame.
This patent application is currently assigned to Cook Incorporated. Invention is credited to Brian C. Case, Sean D. Chambers, Jacob A. Flagle, Ram H. JR. Paul.
Application Number | 20060276882 11/435508 |
Document ID | / |
Family ID | 46324499 |
Filed Date | 2006-12-07 |
United States Patent
Application |
20060276882 |
Kind Code |
A1 |
Case; Brian C. ; et
al. |
December 7, 2006 |
Medical device including remodelable material attached to frame
Abstract
Medical devices for implantation in a body vessel, and methods
of using and making the same, are provided. Medical devices
preferably comprise a remodelable material attached to a frame with
a tension that can change upon implantation of the medical device
within the lumen of a body vessel. Controlled fracture or
bioabsorption of frame material can, in some embodiments, decrease
the tension on the remodelable material after implantation. The
remodelable material can form one or more valve leaflets adapted to
regulate fluid flow in a body vessel, such as a vein.
Inventors: |
Case; Brian C.;
(Bloomington, IN) ; Flagle; Jacob A.;
(Indianapolis, IN) ; Paul; Ram H. JR.;
(Bloomington, IN) ; Chambers; Sean D.;
(Bloomington, IN) |
Correspondence
Address: |
BRINKS HOFER GILSON & LIONE/INDY/COOK
ONE INDIANA SQUARE
SUITE 1600
INDIANAPOLIS
IN
46204-2033
US
|
Assignee: |
Cook Incorporated
Bloomington
IN
|
Family ID: |
46324499 |
Appl. No.: |
11/435508 |
Filed: |
May 17, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11103137 |
Apr 11, 2005 |
|
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11435508 |
May 17, 2006 |
|
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60681863 |
May 17, 2005 |
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Current U.S.
Class: |
623/1.24 ;
623/2.18; 623/23.68 |
Current CPC
Class: |
A61F 2250/0071 20130101;
A61F 2/07 20130101; A61F 2002/075 20130101; A61F 2/2418 20130101;
A61F 2/86 20130101; A61F 2230/0071 20130101; A61F 2/2475 20130101;
A61F 2/90 20130101; A61F 2210/0004 20130101; A61F 2220/0058
20130101; A61F 2220/0016 20130101; A61F 2250/0018 20130101; A61F
2220/005 20130101; A61F 2220/0075 20130101; A61F 2250/0031
20130101 |
Class at
Publication: |
623/001.24 ;
623/002.18; 623/023.68 |
International
Class: |
A61F 2/06 20060101
A61F002/06 |
Claims
1. An endolumenal medical device comprising a support frame having
a support member with a weakened frame portion; and a remodelable
material attached to the support frame at two or more attachment
points with a tension between the first attachment point and the
second attachment point; wherein the controlled fracture of the
support member at the weakened frame portion or the reduction of
the cross sectional area of the support member at the weakened
frame portion results in a decrease in the tension of the
remodelable material between the first attachment point and the
second attachment point.
2. The medical device of claim 1, wherein the remodelable material
is attached to the support member.
3. The medical device of claim 2, wherein the weakened frame
portion is positioned along the support member and between at least
two of the attachment points.
4. The medical device of claim 3, wherein the support member
defines the perimeter of an opening in the support frame having
three or more sides and the attachment points are positioned along
the perimeter of the opening.
5. The medical device of claim 4, wherein the opening in the
support frame is covered by the remodelable material.
6. The medical device of claim 1, wherein the support frame is
configured as a tubular, radially compressible structure having a
lumenal surface defining a tubular lumen and comprising a plurality
of support members defining the tubular lumen of the support
frame.
7. The medical device of claim 6, wherein the remodelable material
is configured as a tube attached to the support frame.
8. The medical device of claim 1, wherein the remodelable material
is configured as a valve leaflet having at least two sides attached
to the support frame.
9. The medical device of claim 1, wherein the remodelable material
is an extracellular matrix material (ECM).
10. The medical device of claim 1, wherein the material is small
intestine submucosa (SIS).
11. The medical device of claim 1, wherein the medical device has a
substantially tubular structure defining a cylindrical lumen
containing a longitudinal axis of the medical device extending
therethrough; wherein the controlled fracture of the support member
at the weakened frame portion decreases the tension of the
remodelable material in a first direction that is substantially
parallel to the longitudinal axis of the medical device.
12. The medical device of claim 11, wherein the weakened frame
portion is a controlled fracture initiation point.
13. The medical device of claim 11, wherein the reduction of the
cross sectional area of the support member at the weakened frame
portion decreases the tension of the remodelable material in the
first direction.
14. The medical device of claim 13, wherein the weakened frame
portion comprises a bioabsorbable material.
15. The medical device of claim 1, wherein the support frame is a
radially self-expanding frame.
16. The medical device of claim 15, wherein at least a portion of
the remodelable material is configured as a valve leaflet attached
to the support member comprising the weakened frame portion, such
that the tension on the valve leaflet in a first direction
perpendicular to a longitudinal axis of the medical device is
reduced by the controlled fracture of the support member at the
weakened frame portion or the reduction of the cross sectional area
of the support member at the weakened frame portion.
17. An endolumenal valve comprising a radially-expandable support
frame including an arcuate support member comprising a weakened
frame portion and at least one bend positioned between two struts;
and a valve leaflet comprising a remodelable material tensionably
attached to the two struts of the arcuate support member; the
remodelable material having a first tension between the two struts,
wherein fracturing of the weakened frame portion or a decrease in
the cross sectional area of the weakened frame portion of the
arcuate support member decreases the first tension of the
remodelable material.
18. The endolumenal valve of claim 17, wherein the endoluminal
valve defines a substantially tubular lumen having a longitudinal
axis of the endoluminal valve passing therethrough, and the two
struts of the arcuate support member are substantially parallel to
the longitudinal axis.
19. The endolumenal valve of claim 17, wherein the remodelable
material comprises small intestine submucosa.
20. The endolumenal valve of claim 17, wherein the valve leaflet is
subject to a force of between about 1-5N between the two struts of
the arcuate support member.
21. A method of treating a subject presenting symptoms of venous
valve insufficiency, varicose veins, esophageal reflux, restenosis
or atherosclerosis comprising the step of endolumenally implanting
a valve comprising a support frame having an arcuate member
comprising a weakened frame portion and at least one bend
positioned between two struts; and a valve leaflet comprising a
remodelable material tensionably attached to the two struts of the
arcuate member, the remodelable material having a first tension in
a first direction, wherein fracturing the weakened frame portion or
decreasing the cross sectional area of the weakened frame portion
decreases the tension of the remodelable material in the first
direction.
Description
[0001] This application is a continuation-in-part of co-pending
U.S. patent application Ser. No. 11/103,137, filed Apr. 11, 2005
(Case et al.), which is incorporated herein by reference in its
entirety; this application also claims the benefit of U.S.
provisional patent application Ser. No. 60/681,863, filed May 17,
2005 (Case et al.), which is also incorporated herein by reference
in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to medical devices. More
particularly, the invention relates to medical devices for
implantation in a body vessel.
BACKGROUND
[0003] Various implantable medical devices are advantageously
inserted within various body vessels, for example from an
implantation catheter. Minimally invasive techniques and
instruments for placement of intralumenal medical devices have been
developed to treat and repair such undesirable conditions within
body vessels, including treatment of venous valve insufficiency.
Intralumenal medical devices can be deployed in a vessel at a point
of treatment, the delivery device withdrawn from the vessel, and
the medical device retained within the vessel to provide sustained
improvement in vascular valve function. For example, implantable
medical devices can function as a replacement venous valve, or
restore native venous valve function by bringing incompetent valve
leaflets into closer proximity. Such devices can comprise an
expandable frame configured for implantation in the lumen of a body
vessel, such as a vein. Venous valve devices can further comprise
features that provide a valve function, such as opposable
leaflets.
[0004] Implantable medical devices can comprise frames that are
highly compliant, and therefore able to conform to both the shape
of the lumen of a body vessel as well as respond to changes in the
body vessel shape. Dynamic fluctuations in the shape of the lumen
of a body vessel pose challenges to the design of implantable
devices that conform to the interior shape of the body vessel. The
shape of a lumen of a vein can undergo dramatic dynamic change as a
result of varying blood flow velocities and volumes there through,
presenting challenges for designing implantable intralumenal
prosthetic devices that are compliant to the changing shape of the
vein lumen.
[0005] For some applications, an implantable frame having a radial
strength that varies over time upon implantation is desirable. In
particular, optimizing the degree to which a medical device for
implantation within a body vessel is compliant to changes in the
shape of the body vessel can involve consideration of various
factors. For example, a medical device comprising a highly
compliant frame can minimize distortion of a body vessel by being
highly responsive to changes in the shape of the body vessel.
[0006] For treatment of many conditions, it is desirable that
implantable medical devices comprise remodelable material.
Implanted remodelable material provides a matrix or support for the
growth of new tissue thereon, and remodelable material is resorbed
into the body in which the device is implanted. Common events
during this remodeling process include: widespread
neovascularization, proliferation of granulation mesenchymal cells,
biodegradation/resorption of implanted remodelable material, and
absence of immune rejection. By this process, autologous cells from
the body can replace the remodelable portions of the medical
device.
[0007] Mechanical loading of remodelable material during the
remodeling process has been shown to advantageously influence the
remodeling process. For example, the remodeling process of one type
of remodelable material, extracellular matrix (ECM), is more
effective when the material is subject to certain types and ranges
of mechanical loading during the remodeling process. See, e.g., M.
Chiquet, "Regulation of extracellular matrix gene expression by
pressure," Matrix Biol. 18(5), 417-426 (October 1999). Mechanical
forces on a remodelable material during the remodeling process can
affect processes such as signal transduction, gene expression and
contact guidance of cells. See, e.g., V C Mudera et al., "Molecular
responses of human dermal fibroblasts to dual cues: contact
guidance and mechanical load," Cell Motil. Cytoskeleton, 45(1):1-9
(June 2000). An earlier study by C A Tozzi et al, found that: (1)
pulmonary vascular endothelial cells responded to mechanical
tension by producing PDGF-like material and (2) a 4-hour
application of 50 mmHg hydrostatic pressure to cultured pulmonary
artery endothelial cells induced v-sis expression, suggesting that
"certain vascular cells can respond to an applied load by
elaborating factors that affect growth and matrix production of
surrounding cells in the blood vessel wall." See C A Tozzi et al.,
"Pressure-induced connective tissue synthesis in pulmonary artery
segments is dependent on intact endothelium," J Clin Invest. 84(3),
pp. 1005-1012,1011 (1989).
[0008] Therefore, a highly compliant frame with minimal radial
strength may provide inadequate mechanical loading to material
attached to the frame to allow or promote certain desirable
processes to occur within the attached material, such as
remodeling, or within the body vessel. In some instances, frame
radial strength can be a trade-off between enabling the remodeling
of material attached to the frame, and minimizing the distortion or
disruption of the body vessel. Implantable endolumenal stent frames
comprising a tubular, radially compressible and axially flexible
structure having one or more controlled fracture initiation sites
have been disclosed, for example, in published U.S. patent
application Ser. No. 10/742,943 by Stinson, published as
US2004/0138738 A1. However, there still exists a need in the art
for an implantable prosthetic device frame that is capable of
balancing concerns of conforming to the shape of a body vessel
lumen and providing optimal tension on a remodelable material
attached to the frame.
[0009] What is needed are medical devices that provide a radial
strength that changes over time so as to provide a reduced amount
of tension on a remodelable material after implantation within a
body vessel for a desired period of time.
SUMMARY
[0010] Implantable frames with radial strength that can vary with
time under certain conditions are adapted to provide desired levels
of radial strength upon implantation within a body vessel. Medical
devices with variable radial strength can provide, for example, an
optimal amount of tension on an attached remodelable material
during the remodeling process, and then provide increased radial
strength and minimal body vessel distortion after the remodeling
process is completed.
[0011] Endolumenal medical devices are provided that comprise a
support frame and a remodelable material maintained under tension
in a first direction by the support frame. The support frame
preferably includes a means for reducing the tension on the
remodelable material in the first direction, such as a weakened
frame portion. Preferably, the remodelable material is tensionably
attached to the support frame to maintain the remodelable material
under tension in a first direction. The weakened frame portion is
preferably adapted to reduce the tension on the remodelable
material after a desired period of implantation within a body
vessel. For example, the tension on the remodelable material can
decrease when the weakened frame portion fractures or weakens after
a period of time effective for the formation of remodeled tissue in
place of the remodelable material. The endolumenal medical device
can have any suitable configuration and function, including valves,
stents, grafts, stent grafts, and shunts.
[0012] For example, an endolumenal medical device may comprise a
support frame including a frame member having a weakened frame
portion and a valve leaflet comprising a remodelable material
tensionably attached between the two struts of the frame member;
the remodelable material having a first tension in a first
direction, wherein fracturing of the weakened frame portion or a
decrease in the cross sectional area of the weakened frame portion
of the arcuate member decreases the tension of the remodelable
material in the first direction.
[0013] The endolumenal medical device is preferably configured as a
valve means for providing substantially unidirectional fluid flow
through a body vessel. The valve means can include a valve leaflet
attached to a support frame along at least one edge of the valve
leaflet to a portion of the support frame comprising the weakened
frame portion. Preferably, attachment of the valve leaflet to the
support frame provides a tension on the valve leaflet in a first
direction perpendicular to the direction of fluid flow through the
valve means, and the tension can be reduced by weakening the
support member. Weakening of the support member preferably occurs
by the controlled fracture of the support member at the weakened
frame portion or the reduction of the cross sectional area of the
support member at the weakened frame portion.
[0014] Preferably, the endolumenal medical device is a
percuteneously implantable valve formed by attaching a remodelable
material to a radially expandable support frame having a weakened
frame portion. The remodelable material can form a valve leaflet
attached to the support frame with a first tension in a first
direction; wherein weakening of the support member by the
controlled fracture of the support member at the weakened frame
portion or the reduction of the cross sectional area of the support
member at the weakened frame portion results in a decrease in the
tension of the remodelable material in the first direction. The
remodelable material is preferably attached to the support member
at two or more attachment points. A controlled fracture initiation
site can be positioned between at least two of the attachment
points. The support member can define the perimeter of an opening
in the support frame having three or more sides and the attachment
points are positioned along the perimeter, and the opening in the
support frame is preferably covered by the remodelable material
maintained under tension by attachment to the support frame. The
valve leaflet is preferably attached to a support member on at
least two sides, and positioned within the tubular lumen of the
support frame. The support frame can be configured as a tubular,
radially compressible structure having a lumenal surface defining a
tubular lumen and comprising a plurality of support members
defining the tubular lumen the support frame. The remodelable
material can be configured as a tube attached to the support frame
to form a stent graft or other fluid conduit.
[0015] In a first embodiment, the weakened frame portion is a
controlled fracture initiation site. Weakening of the support
member by the controlled fracture of the support member at the
weakened frame portion preferably results in a decrease in the
tension of the remodelable material. The controlled fracture
initiation site can include any suitable material adapted to
fracture in a controlled manner after exposure to physiological
conditions, such as conditions within a body vessel, for example in
response to any suitable condition that could be present in a body
vessel, such as physical conditions (e.g., physical deformation,
temperature, pH, dissolution, fluid pressure, and the like) or
biochemical processes (e.g., enzyme digestion, chemical reactions,
and the like). The controlled fracture initiation site may also be
designed to fracture after a desirable period of time, such as the
time for a process occurring during tissue remodeling. For example,
a frame may fracture after substantial growth of endothelial cells
around or into the frame. Preferably, the medical device is
designed to protect the body vessel from damage during or after the
fracture of the frame material.
[0016] In a second embodiment, a medical device can comprise one or
more bioabsorbable materials. Upon implantation, absorption of the
bioabsorbable material within the body can reduce the cross
sectional area of the support frame at the weakened frame portion,
thereby increasing the flexibility of the support frame at the
weakened frame portion. Weakening of the support member by the
reduction of the cross sectional area of the support member at the
weakened frame portion preferably results in a decrease in the
tension of the remodelable material in the first direction. In one
aspect, absorption of a biomaterial can decrease the radial
strength of an implanted frame, for example by reducing the cross
section or surface area of a portion of the frame. In another
aspect, absorption of the bioabsorbable material can allow for the
controlled fracture of a portion of the frame, resulting in a
sudden change in the radial strength of the frame. The frame
itself, or any portion of the frame, can be made from a
bioabsorbable material.
[0017] The implantable medical devices can be used, for example, in
methods of treating a subject, which can be animal or human,
comprising the step of implanting one or more medical devices as
described herein. In some embodiments, methods of treating may also
include the step of delivering a medical device to a point of
treatment in a body vessel, or deploying a medical device at the
point of treatment. Some methods further comprise the step of
implanting one or more medical devices each comprising a frame
attached to one or more valve leaflets, as described herein.
Methods for treating certain conditions are also provided, such as
venous valve insufficiency, varicose veins, esophageal reflux,
restenosis or atherosclerosis.
[0018] Methods for delivering a medical device to any suitable body
vessel are also provided, such as a vein, artery, biliary duct,
ureteral vessel, body passage or portion of the alimentary canal.
In some embodiments, medical devices having a frame with a
compressed delivery configuration with a very low profile, small
collapsed diameter and great flexibility, may be able to navigate
small or tortuous paths through a variety of body vessels. A
low-profile medical device may also be useful in coronary arteries,
carotid arteries, vascular aneurysms, and peripheral arteries and
veins (e.g., renal, iliac, femoral, popliteal, sublavian, aorta,
intercranial, etc.). Other nonvascular applications include
gastrointestinal, duodenum, biliary ducts, esophagus, urethra,
reproductive tracts, trachea, and respiratory (e.g., bronchial)
ducts. These applications may or may not require a sheath covering
the medical device. Some embodiments provide methods of making or
using medical devices as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1A is a schematic flat plan view of an implantable
frame.
[0020] FIG. 1B is a side view of the tubular configuration of the
implantable frame shown in FIG. 1A.
[0021] FIG. 2A is a detail view of a weakened frame portion of an
implantable frame comprising a fracture initiation site.
[0022] FIG. 2B is a detail view of the portion of an implantable
frame shown in FIG. 2A, after a controlled fracture of the frame
portion.
[0023] FIG. 3A is a cross sectional view of a weakened frame
portion of an implantable frame comprising a bioabsorbable material
disposed on the surface of a non-bioabsorbable material in a first
configuration.
[0024] FIG. 3B is a cross sectional view of a weakened frame
portion of an implantable frame comprising a bioabsorbable material
disposed on the surface of a non-bioabsorbable material in a second
configuration.
[0025] FIG. 3C is a detail view of a portion of the cross sectional
view in FIG. 3B.
[0026] FIG. 4A is a side view of an endolumenal valve formed by
attaching a pair of opposable valve leaflets to a frame comprising
weakened frame portions.
[0027] FIG. 4B is a rotated side view of the endolumenal valve
shown in FIG. 4A.
[0028] FIG. 4C is a top view of the endolumenal valve shown in FIG.
4A and FIG. 4B.
[0029] FIG. 5 is a rotated side view of a modified endolumenal
valve formed by removal of the weakened frame portions shown in the
endolumenal valve shown in FIGS. 4A-4C.
[0030] FIG. 6A is a top schematic view of a Flat Plate Fatigue
Testing Apparatus and FIG. 6B is a side schematic view of the
Apparatus of FIG. 6A.
DETAILED DESCRIPTION
[0031] The following detailed description and appended drawings
describe and illustrate various exemplary embodiments. Various
medical devices for implantation in a body vessel, methods of
making the medical devices, and methods of treatment that utilize
the medical devices are provided herein.
[0032] The invention provides medical devices for implantation in a
body vessel, methods of making the medical devices, and methods of
treatment that utilize the medical devices.
[0033] As used herein the terms "comprise(s)," "include(s),"
"having," "has," "contain(s)," and variants thereof, are intended
to be open-ended transitional phrases, terms, or words that do not
preclude the possibility of additional acts or structure.
[0034] The term "effective amount" refers to an amount of an active
ingredient sufficient to achieve a desired affect without causing
an undesirable side effect. In some cases, it may be necessary to
achieve a balance between obtaining a desired effect and limiting
the severity of an undesired effect. It will be appreciated that
the amount of active ingredient used will vary depending upon the
type of active ingredient and the intended use of the composition
of the present invention.
[0035] As used herein, the term "body vessel" means any body
passage cavity that conducts fluid, including but not limited to
biliary ducts, pancreatic ducts, ureteral passages, esophagus, and
blood vessels such as those of the human vasculature system.
[0036] As used herein, the term "implantable" refers to an ability
of a medical device to be positioned at a location within a body,
such as within a body vessel. Furthermore, the terms "implantation"
and "implanted" refer to the positioning of a medical device at a
location within a body, such as within a body vessel.
[0037] As used herein, "endolumenally," "intralumenal" or
"translumenal" all refer synonymously to implantation placement by
procedures wherein the medical device is advanced within and
through the lumen of a body vessel from a remote location to a
target site within the body vessel. As used herein, "endolumenally"
means placement by procedures wherein the prosthesis is
translumenally advanced through the lumen of a body vessel from a
remote location to a target site within the body vessel. In
vascular procedures, a medical device will typically be introduced
"endovascularly" using a catheter over a guidewire under
fluoroscopic guidance. The catheters and guidewires may be
introduced through conventional access sites to the vascular
system, such as through the femoral artery, or brachial and
subclavian arteries, for access to the coronary arteries.
[0038] The medical devices described herein are preferably radially
expandable. By "radially expandable," it is meant that the body
segment can be converted from a small diameter configuration (used
for endolumenal placement) to a radially expanded, usually
cylindrical, configuration which is achieved when the medical
device is implanted at the desired target site. A medical device
can be radially expanded by any suitable mechanism.
[0039] The term "biodegradable" is used herein to refer to
materials selected to dissipate upon implantation within a body,
independent of which mechanisms by which dissipation can occur,
such as dissolution, degradation, absorption and excretion. The
actual choice of which type of materials to use may readily be made
by one ordinarily skilled in the art. Such materials are often
referred to by different terms in the art, including
"bioresorbable," "bioabsorbable," or "biodegradable," depending
upon the mechanism by which the material dissipates. For the
purposes of this application, unless otherwise specified, the term
"biodegradable" includes materials that are "bioresorbable," and
"bioabsorbable." The prefix "bio" indicates that the erosion occurs
under physiological conditions, as opposed to other erosion
processes, caused by, for example, high temperature, strong acids
or bases, UV light or weather conditions. As used herein,
"biodegradable material" includes materials, such as a polymer or
copolymer, that are absorbed by the body, as well as materials that
degrade and dissipate without absorption into the body. As used
herein, "biodegradable polymer" refers to a polymer or copolymer
which dissipates upon implantation within the body. A large number
of different types of materials are known in the art which may be
inserted within the body and later dissipate.
[0040] "Non-bioabsorbable" material refers to a material, such as a
polymer or copolymer, which remains in the body without substantial
bioabsorption.
[0041] The recitation of a "first" direction is provided as an
example. Any suitable orientation or direction may correspond to a
"first" direction. The medical devices of the embodiments described
herein may be oriented in any suitable absolute orientation with
respect to a body vessel. For example, the first direction can be a
radial direction in some embodiments.
[0042] "Radial strength" (also called "hoop strength") refers to
the ability of a medical device to resist external circumferential
pressure directed radially inward toward the center of a cross
sectional area of the medical device, as measured by the change in
diameter of the medical device as a function of inward
circumferential pressure. A reduction in radial strength over time
is measured by comparing the frame displacement in response to a
force applied to the frame in the same manner at two different
points in time. Preferably, the radial strength is measured using a
Radial Force Gauge.
[0043] "Radial expansion force" refers to the outward radial force
exerted by the expansion of a medical device from a radially
compressed configuration.
[0044] Preferably, the medical device comprises a frame having a
first radial strength in an inward radial direction, and a material
or structure to decrease the radial strength of the frame along the
inward radial direction after implantation of the frame in a body
vessel. Also preferably, a decrease in radial strength occurs in
response to conditions within a body vessel. The decrease in radial
strength of the frame upon implantation can occur in several ways.
For example, a portion of a frame can be bioabsorbed or fracture in
a controlled fraction to reduce the radial strength of the frame.
In some embodiments, the frame can comprise various materials or
configurations to provide a reduced radial strength after a period
of time after implantation.
[0045] Preferably, the medical devices described herein comprise an
endolumenally-implantable frame having a first radial strength and
a means for reducing the radial strength within a body vessel.
Preferably, the frame is designed to undergo a reduction in radial
strength in response to conditions typically encountered in a body
vessel in which the frame is intended to be implanted. More
preferably, the frame is designed to undergo a reduction after a
desirable period of exposure to such conditions.
Medical Devices Comprising an Implantable Frame
[0046] In a first embodiment the medical device frame comprises a
material that is mechanically altered to reduce the radial strength
of the frame after exposure to one or more physiological
conditions, such as conditions within a body vessel, for a
desirable period of time. Mechanical alteration of the frame can
include increased flexibility of the frame, or portions thereof,
cracking or breaking of portions of the frame. The mechanical
alteration of the frame can result from any suitable condition,
including physical or biochemical characteristics found within a
body vessel.
[0047] In one aspect, the frame, or portions thereof, is designed
to bend, crack or break upon exposure of the frame to conditions
present in a body vessel for a desirable period of time. For
example, a frame can be designed to reduce its radial strength in
response to physical conditions within a body vessel. Physical
conditions in a body vessel include physical deformation or
movement, body temperature, fluid pH, degree of solubility of the
frame in fluid found in a body vessel, fluid pressure, and the
like. A frame can also be designed to reduce its radial strength in
response to biochemical conditions or processes within a body
vessel. Biochemical processes include enzyme digestion, chemical
reactions, and the like.
[0048] A frame may comprise one or more weakened frame portions
designed to undergo mechanical alteration in response to conditions
encountered in a body vessel. In one aspect, a frame comprises one
or more weakened frame portions positioned along the frame such
that mechanical alteration of the weakened frame portion reduces
the overall radial strength of the frame. A "weakened frame
portion" or "weakened frame portion" refer synonymously to the
relative stiffness or resistance of a weakened region to mechanical
alteration such as bending, cracking or breaking, compared to the
susceptibility of any adjacent region of the frame to such
mechanical alteration. In one aspect, the weakened frame portions
are bent frame regions that are more flexible than adjacent frame
regions. In another aspect, the weakened frame portions are more
likely to fracture (i.e., crack or break) after a desired period of
exposure to one or more physiological conditions in a body
vessel.
[0049] In one aspect, an implantable frame is a serpentine or
zig-zag structure comprising a plurality of parallel, adjacent
struts, some of which are joined by weakened frame portions between
pairs of struts. Referring to FIG. 1A, a flat plan view of an
implantable frame 10 includes a first hoop 14 connected to a second
hoop 18 by a plurality of struts 12, including struts labeled 12a,
12b, 12c, 12d, 12e, 12f and 12g. The implantable frame can be
assembled from a flat plan view in FIG. 1A to a cylindrical
configuration shown in FIG. 1B by "rolling" the frame to join
points A to A', B to B' and C to C'. FIG. 1B shows a side view of
the frame in FIG. 1A in the radially-expanded, cylindrical
configuration. The cylindrical configuration is radially symmetric
about a longitudinal axis 2 passing through the lumen of the frame
10. Preferrably, the frame 10 is formed in the cylindrical
configuration by laser-cutting the array of hoops 14, 18 and struts
12 from a cylinder of self-expanding material. The frame 10 may
further include a plurality of reinforcing members 20, including
reinforcing members 20a and 20b. The frame 10 in the cylindrical
configuration may be radially compressed around the longitudinal
axis 2 by crimping the frame around a catheter delivery device, and
then radially expanded at a site of implantation within a body
vessel to the radially expanded configuration of FIG. 1B.
[0050] The frame 10 may further include weakened frame portions 16a
and 16b, which are configured to reduce the radial expansion force
of the frame 10 when weakened or broken. The frame 10 is preferably
formed from a self-expanding material that permits the frame 10 to
exert a force directed radially outward from the longitudinal axis
2 when the frame 10 is less than fully radially expanded (i.e.,
when the frame 10 has a radius that is less than the fully-expanded
radius shown in FIG. 1B). The outward radial force of the frame 10
is reduced when the weakened frame portions 16a and/or 16b are
weakened or broken.
[0051] The relative weakness and strength of the various weakened
frame portions, such as weakened frame portion 16a, can be obtained
in a variety of ways. For example, it may be possible to
selectively treat individual frame regions with heat, radiation,
mechanical working, or combinations thereof, so that the mechanical
characteristics of the hinge region are altered, i.e., so that
selected hinge regions will bend, crack or break with a greater or
lesser force than others of the hinge regions.
[0052] In one aspect, the strength of the weakened frame portions
can be controlled by selecting the relative cross-sectional
dimensions of the different frame regions. Usually, the weakened
frame portions will have cross-sectional dimensions which are
selected so that the force required to bend, crack or sever the
weakened frame portion is less than that required for other
non-weakened frame portions. Usually, the weakened frame portion
will have a section in which the height in the radial direction
remains constant (i.e. it will be the same as the remainder of the
frame) while the width in the circumferential direction will be
reduced about 20-30% relative to the non-weakened hinge regions.
The terms "weakened" and "non-weakened" are relative terms, and it
would be possible to augment or increase the width of the
non-weakened regions relative to the weakened regions. It will also
be possible to provide two or more discrete narrowings within a
single weakened frame portion, or to provide one or more narrowings
in the regions of the struts immediately adjacent to the weakened
frame portions. In another aspect, a weakened frame portion may be
created by cutting notches or voids into a portion of the frame.
For example, V-shaped notches may be cut into the hinge region on
the side which undergoes compression during opening of the hinge.
Alternatively, the frame can be sanded or beveled to create a
weakened frame portion.
[0053] In yet another aspect, a weakened frame portion can be
created altering one or more joints between portions of a frame in
response to one or more conditions in a body vessel. For example,
the frame can comprise separate segments that are joined together
with an adhesive that is gradually dissolved in fluid within a body
vessel, such as blood. For example, the frame 10 in FIG. 1A or FIG.
1B can comprise weakened frame portion 16a, as depicted in frame
portion 20 of FIG. 2A. Referring to FIG. 2A, a frame portion 20
comprises a weakened frame portion 16a including two substantially
parallel struts, 12a, 12e, joined to a curved "elbow" frame segment
26. The weakened frame portion 16a further comprises a first
dislocating joint 29a and a second dislocating joint 29b between a
first strut 12a and a second strut 12e each attached to opposite
ends of a curved "elbow" frame segment 26 in the middle. Upon
implantation in a body vessel, weakened frame portion 16a has a
first configuration 20. When the frame is in the first
configuration 20, a first biodegradable adhesive 27a joins the
first strut 12a to the curved elbow frame segment 26 at the first
dislocating joint 29a, and a second biodegradable adhesive 27b
joins the second strut 12e to the opposite end of the elbow frame
segment 26 at the second dislocating joint 29b. The curved elbow
frame segment 26 forms a bent structure, and can be made from any
material with an appropriate level of flexibility. For example, one
or more struts or elbow frame segments 26 can comprise a
bioabsorbable material or a non-bioabsorbable material, a
remodelable material, or any combination thereof. An elbow frame
segment 26 can also be designed to partially fracture in response
to force above a desired threshold level. A plurality of flexible
retaining rings 28a, 28b encircle the joints of the first strut 12a
and the second strut 12e to the elbow frame segment 26. The
weakened frame portion 16a has a first radial strength in the first
configuration 20.
[0054] After implantation in a body vessel for a desired period of
time, the first biodegradable adhesive 27a and the second
biodegradable adhesive 27b are dissolved, resulting in a decrease
in the radial strength of the frame in a second configuration 30,
including weakened frame portion 16a as depicted in FIG. 2B. In
FIG. 2B, a portion of the weakened frame portion 16a is shown in
the second configuration 30, with a second radial strength that is
less than the first radial strength of the frame when weakened
frame portion 16a in the first configuration 20. In the second
configuration 30, the first flexible retaining ring 28a permits the
first strut 12a to move relative to the elbow frame segment 26
within a first gap region 32a. Similarly, a second flexible
retaining ring 28b permits the second strut 12e to move relative to
the elbow frame segment 26 within a second gap region 32b. Movement
of the frame components within a plurality of gap regions 32a, 32b
reduces the radial strength of the frame by allowing the struts to
move in a confined manner with respect to the adjacent elbow frame
segments. Overall, the frame comprises a plurality of
interconnected struts and elbow frame segments arranged around a
cylindrical form. Preferably, the medical device is designed to
protect the body vessel from damage during or after the fracture of
the frame material. In one aspect, the frame is designed to undergo
a controlled fracture, meaning that the fracture does not harm
surrounding tissue. In one aspect, a flexible sleeve comprising an
elastic polymeric material can be wrapped around weakened regions
in the frame. For example, in FIG. 2B, the first flexible retaining
ring 28a and the second flexible retaining ring 28b prevent an end
of the first strut 12a or an end of the second strut 12e,
respectively, from extending into surrounding tissue within the
body vessel.
[0055] The frame can further comprise any suitable structure to
protect surrounding tissue from undesirably contacting the body
vessel wall. In one aspect, the frame can fracture without
presenting exposed sharpened ends to surrounding tissue. In another
embodiment, the frame can cleanly break, and the fractured ends of
the frame can be shielded from the surrounding material, for
example by an elastic retaining sleeve. In another embodiment, the
frame can be embedded in remodeled tissue when the fracture occurs,
and the frame can be designed to fracture in a manner that will not
harm surrounding tissue (for example, by crumbling and then being
bioabsorbed). Preferably, the frame is designed to comply with
applicable governmental regulatory guidelines promulgated, for
example, by the FDA. In one aspect, the adjacent portions of the
frame are tethered together so that when the adhesive dissolves,
the adjacent segments of the frame remain closely associated but
slightly moveable with respect to each other. Relative movement of
the adjacent frame segments preferably reduces the radial strength
of the overall frame.
[0056] In a second embodiment, the medical device frame comprises a
material that is chemically altered or absorbed to reduce the
radial strength of the frame after exposure to one or more
physiological conditions for a desirable period of time. According
to this embodiment, the medical device preferably comprises one or
more bioabsorbable materials. The frame itself, or any portion of
the frame, can be made from a bioabsorbable material. In one
aspect, a weakened frame portion can comprise a bioabsorbable
material.
[0057] In one aspect, absorption of a biomaterial can decrease the
radial strength of an implanted frame, for example by reducing the
cross section or surface area of a portion of the frame. In some
aspects, absorption of a portion of the frame comprising
bioabsorbable material can allow for the controlled fracture of a
portion of the frame, resulting in a sudden change in the radial
strength of the frame.
[0058] Methods of engineering planned implantable frame
disintegration and/or fracture may include but are not limited to:
controlling the formation of heterogeneous structure of amorphous
and crystalline regions within the stent or stent filaments,
creating multiple internal or surface fracture initiation sites,
creating localized predegraded material, or using multiple strands
with small section size to construct the stent.
[0059] One method of creating multiple fracture initiation sites in
a biodegradable polymer is to create periodic regions of
pre-degraded material along a stent or a structural element of a
stent, such as a monofilament. Post-extrusion or molding operations
such as localized degradation of molecular weight of crystalline
materials may be performed with lasers, focal UV light sources,
water or steam hydrolysis, or irradiation. When the material is
presented into an environment that provides heat and moisture for
hydrolytic polymer degradation, the pre-degraded regions will lose
strength and disintegrate sooner than regions of the material that
were not pre-degraded. The frequency of occurrence of the
pre-degraded regions will affect the size of the fracture pieces
from disintegration. A low frequency of predegradation regions will
result in disintegration into relatively large pieces. A high
frequency will result in disintegration into relatively small
pieces.
[0060] In addition to, or as an alternative to, manipulating the
molecular structure of polymer support frame materials, mechanical
disintegration and/or fracture sites may be designed into the
implant to cause predictable, controlled fracture and/or
disintegration. Mechanical disintegration initiation sites may be
created in the material or implant, for example, by purposely
notching, grooving, indenting, or contouring the surface. Internal
mechanical initiation sites may be created by purposely introducing
porosity or foreign particles in the solidifying polymer.
[0061] Preferably, the exposure of the bioabsorbable material under
one or more conditions present in a body vessel results in the
reduction of the radial strength of the frame. In one aspect,
bioabsorbable materials are disposed within the frame so that
absorption of the bioabsorbable material results in a desired
amount and manner of radial strength reduction. In one aspect,
increased flexibility is imparted to a weakened frame portion by
incorporating a bioabsorbable material into the weakened frame
portion of the frame. In another aspect, a portion of a frame
comprising a bioabsorbable material easily breaks after absorption
of all or part of the bioabsorbable material.
[0062] In some embodiments, the radial strength of the frame can be
designed to decrease after a period of time following implantation,
and the radial strength can change suddenly or gradually. The
change in radial strength of the frame can occur by various
mechanisms. For example, the radial strength of a frame comprising
a bioabsorbable material can gradually decrease with the
bioabsorption of the bioabsorbable material after implantation. In
another embodiment, the bioabsorption of a bioabsorbable support
arm can result in a fracture of the arm in response to shear forces
of blood flow, thereby suddenly decreasing the radial strength of
the frame. In another embodiment, micro fractures in portions of
the frame can increase the flexibility of portions of the frame,
thereby decreasing the radial strength of the frame along a first
direction.
[0063] Diminution in the radial strength of the frame can occur
gradually over any desirable time period. The time period after
implantation when the frame can decrease radial strength can, in
some embodiments, be similar to the time period for bioabsorption
of various bioabsorbable materials used to construct the frame.
Other aspects provide a frame with a radial strength that decreases
as a safety feature in response to a sudden pressure along a first
direction so as to prevent damage to the lining of a body vessel.
Still other aspects provide a frame that decreases radial strength
after a pre-determined period of implantation, for example, within
about 3 weeks, about 2 weeks or about 1 week. In preferred aspects,
the frame can decrease radial strength after a longer period of
time, such as at least 30 days, including periods of 44, 58, 72,
86, 90 100, 114, 128, 142, 156, 170, 180, or 184 days, or longer,
and any number of days therebetween. Preferably, selection of the
bioabsorbable materials, and the configuration of the bioabsorbable
materials in the implantable frame, can be chosen to provide a
desirable time period of bioabsorption of the material and the
accompanying decrease in radial strength after implantation.
[0064] An implantable frame can comprise any suitable configuration
of bioabsorbable material. In one embodiment, the frame can further
comprise a first bioabsorbable material or a non-bioabsorbable
material as a "core" material. The core material can be at least
partially enclosed by a second bioabsorbable material. The frame
can also comprise a surface area presenting both a bioabsorbable
material and a non-bioabsorbable material, and absorption of the
bioabsorbable material can increase the surface area, resulting in
a decrease of the radial strength of the frame in a first
direction. The frame can further include one or more support arms
comprising a bioabsorbable material, and absorption of the
bioabsorbable material can decrease the radial strength of the
frame in a first direction.
[0065] The frame 10 in FIG. 1A or FIG. 1B can comprise weakened
frame portion 16a having a cross section as depicted in FIG. 3A.
The cross section 105 of weakened frame portion 16a or 16b in FIGS.
1A-1B may be used as the weakened frame portion instead of, or in
combination with, the configuration 20 shown in FIG. 2A. FIG. 3A
shows a cross section 105 comprising a non-bioabsorbable core
material 112 (e.g., a self-expanding metal alloy) surrounded by a
bioabsorbable material 110. Bioabsorption of the bioabsorbable
material 110 decreases the radial strength of the frame 10 at the
weakened frame portion 16a in FIG. 1B. When implanted in a body
vessel, the outer layer 110 is bioabsorbed, thereby increasing the
flexibility of the frame 10 at the weakened frame portion 16a and
decreasing the radial strength of the frame 10.
[0066] FIG. 3B is an alternative cross section 165 to the cross
section 105 in FIG. 3A, of the weakened frame portion 16a or 16b in
FIGS. 1A-1B. The cross section 165 comprises a flexible
non-bioabsorbable core material 162 having a series of grooves,
wells or holes 160 on the surface that are at least partially
filled with a rigid bioabsorbable material 164. Bioabsorption of
the bioabsorbable material 164 decreases the radial strength of the
frame by permitting the non-bioabsorbable core material 162 (e.g.,
a flexible metal or metal alloy or a flexible rubber or polymeric
material) to bend more easily in the absence of the rigid
bioabsorbable material 164. FIG. 3C is a detailed close-up view of
a portion of the cross section 165, showing a series of
indentations (such as grooves or pits) along the surface of the
flexible non-bioabsorbable material 162. Rigid bioabsorbable
material 164 is deposited in the indentations. Upon implantation,
the bioabsorbable material 164 is bioabsorbed 150 and the
flexibility of a weakened frame portion 16a comprising the
non-bioabsorbable material 162 is gradually increased.
Bioabsorbable Materials
[0067] An implantable frame can comprise any suitable bioabsorbable
material, or combination of bioabsorbable materials. For example,
the weakened frame portion (including regions 16a or 16b in frame
10 in FIG. 1A) can comprise a biodegradable or bioabsorbable
material. For example, the weakened frame portion 16a can be formed
entirely from a segment of a bioabsorbable material, the weakened
frame portion 16a can have a configuration 20 shown in FIG. 2A, the
weakened frame portion 16a can have a cross section configuration
105 shown in FIG. 3A or the weakened frame portion 16a can have the
cross section configuration 165 shown in FIGS. 3B-3C. The types of
bioabsorbable materials are preferably selected to provide a
desired time scale for diminution in the radial strength of the
frame. Variations in selected times for bioabsorption may depend
on, for example, the overall health of the patient, variations in
anticipated immune reactions of the patient to the implant, the
site of implantation, and other clinical indicia. Bioabsorbable
materials may be selected to form at least a portion of a frame so
as to provide an decreased frame radial strength after a particular
period of time. In certain embodiments, bioabsorption of a
biomaterial in a frame can decrease the radial strength of the
frame in a first direction. In some embodiments, the frame may be
designed to bend radially inward in response to a pressure.
[0068] The bioabsorbable material may comprise any suitable
composition, including without limitation, a polyester, a
polyester-ethers, a copoly(ether-esters), a poly(hydroxy acid), a
poly(lactide), a poly(glycolide), or co-polymers and mixtures
thereof. In another aspect, the bioabsorbable material is
poly(p-dioxanone), poly(epsilon-caprolactone), poly(dimethyl
glycolic acid), poly(D,L-lactic acid), L-polylactic acid, or
glycolic acid, poly(lactide-co-glycolide),
poly(hydroxybutyrate-co-valerate), poly(glycolic
acid-co-trimethylene carbonate),
poly(epsilon-caprolactone-co-p-dioxanone), poly-L-glutamic acid or
poly-L-lysine, poly(hydroxy butyrate), polydioxanone, PEO/PLA or a
co-polymer or mixture thereof. Bioabsorbable materials further
include modified polysaccharides (such as cellulose, chitin, and
dextran), modified proteins (such as fibrin and casein),
fibrinogen, starch, collagen and hyaluronic acid. The bioabsorbable
material may also be, without limitation, hydroxyethyl starch,
gelatin, and derivatives of gelatin.
[0069] In one aspect, an implantable frame, or a portion thereof,
comprises a bioabsorbable material selected from the following
group of FDA-approved polymers: polyglycolic acid (PGA), polylactic
acid (PLA), Polyglactin 910 (comprising a 9:1 ratio of glycolide
per lactide unit, and known also as VICRYL.TM.), polyglyconate
(comprising a 9:1 ratio of glycolide per trimethylene carbonate
unit, and known also as MAXON.TM.), and polydioxanone (PDS). In
general, these materials biodegrade in vivo in a matter of months,
although some more crystalline forms can biodegrade more slowly.
These materials have been used in orthopedic applications, wound
healing applications, and extensively in sutures after processing
into fibers.
[0070] Other useful materials for creating weakened frame portions
include those disclosed in U.S. Pat. No. 4,838,267, for example,
including block copolymers derived from p-dioxanone and glycolide
that exhibit a high order of initial strength but lose their
strength rapidly after implantation in the body. U.S. Pat. No.
4,605,730 and U.S. Pat. No. 4,700,704 disclose copolymers of
epsilon-caprolactone and glycolide that are also useful in making
bioabsorbable frame portions. In addition, U.S. Pat. No. 4,624,256
discloses high molecular weight caprolactone polymers, while U.S.
Pat. No. 4,429,080 discloses triblock copolymers prepared from
copolymerizing glycolide with trimethylene carbonate. Homopolymers
and copolymers such as those disclosed in U.S. Pat. No. 5,412,068
are also appropriate for the resorbable frame portions.
[0071] Still other bioabsorbable materials can be synthesized from
protein-based polymers, particularly polymers containing
elastomeric polypeptide sequences (Wong, et al., "Synthesis and
properties of bioabsorbable polymers used as synthetic matrices for
tissue engineering" in Synthetic Bioabsorbable Polymer Scaffolds
(Atala & Mooney, eds.) pp. 51-82 (Birkhauser, Boston, 1997).
Cells can invade matrices derived from these materials. U.S. Pat.
Nos. 5,468,253 and 5,713,920, both to Bezwada et al., disclose
other bioabsorbable elastomeric materials which are used to form
devices that, based on in vitro data, are alleged to completely
bioabsorb within one year or six months.
[0072] Preparation of these and other bioabsorbable polymers or
copolymers are known in the art. Such polymers may be manufactured
and configured as disclosed, for example, in U.S. Pat. No.
5,133,755, incorporated by reference herein. U.S. Pat. Nos.
5,705,181 and 5,393,594, relate to the preparation and use
poly(lactide), poly(glycolide), poly(epsilon-caprolactone),
poly(p-dioxanone), poly(epsilon-caprolactone-co-p-dioxanone) and
poly(lactide-co-glycolide). U.S. Pat. No. 5,522,841, incorporated
herein by reference, relates to the preparation and use of
bioabsorbable block copolymers made of hard phase forming monomers,
e.g., glycolide and lactide, and soft phase monomers, e.g., 1,4
dioxane-2-one and caprolactone, as described. Bioabsorbable
polymers derived in whole or in part from dioxanone can be used in
some embodiments. Homopolymers of p-dioxanone are described, e.g.,
in U.S. Pat. Nos. 3,063,967; 3,063,968; 3,391,126; 3,645,941;
4,052,988; 4,440,789; and, 4,591,630. Copolymers containing units
derived from p-dioxanone and one or more other monomers that are
copolymerizable therewith are described, e.g., in U.S. Pat. Nos.
4,243,775; 4,300,565; 4,559,945; 4,591,630; 4,643,191; 4,549,921;
4,653,497; 4,791,929; 4,838,267; 5,007,923; 5,047,048; 4,076,807;
5,080,665; and 5,100,433 and European Patent Application Nos.
501,844 and 460,428.
[0073] Further relevant references can include, for example, D. K.
Gilding et al., "Biodegradable polymers for use in
surgery-polyglycolic/poly(lactic acid) homo- and copolymers: 1,"
Polymer, 20: 1459-1464 (1979), and D. F. Williams (ed.),
Biocompatibility of Clinical Implant Materials, Volume II, chapter
9: "Biodegradable Polymers" (1981), which are incorporated herein
by reference. Polymers, copolymers and devices made from
.epsilon.-caprolactone and/or related compounds have also been
described in U.S. Pat. Nos. 3,169,945, 3,912,692, 3,942,532,
4,605,730, 4,624,256, 4,643,734, 4,700,704, 4,788,979, 4,791,929,
4,994,074, 5,076,807, 5,080,665, 5,085,629 and 5,100,433.
Implantable Frames
[0074] Suitable support frames can have a variety of
configurations, including braided strands, helically wound strands,
ring members, consecutively attached ring members, tube members,
and frames cut from solid tubes. The configuration of the support
frame is not limited to the frame 10 shown in FIGS. 1A-1B. Other
suitable frames can have a variety of sizes. The exact
configuration and size chosen will depend on several factors,
including the desired delivery technique, the nature of the vessel
in which the device will be implanted, and the size of the vessel.
A frame structure and configuration can be chosen to facilitate
maintenance of the device in the vessel following implantation.
[0075] The frame can, in one embodiment, comprise a plurality of
struts. Struts are structures that can resist compression along the
longitudinal axis of the strut. Struts can be an identifiable
segment of an elongated frame member, for example separated by
bends in the member, individual segments joined together, or any
combination thereof. Struts can have any suitable structure or
orientation to allow the frame to provide desirable radial strength
properties to the frame. For example, struts can be oriented
substantially parallel to, substantially perpendicular to, or
diagonal to the longitudinal axis of a tubular frame, or some
combination thereof. Struts can be straight or arcuate in shape,
and can be joined by any suitable method, or can form one or more
distinct rings.
[0076] In one aspect, implantable frames comprise a serpentine (or
zig-zag) plurality of struts having substantially equal lengths
joined together in a reversing pattern. In another aspect,
implantable frames comprise repeating S-shaped hinge regions or
repeating Z-shaped hinge regions. The latter pattern is commonly
referred to a zig-zag stent.
[0077] In another embodiment, the frame comprises a combination of
bioabsorbable and nonabsorbable polymers. Examples of synthetic
biocompatible non-bioabsorbable polymers include, but are not
limited to, homopolymers and copolymers of polypropylene,
polyamides, polyvinylchlorides, polysulfones, polyurethanes,
polytetrafluoroethylene, ethylene vinyl acetate (EVAC),
polybutylmethacrylate (PBMA) or methylmethacrylate (MMA). The frame
can comprise the non-absorbable polymer in amounts from about 0.5
to about 99% of the final composition. The addition of EVAC, PBMA
or methylmethacrylate increases malleability of the matrix so that
the device is more plastically deformable.
[0078] Various constructs of the elongate elements, fibers and
threads can be formed utilizing well known techniques, e.g.,
braiding, plying, knitting, weaving, that are applied to processing
natural fibers, e.g., cotton, silk, etc., and synthetic fibers made
from synthetic bioabsorbable polymers, e.g., poly(glycolide) and
poly(lactic acid), nylon, cellulose acetate, etc. See, e.g.,
Mohamed, American Scientist, 78: 530-541 (1990). Specifically,
collagen thread is wound onto cylindrical stainless steel spools.
The spools are then mounted onto the braiding carousel, and the
collagen thread is then assembled in accordance with the
instructions provided with the braiding machine. In one particular
run, a braid was formed of four collagen threads, which consisted
of two threads of uncrosslinked collagen and two threads of
crosslinked collagen.
[0079] The dimensions of the implantable frame will depend on its
intended use. Typically, the implantable frame will have a length
in the range from 0.5 cm to 10 cm, usually being from about 1 cm to
5 cm, for vascular applications. The small (radially collapsed)
diameter of a cylindrical frame will usually be in the range from
about 1 mm to 10 mm, more usually being in the range from 1.5 mm to
6 mm for vascular applications. The expanded diameter will usually
be in the range from about 2 mm to 30 mm, preferably being in the
range from about 2.5 mm to 15 mm for vascular applications. The
body segments may be formed from conventional malleable materials
used for body lumen stents and grafts, typically being formed from
metals.
Medical Devices Comprising a Remodelable Material
[0080] In a third embodiment, a medical device can comprise a frame
and a remodelable material attached to the frame. Preferably, the
remodelable material is subject to a mechanical load adequate to
allow remodeling of the remodelable material when the frame has the
first radial strength. A "mechanical load" means any force applied
to a material that results in tension within the material. In
preferred embodiments, a remodelable material is subject to
adequate mechanical load to allow remodeling processes to occur.
The phrase "tensionably attach a material to a frame" refers to
attachment of a material to a frame results in a tension within the
attached material. A tensionably attached material is subject to
one form of a mechanical load. The tension in the material is
preferably provided by the restraint of radial expansion of the
frame by the material. For example, the frame may be configured as
a radially self-expanding frame, and the material may be configured
and attached to the frame so as to restrict the expansion of the
frame. Accordingly, in one aspect, the tension in the material may
be related to the degree to which the material restricts the radial
expansion of a self-expanding frame. Typically, the material is
tensionably attached to struts of a self-expanding frame that are
positioned along the perimeter of a lumen defined by the frame,
thereby restricting the radial expansion of the frame. Preferably,
a remodelable material extends across the lumen defined by a
radially self-expanding frame between at least two struts, thereby
restricting the diameter of the frame lumen would have if fully
expanded in the absence of the remodelable material.
[0081] Mechanical loading of remodelable material during the
remodeling process can advantageously influence the remodeling
process. For example, the remodeling process of one type of
remodelable material, extracellular matrix (ECM), is more effective
when the material is subject to certain types and ranges of
mechanical loading during the remodeling process. See, e.g., M.
Chiquet, "Regulation of extracellular matrix gene expression by
pressure," Matrix Biol. 18(5), 417-426 (October 1999). Applying
mechanical forces to a remodelable material during the remodeling
process is believed to affect processes such as signal
transduction, gene expression and contact guidance of cells.
Various references describe the influence of mechanical loading on
remodelable materials, such as extracellular matrix material (ECM).
For example, mediation of numerous physiological and pathological
processes by vascular endothelial cells is influenced by mechanical
stress, as discussed, for example, in Chien, Shu et al., "Effects
of Mechanical Forces on Signal Transduction and Gene Expression in
Endothelial Cells," Hypertension 31(2): 162-169 (1998). Expression
of bioactive agents can be stimulated by mechanical stress on
certain cells involved in remodeling processes, such as
fibroblasts, as discussed, for example, by Schild, Christof et al.,
"Mechanical Stress is Required for High-Level Expression of
Connective Tissue Growth Factor," Experimental Cell Research, 274:
83-91 (2002). Furthermore, another study suggests that fibroblasts
attached to a remodelable material such as a strained collagen
matrix produce increased amounts of ECM glycoproteins like tenascin
and collagen XII compared to cells in a relaxed matrix. Chiquet,
Matthias, et al., "Regulation of Extracellular Matrix Synthesis by
Mechanical Stress," Biochem. Cell. Biol., 74:737-744 (1996). Other
studies of remodelable material have found that remodeling
processes are sensitive to alterations in mechanical load. See,
e.g., Wong, Mary et al., "Cyclic Compression of Articular Cartilage
Explants is Associated with Progressive Consolidation and Altered
Expression Pattern of Extracellular Matrix Proteins," Matrix
Biology, 18: 391-399 (1999); Grodzinsky, Alan J. et al., "Cartilage
Tissue Remodeling in Response to Mechanical Forces," Annual Review
of Biomedical Engineering, 2: 691-713 (2000). In addition, the
alignment of cells with respect to mechanical loads can affect
remodeling processes, as studied, for example, by VC Mudera et al.,
"Molecular responses of human dermal fibroblasts to dual cues:
contact guidance and mechanical load," Cell Motil. Cytoskeleton,
45(1):1-9 (June 2000). These references are incorporated herein by
reference.
[0082] To facilitate ingrowth of host or other cells during the
remodeling process, either before or after implantation, a variety
of biological response modifiers may be incorporated into the
remodelable material. Appropriate biological response modifiers may
include, for example, cell adhesion molecules, cytokines, including
growth factors, and differentiation factors. Mammalian cells,
including those cell types useful or necessary for populating the
resorbable stent of the present invention, are anchorage-dependent.
That is, such cells require a substrate on which to migrate,
proliferate and differentiate.
[0083] In some embodiments, upon implantation in a body vessel, a
remodelable material can be subject to both a mechanical load, for
example from the manner of attachment to a frame, as well as a
variable shear stress from the fluid flow within the body vessel.
For example, Helmlinger, G. et al., disclose a model for laminar
flow over vascular endothelial cells in "Calcium responses of
endothelial cell monolayers subjected to pulsatile and steady
laminar flow differ," Am. J. Physiol. Cell Physiol. 269:C367-C375
(1995). Shear forces within a body vessel can also influence
biological processes involved in remodeling. For example, the role
of hemodynamic forces in gene expression in vascular endothelial
cells is discussed by Li, Y. S. et al., "The Ras-JNK pathway is
involved in shear-induced gene expression," Mol. Cell Biol.,
16(11): 5947-54 (1996). Many other studies of the range of shear
forces and the effect of shear forces on the remodeling process are
found in the art. Using these references and others, one skilled in
the art can select a level of mechanical loading that, when taking
into account the range of fluid flow shear forces within a body
vessel, will provide optimal mechanical loading conditions for
remodeling of the remodelable material.
[0084] Reconstituted or naturally-derived collagenous materials can
be used as remodelable materials. Such materials that are at least
bioresorbable will provide advantage in the present invention, with
materials that are bioremodelable and promote cellular invasion and
ingrowth providing particular advantage. Suitable bioremodelable
materials can be provided by collagenous extracellular matrix
materials (ECMs) possessing biotropic properties, including in
certain forms angiogenic collagenous extracellular matrix
materials. For example, suitable collagenous materials include ECMs
such as submucosa, renal capsule membrane, dermal collagen, dura
mater, pericardium, fascia lata, serosa, peritoneum or basement
membrane layers, including liver basement membrane. Suitable
submucosa materials for these purposes include, for instance,
intestinal submucosa, including small intestinal submucosa, stomach
submucosa, urinary bladder submucosa, and uterine submucosa.
[0085] As prepared, the submucosa material and any other ECM used
may optionally retain growth factors or other bioactive components
native to the source tissue. For example, the submucosa or other
ECM may include one or more growth factors such as basic fibroblast
growth factor (FGF-2), transforming growth factor beta (TGF-beta),
epidermal growth factor (EGF), and/or platelet derived growth
factor (PDGF). As well, submucosa or other ECM used in the
invention may include other biological materials such as heparin,
heparin sulfate, hyaluronic acid, fibronectin and the like. Thus,
generally speaking, the submucosa or other ECM material may include
a bioactive component that induces, directly or indirectly, a
cellular response such as a change in cell morphology,
proliferation, growth, protein or gene expression.
[0086] Submucosa or other ECM materials of the present invention
can be derived from any suitable organ or other tissue source,
usually sources containing connective tissues. The ECM materials
processed for use in the invention will typically include abundant
collagen, most commonly being constituted at least about 80% by
weight collagen on a dry weight basis. Such naturally-derived ECM
materials will for the most part include collagen fibers that are
non-randomly oriented, for instance occurring as generally uniaxial
or multi-axial but regularly oriented fibers. When processed to
retain native bioactive factors, the ECM material can retain these
factors interspersed as solids between, upon and/or within the
collagen fibers. Particularly desirable naturally-derived ECM
materials for use in the invention will include significant amounts
of such interspersed, non-collagenous solids that are readily
ascertainable under light microscopic examination with specific
staining. Such non-collagenous solids can constitute a significant
percentage of the dry weight of the ECM material in certain
inventive embodiments, for example at least about 1%, at least
about 3%, and at least about 5% by weight in various embodiments of
the invention.
[0087] The submucosa or other ECM material used in the present
invention may also exhibit an angiogenic character and thus be
effective to induce angiogenesis in a host engrafted with the
material. In this regard, angiogenesis is the process through which
the body makes new blood vessels to generate increased blood supply
to tissues. Thus, angiogenic materials, when contacted with host
tissues, promote or encourage the infiltration of new blood
vessels. Methods for measuring in vivo angiogenesis in response to
biomaterial implantation have recently been developed. For example,
one such method uses a subcutaneous implant model to determine the
angiogenic character of a material. See, C. Heeschen et al., Nature
Medicine 7 (2001), No. 7, 833-839. When combined with a
fluorescence microangiography technique, this model can provide
both quantitative and qualitative measures of angiogenesis into
biomaterials. C. Johnson et al., Circulation Research 94 (2004),
No. 2, 262-268.
[0088] Further, in addition or as an alternative to the inclusion
of native bioactive components, non-native bioactive components
such as those synthetically produced by recombinant technology or
other methods, may be incorporated into the submucosa or other ECM
tissue. These non-native bioactive components may be
naturally-derived or recombinantly produced proteins that
correspond to those natively occurring in the ECM tissue, but
perhaps of a different species (e.g. human proteins applied to
collagenous ECMs from other animals, such as pigs). The non-native
bioactive components may also be drug substances. Illustrative drug
substances that may be incorporated into and/or onto the ECM
materials used in the invention include, for example, antibiotics
or thrombus-promoting substances such as blood clotting factors,
e.g. thrombin, fibrinogen, and the like. These substances may be
applied to the ECM material as a premanufactured step, immediately
prior to the procedure (e.g. by soaking the material in a solution
containing a suitable antibiotic such as cefazolin), or during or
after engraftment of the material in the patient.
[0089] Submucosa or other ECM tissue used in the invention is
preferably highly purified, for example, as described in U.S. Pat.
No. 6,206,931 to Cook et al. Thus, preferred ECM material will
exhibit an endotoxin level of less than about 12 endotoxin units
(EU) per gram, more preferably less than about 5 EU per gram, and
most preferably less than about 1 EU per gram. As additional
preferences, the submucosa or other ECM material may have a
bioburden of less than about 1 colony forming units (CFU) per gram,
more preferably less than about 0.5 CFU per gram. Fungus levels are
desirably similarly low, for example less than about 1 CFU per
gram, more preferably less than about 0.5 CFU per gram. Nucleic
acid levels are preferably less than about 5 .mu.g/mg, more
preferably less than about 2 .mu.g/mg, and virus levels are
preferably less than about 50 plaque forming units (PFU) per gram,
more preferably less than about 5 PFU per gram. These and
additional properties of submucosa or other ECM tissue taught in
U.S. Pat. No. 6,206,931 may be characteristic of the submucosa
tissue used in the present invention.
Medical Devices Comprising a Means for Regulating Fluid Flow
[0090] In a fourth embodiment, the medical device can comprise a
means for regulating fluid through a body vessel. In some
embodiments, the fluid can flow through an implantable frame, while
other embodiments provide for fluid flow through a lumen defined by
the frame. In some aspects, a frame and a first valve leaflet are
connected to a frame.
[0091] A valve leaflet, according to some aspects, can comprise a
valve leaflet, such as a leaflet comprising a free edge, responsive
to the flow of fluid through the body vessel. A "free edge" refers
to a portion of a leaflet that is not attached to a frame, but
forms a portion of a valve orifice. Preferably a leaflet free edge
is a portion of the edge of the leaflet that is free to move in
response to the direction of fluid flow in contact with the
leaflet, independently of the movement of the frame.
[0092] Preferably, one or more valve leaflets attached to a frame
may, in one embodiment, permit fluid to flow through a body vessel
in a first direction while substantially preventing fluid flow in
the opposite direction. In some embodiments, the valve leaflet
comprises an extracellular matrix material, such as small intestine
submucosa (SIS). The valve leaflet can be made from any suitable
material, including a remodelable material or a synthetic polymer
material.
[0093] Perferably, medical devices comprising a frame and a valve
leaflet can be used to regulate fluid flow in a vein, for example
to treat venous valve incompetency. For example, one or more
medical devices comprising a frame and one or more valve leaflets
can be implanted in a vein with incompetent venous valves so as to
provide a valve to replace the incompetent valves therein. FIG. 4A
is a side view of a medical device 100 configured as a valve
comprising the support frame 10 shown in FIGS. 1A-1B and a
remodelable material 50. FIG. 4B is a rotated side view of the
medical device 100 shown in FIG. 4A, and FIG. 4C is an top view of
the medical device 100 shown in FIGS. 4A-4B. The medical device 100
is configured as an endolumenal valve by tensionably attaching two
pieces of the remodelable material 50 to the frame 10 to form a
first valve leaflet 54 and a second valve leaflet 52. The first
valve leaflet 54 is formed by tensionably attaching the first piece
of the remodelable material 50 to the strut 12b and the strut 12f.
Similarly, the second valve leaflet 52 is tensionably attached
between the strut 12c and strut 12g. The leaflets 52, 54 are
configured to at least partially restrain the radial expansion of
the self-expanding frame 10, thereby maintaining a tension on each
leaflet. For example, radial expansion of the frame 10 moves struts
12b and 12f radially apart from each other, thereby providing a
mechanical load on the first leaflet 54 by stretching the
remodelable material of the first leaflet 54 between strut 12b and
strut 12f, in a first radial direction 90 extending radially
outward from, and perpendicular to, the longitudinal axis 2.
Referring to FIG. 4C, the first leaflet 54 and the second leaflet
52 restrict the radial self-expansion of the frame 10. Absent the
first and second leaflets 54, 52, the frame 10 would expand to a
larger circular profile having a circumference indicated by dashed
line 96, having a unrestrained frame lumen radius 94. Attachment of
the first leaflet 54 and the second leaflet 52 reduce the frame
lumen radius from the opposably to the second free edge 62. The
portion of each leaflet 52, 54 distal to the free edge 62, 64 is
connected to the hoop 18 to form the base of each leaflet 52, 54.
Optionally, the base of each leaflet 52, 54 can be configured as a
cuff forming a sinus region 70, 72 between the leaflet and the wall
of a body vessel. The base of the first leaflet 52 forms a first
sinus region 70, while the base of the second leaflet 54 forms a
second sinus region 72. Optionally, the sinus region 70, 72 may
comprise one or more holes in the leaflet material to provide for
controlled fluid flow in a regrograde direction, or to drain the
sinus region between pulses of fluid in the antegrade direction.
FIG. 5 shows a rotated side view of the medical device 100 after
weakening or removal of the weakened frame portion 16a, reducing
the outward radial force of the frame 10 in the first radial
direction 90, and thereby decreasing the tension of on the first
valve leaflet 54 and the second valve leaflet 52.
[0094] A wide variety of materials acceptable for use as the valve
leaflets are known in the art, and any suitable material can be
utilized. The material chosen need only be able to perform as
described herein, and be biocompatible, or able to be made
biocompatible. Examples of suitable materials include flexible
materials, natural materials, and synthetic materials.
[0095] A valve leaflet can optionally further comprise a suitable
synthetic material including polymeric materials, such as
polypropylene, expanded polytetrafluoroethylene (ePTFE),
polyurethane (PU), polyethylene terphthalate (PET), silicone,
latex, polyethylene, polypropylene, polycarbonate, nylon,
polytetrafluoroethylene, polyimide, polyester, and mixture thereof,
or other suitable materials. One preferred synthetic material
comprises a polyurethane polymer and a suitable surface modifying
agent, such as the biocompatible synthetic material sold under the
tradename THORALON (THORATEC, Pleasanton, Calif.). Various suitable
biocompatible synthetic materials comprising polyurethane,
including THORALON, are described in U.S. Pat. Application
Publication No. 2002/0065552 A1 and U.S. Pat. No. 4,675,361, both
of which are incorporated herein by reference.
[0096] A valve leaflet can be attached to an implantable frame with
any suitable attachment mechanism, such as sutures, adhesives,
bonding, tissue welding, self-adhesion between regions of the
material, chemical adhesion between the valve leaflet material and
the frame, cross-linking and the like. The attachment mechanism
chosen will depend on the nature of the frame and valve leaflets.
Sutures provide an acceptable attachment mechanism when SIS or
other ECM materials are used as the valve leaflets with a metal or
plastic frame.
[0097] The device can include any suitable number of valve
leaflets. The valve leaflets need only be able to provide the
functionality described herein. The specific number chosen will
depend on several factors, including the type and configuration of
the frame. Some aspects provide medical devices comprising 1, 3, 4,
5, 6, 7, 8 or more valve leaflets. The valve leaflets can be
arranged in any suitable configuration with respect to one another
and the frame. In one preferred embodiment, a medical device can
comprise a frame and three valve leaflets that are leaflets
comprising free edges. In another preferred embodiment, a medical
device can comprise one leaflet having a free edge that can
sealably engage the interior of a vessel wall. Other suitable
configurations of valve leaflets are provided by further
embodiments, including differently shaped valve leaflets, and
different points of attachment by valve leaflets to the frame.
[0098] In some aspects, the frame provides one or more structural
features that protect a valve leaflet. For example, the frame can
include a portion positioned between a portion of a leaflet and the
interior wall of a body vessel upon implantation. Another example
of a protecting feature in a frame includes arms or members of the
frame extending between portions of a leaflet and the inner wall of
a body vessel. Referring to FIG. 4A, strut 12a is positioned
between the first leaflet 54 and the wall of a body vessel upon
implantation of the medical device 100, and may protect the body of
the first leaflet 54 from adhering to the body vessel wall. The
"body" of the first valve leaflet 54 refers to the portion of the
valve leaflet between the free edge 64 and the base region (sinus
72). The base of the first leaflet 54, configured as sinus region
72, is configured to form a seal with the body vessel wall,
preventing fluid flow in the retrograde direction 6. Similarly,
strut 12d protects the body of the second leaflet 52 from
contacting the wall of a body vessel upon implantation of the
medical device 100. As another example, a narrowed portion of an
inner diameter of a frame around a leaflet can protect a portion of
the leaflet from adhering to the inner wall of a body vessel upon
implantation of a medical device therein. In one embodiment, the
leaflet can comprise a remodelable material and the protecting
structural feature of the frame can be bioabsorbed gradually in a
time period sufficient for remodeling of at least a portion of the
leaflet. Bioabsorption of the protecting feature of the frame can
also gradually decrease the radial strength of the frame. In
another embodiment, the protecting feature of the frame can
fracture in a controlled manner, for instance by microfractures
along a portion of the frame, after a suitable period of
implantation (for example after about 30 days post implantation).
Frames that comprise materials that decrease frame radial strength
upon implantation by other means such as the absorption of fluid,
responsive to changes in pH or body temperature, or various
biochemical processes can also be used, for example as a structural
feature to protect a leaflet or portion thereof from undesirable
contact with the inner wall of a body vessel.
[0099] The overall configuration, cross-sectional area, and length
of the valve support frame will depend on several factors,
including the size and configuration of the device, the size and
configuration of the vessel in which the device will be implanted,
the extent of contact between the device and the walls of the
vessel, and the amount of retrograde flow through the vessel that
is desired.
[0100] In devices including multiple openings that permit a
controlled amount of fluid flow in the second, opposite direction
to flow through the vessel in which the device is implanted, the
total open area of all openings can be optimized as described
above, but it is not necessary that the individual openings have
equivalent total open areas.
[0101] In one aspect, the method comprises the step of attaching a
first valve leaflet to a frame. The valve leaflet can be responsive
to the flow of fluid through the frame, and adapted to permit fluid
flow through said vessel in a first direction or substantially
prevent fluid flow through said vessel in a second, opposite
direction. The frame can have a longitudinal axis, a first radial
compressibility along a first radial direction that is less than a
second radial compressibility along a second radial direction.
Implantable Frame Materials
[0102] Implantable frames can be constructed of any suitable
material. Suitable materials are biocompatible. Preferably, the
frame materials and design configurations are selected to reduce or
minimize the likelihood of undesirable effects such as restenosis,
corrosion, thrombosis, arrhythmias, allergic reactions, myocardial
infarction, stroke, or bleeding complications. Examples of suitable
materials include, without limitation: stainless steel, titanium,
niobium, nickel titanium (NiTi) alloys (such as Nitinol) and other
shape memory and/or superelastic materials, MP35N, gold, tantalum,
platinum or platinum alloy including platinum iridium, Elgiloy,
Phynox (a cobalt-based alloy), or any cobalt-chromium alloy. The
stainless steel may be alloy-type: 316L SS, Special Chemistry per
ASTM F138-92 or ASTM F139-92 grade 2, Special Chemistry of type
316L per ASTM F138-92 or ASTM F139-92 Stainless Steel for Surgical
Implants.
[0103] A radially self-expanding frame is preferably formed
partially or completely of alloys such as nitinol, which is
believed to consist essentially of 55% Ni, 45% Ti, and which have
superelastic (SE) characteristics. When a frame is formed from
superelastic nickel-titanium (NiTi) alloys, the self-expansion
occurs when the stress of compression is removed. This allows the
phase transformation from martensite back to austenite to occur,
and as a result the stent expands. Materials having superelastic
properties generally have at least two phases: a martensitic phase,
which has a relatively low tensile strength and which is stable at
relatively low temperatures, and an austenitic phase, which has a
relatively high tensile strength and which can be stable at
temperatures higher than the martensitic phase. Shape memory alloys
undergo a transition between an austenitic phase and a martensitic
phase at certain temperatures. When they are deformed while in the
martensitic phase, they retain this deformation as long as they
remain in the same phase, but revert to their original
configuration when they are heated to a transition temperature, at
which time they transform to their austenitic phase. The
temperatures at which these transitions occur are affected by the
nature of the alloy and the condition of the material.
Nickel-titanium-based alloys (NiTi), wherein the transition
temperature is slightly lower than body temperature, are preferred
for the present invention. It can be desirable to have the
transition temperature set at just below body temperature to insure
a rapid transition from the martinsitic state to the austenitic
state when the frame can be implanted in a body lumen. For example,
a nitinol frame can be deformed by collapsing the frame and
creating stress which causes the NiTi to reversibly change to the
martensitic phase. The frame can be restrained in the deformed
condition inside a delivery sheath typically to facilitate the
insertion into a patient's body, with such deformation causing the
isothermal phase transformation. Once within the body lumen, the
restraint on the frame can be removed, thereby reducing the stress
thereon so that the superelastic frame returns towards its original
undeformed shape through isothermal transformation back to the
austenitic phase. The shape memory effect allows a nitinol
structure to be deformed to facilitate its insertion into a body
lumen or cavity, and then heated within the body so that the
structure returns to its original, set shape.
[0104] The recovery or transition temperature may be altered by
making minor variations in the composition of the metal and in
processing the material. In developing the correct composition,
biological temperature compatibility must be determined in order to
select the correct transition temperature. In other words, when the
frame can be heated, it must not be so hot that it can be
incompatible with the surrounding body tissue. Other shape memory
materials may also be utilized, such as, but not limited to,
irradiated memory polymers such as autocrosslinkable high density
polyethylene (HDPEX). Shape memory alloys are known in the art and
are discussed in, for example, "Shape Memory Alloys," Scientific
American, 281: 74-82 (November 1979), incorporated herein by
reference.
[0105] The frame may comprise one or more synthetic materials
described herein, such as polyurethane synthetic materials
including the polyurethane blend material sold under the tradename
THORALON, as discussed herein. In other aspects, the frame may
comprise a suitable biomaterial such as an ECM material, collagen,
fibrin, dextran and the like.
[0106] The frame can include structural features, such as barbs,
that maintain the frame in position following implantation in a
body vessel. The art provides a wide variety of structural features
that are acceptable for use in the medical device, and any suitable
structural feature can be used. Furthermore, barbs can also
comprise separate members attached to the frame by suitable
attachment means, such as welding and bonding.
[0107] Also provided are embodiments wherein the frame comprises a
means for orienting the frame within a body lumen. For example, the
frame can comprise a marker, such as a radiopaque portion of the
frame that would be seen by remote imaging methods including X-ray,
ultrasound, Magnetic Resonance Imaging and the like, or by
detecting a signal from or corresponding to the marker. In other
embodiments, the delivery device can comprise a frame with indicia
relating to the orientation of the frame within the body vessel. In
other embodiments, indicia can be located, for example, on a
portion of a delivery catheter that can be correlated to the
location of the frame within a body vessel. The addition of
radiopacifiers (i.e., radiopaque materials) to facilitate tracking
and positioning of the medical device may be added in any
fabrication method or absorbed into or sprayed onto the surface of
part or all of the medical device. The degree of radiopacity
contrast can be altered by implant content. Radiopacity may be
imparted by covalently binding iodine to the polymer monomeric
building blocks of the elements of the implant. Common radiopaque
materials include barium sulfate, bismuth subcarbonate, and
zirconium dioxide. Other radiopaque elements include: cadmium,
tungsten, gold, tantalum, bismuth, platinum, iridium, and rhodium.
In one preferred embodiment, iodine may be employed for its
radiopacity and antimicrobial properties. Radiopacity is typically
determined by fluoroscope or x-ray film.
[0108] The frame can be manufactured by any suitable approach. In
one aspect, wire struts can be formed by folding a continuous
member, or be joined by soldering, welding, or other methods to
join ends. In another aspect, besides joining strut segments, the
frame can be fabricated as a single piece of material, by stamping
or cutting the frame from another sheet (e.g., with a laser),
fabricating from a mold, or some similar method of producing a
unitary frame.
[0109] In yet another aspect, bioabsorbable materials can be
incorporated in the frame by any suitable method, including
directly fabricating the frame from the bioabsorbable material, or
coating one or more bioabsorbable materials onto each other or onto
another material. Bioabsorbable struts can be joined to
non-bioabsorbable struts by any suitable method.
Radial Strength Measurement
[0110] The radial strength of a frame is preferably measured using
a Radial Force Gauge. One preferred Radial Force Gauge the RX600
Radial Expansion Force Gage equipment from Machine Solutions Inc.
(MSI). A Radial Force Gauge measures the radial strength of both
balloon expandable and self-expanding stent and stent graft
products during expansion and compression. The RX600 equipment uses
a segmental compression mechanism controlled by a micro-stepping
linear actuator that is designed to provide an extremely low
friction testing environment. Preferably, the Radial Force Gauge
maintains resolution at force levels from 0 to 80 Newtons, for
example using a software-controlled interchangeable linear force
transducer, or other suitable means. The Radial Force Gauge
preferably measures the hoop strength of the frame. Optionally, the
Radial Force Gauge allows the hoop strength of the frame to be
visualized and recorded as the product is cycled through programmed
open and close diameters.
Radial Strength Reducing Tests
[0111] The radial strength of a frame can preferably be reduced by
a radial strength reducing test outside a body vessel, or by
implantation within a body vessel. A radial strength reducing test
refers to subjecting the frame to any environment for any time
period sufficient to reduce the radial strength of the frame.
Preferably, a radial strength reducing test subjects the frame to
test conditions that simulate one or more conditions within a body
vessel after implantation that promote the reduction in radial
strength of the frame within the body vessel. In one aspect, a
frame is subjected to radial strength reducing test conditions
("test conditions") of mechanical stress or a chemical environment,
or combination thereof, such that a reduction in radial strength
under test conditions is predictive of a reduction in radial
strength upon implantation in a body vessel. Examples of test
conditions include mechanical fatigue testing and biochemical
reactor conditions. Preferably, a frame is initially characterized
by a first radial strength measurement prior to subjecting the
frame to a test condition that reduces the radial strength, and the
frame is subsequently characterized by a second radial strength
measurement after exposure to the test condition. Preferably, the
first radial strength measurement and the second radial strength
measurement are comparable. For example, both radial strength
measurements can be obtained using the same a Radial Force Gauge
and radial strength measurement protocol.
[0112] In one embodiment, the test conditions are a type of
mechanical fatigue testing. For example, conditions of temperature,
pressure, biochemical exposure, and mechanical loading or movement
found within a body vessel can be simulated by the Flat Plate
Fatigue Test. A Flat Plate Fatigue Test is a preferred mechanical
fatigue test. Other mechanical fatigue tests include variations of
the Flat Plate Fatigue Test. The Flat Plate Fatigue Test can be
described with reference to FIG. 6A and FIG. 6B. The flat plate
fatigue apparatus 600, shown schematically from a top view in FIG.
6A and a side view in FIG. 6B, comprises a first plate 610
maintained parallel to a second plate 612 that adapted to be
translated in rapid oscillation with respect to each other
(oscillation of the first plate 610 is indicated by arrow 652;
oscillation of second plate 620 is shown by arrow 650). A tubular
frame 620 has a first leaflet 630 and a second leaflet 632 attached
to one end that can open to form a valve orifice 634 that opens to
allow fluid flow 636 in only one direction. The tubular frame 620
is placed in a silicone tube 622, to form a frame-tube assembly
that is securely positioned between the first plate 610 and the
second plate 612. The flat plate fatigue apparatus 600 is
positioned within a fluid-containing cell (not shown) that allows
for immersing the frame 620 in a fluid. When performing the Flat
Plate Fatigue Test, a fluid flow 636 of phosphate-buffered saline
at about 37.degree. C. is maintained within the silicone tube 622,
passing through the frame 620. The maximum distance between the
first plate 610 and the second plate 612 is set to maintain each
plate 610, 612 in parallel and in contact with the silicone tube
622 during the testing. During the Flat Plate Fatigue Test, the
frame 620 and the silicone tube 622 are cyclically compressed
between the first plate 610 and the second plate 612 for a
compression of about 10% of the diameter of the uncompressed frame
620, at a rate of about 30 Hz for about 9 hours.
[0113] In other embodiments, other mechanical fatigue tests can be
performed as radial strength reducing test conditions that simulate
conditions within a body vessel. For example, a frame can be tested
in a test similar to the Flat Plate Fatigue test, where the frame
is not exposed to a fluid. Alternatively, a frame may be exposed to
a fluid with certain biochemically active properties, such as the
presence of enzymes. A fluid may have a particular pH range, for
example to simulate pH conditions in portions of the
gastrointestinal, urinary or bile tracts. The fluid may comprise
whole blood or any compositions thereof, derived from any suitable
source such as bovine or porcine sources. Various cycling rates may
also be used, such as ranges of about 10 Hz to about 50 Hz. Also,
the amount of compression of the frame may be varied, for example
from about 1% to about 25% of the non-compressed diameter. The
temperature of the frame or a fluid contacting the frame may be
varied as well, but preferably simulates the temperature within a
body vessel (about 37.degree. C. for humans). The number of
oscillation cycles of the frame by movement of the flat plates can
be varied to any suitable number. The number of cycles will depend
on the intended use.
[0114] Frames can be designed to reduce radial strength after an
intended period of time. For a frame designed to undergo a
reduction in radial strength after about 6 months within a vein,
about one million cycles at 30 Hz is preferred. Within the lumen of
a vein in the human leg, an implanted frame is believed to undergo
an estimated 5,000 oscillations per day. In one aspect, an SIS
remodelable material is attached to a frame for implantation in a
vein. In this environment, SIS is expected to remodel within about
6 months. Accordingly, the frame for such an application desirably
loses radial strength after the number of oscillations equivalent
to 6 months in a vein, or about 900,000 to one million
oscillations. At an oscillation rate of about 30 Hz, the frame
should undergo a reduction in radial strength after about 8.3
hours. Accordingly, the frame should have a first radial strength
before the mechanical fatigue testing, and a reduced radial
strength measured after about 9 hours of mechanical fatigue
testing.
[0115] Frames can also be exposed to biochemical conditions that
reduce the radial strength. For example, the frame can be contacted
with living tissue, or placed in a bioreactor that simulates
biochemical conditions within a body vessel. In one embodiment, the
frame is subjected to a Blood Component Contact test, where the
frame is contacted with blood for a period sufficient to reduce the
radial strength of the frame, such as 30, 60, or 90 days. The blood
for the Blood Contact Test can be obtained from a suitable source,
such as bovine or porcine sources. Any suitable test can be used to
simulate one or more conditions typically found within a body
vessel where the frame is intended for implantation. For example, a
frame comprising a bioabsorbable polymer can be exposed to
conditions that promote the dissolution of the bioabsorbable
polymer to an extent present after a desired period of implantation
in a body vessel. The test conditions can be calibrated to expose
the frame to conditions that cause the reduction of the frame
within the body vessel, such as pH, temperature, or presence of
particular bioactive blood components.
[0116] Preferably, a medical device for implantation in a body
vessel comprising a frame is characterized by a first radial
strength measurement prior to conducting a radial strength reducing
test, and a second radial strength measurement after conducting the
radial strength reducing test, where the first radial strength and
the second radial strength are measured by a Radial Force Gauge;
and the second radial strength measurement is less than the first
radial strength measurement. More preferably, the radial strength
reducing test is a Flat Plate Fatigue Test.
Delivery of Medical Devices
[0117] Medical devices are preferably delivered intralumenally, for
example using various types of delivery catheters, and be expanded
by any suitable mechanism. For example, a medical device can be
self-expanding or non-resilient. A self-expanding medical device is
restrained in a compressed configuration until deployed at a point
of treatment within a body vessel by releasing the medical device.
Typically, a self-expanding medical device is housed within an
outer sheath of a catheter delivery system, and deployed by
translating the outer sheath to expose the medical device to the
body vessel at the point of deployment. In contrast, a
non-resilient medical device requires the application of an
internal force to expand it at the target site. Typically, the
expansive force can be provided by a balloon catheter, such as an
angioplasty balloon for vascular procedures.
[0118] In some aspects, a frame can expand from a compressed, or
unexpanded, delivery configuration to one or more radially expanded
deployment configurations, for example through self-expansion or
balloon expansion of the frame. In one aspect, a medical device
comprises a self-expanding material. In another aspect, a medical
device is expanded using a balloon catheter. The expanded frame
configuration can have any suitable cross-sectional shape,
including circular or elliptical. In one embodiment, the frame can
be oriented along the longitudinal axis of a body vessel in the
expanded or compressed configurations.
[0119] In some embodiments, the frame is self-expanding. In one
aspect, a self-expanding medical device can be compressed to a
delivery configuration within a retaining sheath that is part of a
delivery system, such as a catheter-based system. In some aspects,
a self-expanding frame can be compressed into a low-profile
delivery conformation and then constrained within a delivery system
for delivery to a point of treatment in the lumen of a body vessel.
Upon compression, self-expanding frames can expand toward their
pre-compression geometry. At the point of treatment, the
self-expanding frame can be released and allowed to subsequently
expand to another configuration. In one aspect, self-expanding
frames preferably have an overall expansion ratio of about 1.0 up
to about 4.0 times the original diameter, or more.
[0120] In some aspects, a bioabsorbable suture or sheath can be
used to maintain a medical device in a compressed configuration
both prior to and after deployment. As the bioabsorbable sheath or
suture is degraded by the body after deployment, the medical device
can expand within the body vessel. In some embodiments, a portion
of the medical device can be restrained with a bioabsorbable
material and another portion allowed to expand immediately upon
implantation. For example, a self-expanding frame can be partially
restrained by a bioabsorbable material upon deployment and later
expand as the bioabsorbable material is absorbed.
[0121] Frames can also be expanded by a balloon. A medical device
can be readily delivered to the desired location by mounting it on
an expandable member, such as a balloon, of a delivery catheter and
passing the catheter-medical device assembly through the body lumen
to the implantation site. A variety of means for securing the
stents to the expandable member of the catheter for delivery to the
desired location arc available. It is presently preferred to
compress or crimp the stent onto the unexpanded balloon. Other
means to secure the stent to the balloon include providing ridges
or collars on the inflatable member to restrain lateral movement,
using bioabsorbable temporary adhesives, or adding a retractable
sheath to cover the stent during delivery through a body lumen.
[0122] Methods for delivering a medical device as described herein
are generally applicable to any suitable body vessel, such as a
vein, artery, biliary duct, ureteral vessel, body passage or
portion of the alimentary canal. In some embodiments, medical
devices having a frame with a compressed delivery configuration
with a very low profile, small collapsed diameter and great
flexibility, may be able to navigate small or tortuous paths
through a variety of body vessels. A low-profile medical device may
also be useful in coronary arteries, carotid arteries, vascular
aneurysms, and peripheral arteries and veins (e.g., renal, iliac,
femoral, popliteal, sublavian, aorta, intercranial, etc.). Other
nonvascular applications include gastrointestinal, duodenum,
biliary ducts, esophagus, urethra, reproductive tracts, trachea,
and respiratory (e.g., bronchial) ducts. These applications may or
may not require a sheath covering the medical device.
Methods of Treatment
[0123] The invention also provides methods of treating a patient.
In one embodiment the method comprises a step of delivering a
medical device as described herein to a point of treatment in a
body vessel, and deploying the medical device at the point of
treatment. The delivering step can comprise delivery by surgical or
by percutaneous delivery techniques known to those skilled in the
art. Methods for delivering a medical device as described herein to
any suitable body vessel are also provided, such as a vein, artery,
biliary duct, ureteral vessel, body passage or portion of the
alimentary canal.
[0124] Medical devices can be deployed in a body lumen by means
appropriate to their design. The medical devices of the present
invention can be adapted for deployment using conventional methods
known in the art and employing percutaneous translumenal catheter
devices. The medical devices are designed for deployment by any of
a variety of in situ expansion means.
[0125] The medical device may be mounted onto a catheter that holds
the medical device as it is delivered through the body lumen and
then releases the medical device and allows it to self-expand into
contact with the body lumen. This deployment is effected after the
medical device has been introduced percutaneously, transported
translumenally and positioned at a desired location by means of the
catheter. The restraining means may comprise a removable sheath.
The self-expanding medical device according to the invention may be
deployed according to well-known deployment techniques for
self-expanding medical devices. The medical device is positioned at
the distal end of a catheter with a lubricous sleeve placed over
the medical device to hold the medical device in a contracted state
with a relatively small diameter. The medical device may then be
implanted at the point of treatment by advancing the catheter over
a guidewire to the location of the lesion and then withdrawing the
sleeve from over the medical device. The medical device will
automatically expand and exert pressure on the wall of the blood
vessel at the site of the lesion. The catheter, sleeve, and
guidewire may then be removed from the patient.
[0126] For example, the tubular body of the medical device is first
positioned to surround a portion of an inflatable balloon catheter.
The medical device, with the balloon catheter inside is configured
at a first, collapsed diameter. The medical device and the
inflatable balloon are percutaneously introduced into a body lumen,
following a previously positioned guidewire in an over-the-wire
angioplasty catheter system, and tracked by a fluoroscope, until
the balloon portion and associated medical device are positioned
within the body passageway at the point where the medical device is
to be placed. Thereafter, the balloon is inflated and the medical
device is expanded by the balloon portion from the collapsed
diameter to a second expanded diameter. After the medical device
has been expanded to the desired final expanded diameter, the
balloon is deflated and the catheter is withdrawn, leaving the
medical device in place. The medical device may be covered by a
removable sheath during delivery to protect both the medical device
and the vessels.
[0127] The medical devices are useful for treating certain
conditions, such as venous valve insufficiency, varicose veins,
esophageal reflux, restenosis or atherosclerosis. In some
embodiments, the invention relates to methods of treating venous
valve-related conditions.
[0128] A "venous valve-related condition" is any condition
presenting symptoms that can be diagnostically associated with
improper function of one or more venous valves. In mammalian veins,
venous valves are positioned along the length of the vessel in the
form of leaflets disposed annularly along the inside wall of the
vein which open to permit blood flow toward the heart and close to
prevent back flow. These venous valves open to permit the flow of
fluid in the desired direction, and close upon a change in
pressure, such as a transition from systole to diastole. When blood
flows through the vein, the pressure forces the valve leaflets
apart as they flex in the direction of blood flow and move towards
the inside wall of the vessel, creating an opening therebetween for
blood flow. The leaflets, however, do not normally bend in the
opposite direction and therefore return to a closed position to
restrict or prevent blood flow in the opposite, i.e. retrograde,
direction after the pressure is relieved. The leaflets, when
functioning properly, extend radially inwardly toward one another
such that the tips contact each other to block backflow of blood.
Two examples of venous valve-related conditions are chronic venous
insufficiency and varicose veins.
[0129] In the condition of venous valve insufficiency, the valve
leaflets do not function properly. For example, the vein can be too
large in relation to the leaflets so that the leaflets cannot come
into adequate contact to prevent backflow (primary venous valve
insufficiency), or as a result of clotting within the vein that
thickens the leaflets (secondary venous valve insufficiency).
Incompetent venous valves can result in symptoms such as swelling
and varicose veins, causing great discomfort and pain to the
patient. If left untreated, venous valve insufficiency can result
in excessive retrograde venous blood flow through incompetent
venous valves, which can cause venous stasis ulcers of the skin and
subcutaneous tissue. Venous valve insufficiency can occur, for
example, in the superficial venous system, such as the saphenous
veins in the leg, or in the deep venous system, such as the femoral
and popliteal veins extending along the back of the knee to the
groin.
[0130] The varicose vein condition consists of dilatation and
tortuosity of the superficial veins of the lower limb and resulting
cosmetic impairment, pain and ulceration. Primary varicose veins
are the result of primary incompetence of the venous valves of the
superficial venous system. Secondary varicose veins occur as the
result of deep venous hypertension which has damaged the valves of
the perforating veins, as well as the deep venous valves. The
initial defect in primary varicose veins often involves localized
incompetence of a venous valve thus allowing reflux of blood from
the deep venous system to the superficial venous system. This
incompetence is traditionally thought to arise at the
saphenofemoral junction but may also start at the perforators.
Thus, gross saphenofemoral valvular dysfunction may be present in
even mild varicose veins with competent distal veins. Even in the
presence of incompetent perforation, occlusion of the
saphenofemoral junction usually normalizes venous pressure.
[0131] The initial defect in secondary varicose veins is often
incompetence of a venous valve secondary to hypertension in the
deep venous system. Since this increased pressure is manifested in
the deep and perforating veins, correction of one site of
incompetence could clearly be insufficient as other sites of
incompetence will be prone to develop. However, repair of the deep
vein valves would correct the deep venous hypertension and could
potentially correct the secondary valve failure. Apart from the
initial defect, the pathophysiology is similar to that of varicose
veins.
[0132] While many preferred embodiments discussed herein discuss
implantation of a medical device in a vein, other embodiments
provide for implantation within other body vessels. In another
matter of terminology there are many types of body canals, blood
vessels, ducts, tubes and other body passages, and the term
"vessel" is meant to include all such passages.
EXAMPLES
[0133] The tension on valve leaflet material in two implantable
valves having the configuration shown in FIGS. 4A-4C was measured
perpendicular to the longitudinal axis of the valve as a function
of the diameter of the frame lumen. The first implantable valve
(Sample 1) and the second implantable valve (Sample 2) had the same
configuration, except that the scale of the Sample 1 valve was
smaller than the Sample 2 valve. First, the internal lumen of the
implantable frame 10 was measured without the attached valve
leaflets, in the radially expanded state. Each frame had the
configuration shown in FIGS. 1A-1B. Next, SIS valve leaflets were
tensionably attached to to each frame 10 in the manner shown in
FIGS. 4A-4C. Attachment of the valve leaflets 52, 54 restricted the
radial expansion of the frame 10 and the reduced lumen diameter was
measured after leaflet attachment. The tension on each SIS leaflet
was measured perpendicular to the longitudinal axis 2 of each valve
by subtracting the outward radial force exerted by the frame before
attachment of the leaflets, and the outward radial force exerted by
the frame with the SIS leaflets attached. The results of the
measurements are shown in Table 1 below. TABLE-US-00001 TABLE 1 SIS
Lateral Bare Frame, Tension (N) Fully Expanded Lumen Dia. With
(perpendicular to Lumen Dia. Attached SIS longitudinal axis (mm)
Leaflets (mm) of lumen) Sample 1 14.00 .+-. 0.25 13.0 .+-. 1.0 1.5
N Sample 2 16.50 .+-. 0.25 15.0 .+-. 1.0 3.5 N
[0134] In Sample 1, attachment of the leaflets restrained the
radial expansion of the frame, reducing the diameter by about 1 mm
(a reduction in diameter from about 14 mm to about 13 mm, or about
a 7% reduction). The valve leaflets of Sample 1 were subject to an
estimated force of about 1.5 N between two struts opposably
positioned across the lumen of the frame. The valve of Sample 2 was
slightly larger than Sample 1, having an expanded diameter of about
16.50 mm. Attachment of the valve leaflets to the frame of Sample 2
reduced the diameter of the frame to about 15 mm, about a 9%
reduction in the lumen diameter that subjected the valve leaflets
to an estimated force of about 3.5 N. The leaflet preferably is
subjected to a tension between attachment points located on two
struts positioned opposite the valve lumen from each other.
[0135] The invention includes other embodiments within the scope of
the claims, and variations of all embodiments, and is limited only
by the claims made by the Applicants. Some methods further comprise
the step of implanting one or more frames attached to one or more
valve leaflets, as described herein. In some embodiments, methods
of treating may also include the step of delivering a medical
device to a point of treatment in a body vessel, or deploying a
medical device at the point of treatment.
* * * * *