U.S. patent application number 10/287416 was filed with the patent office on 2003-04-03 for reduction of stent thrombogenicity.
Invention is credited to Babbs, Charles F., Badylak, Stephen F., Bourland, Joe D., Fearnot, Neal F., Geddes, Leslie A., Hiles, Michael C..
Application Number | 20030065379 10/287416 |
Document ID | / |
Family ID | 26708749 |
Filed Date | 2003-04-03 |
United States Patent
Application |
20030065379 |
Kind Code |
A1 |
Babbs, Charles F. ; et
al. |
April 3, 2003 |
Reduction of stent thrombogenicity
Abstract
A tissue graft construct and method for repairing the inner
linings of damaged or diseased vertebrate vessels is described. The
method comprises the steps of positioning a tissue graft construct
within a blood vessel at a site in need of repair. The tissue graft
construct comprises a stent (3) covered with submucosal tissue (4)
wherein the stent (3) is formed for receiving the distal end of a
catheter (1) having an inflatable balloon (2).
Inventors: |
Babbs, Charles F.; (West
Lafayette, IN) ; Fearnot, Neal F.; (West Lafayette,
IN) ; Badylak, Stephen F.; (West Lafayette, IN)
; Geddes, Leslie A.; (West Lafayette, IN) ; Hiles,
Michael C.; (Lafayette, IN) ; Bourland, Joe D.;
(West Lafayette, IN) |
Correspondence
Address: |
BARNES & THORNBURG
11 SOUTH MERIDIAN
INDIANAPOLIS
IN
46204
|
Family ID: |
26708749 |
Appl. No.: |
10/287416 |
Filed: |
November 4, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10287416 |
Nov 4, 2002 |
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09319718 |
Jun 10, 1999 |
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6475232 |
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09319718 |
Jun 10, 1999 |
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PCT/US97/22586 |
Dec 10, 1997 |
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09116734 |
Jul 16, 1998 |
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08429308 |
Apr 26, 1995 |
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5693085 |
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08429308 |
Apr 26, 1995 |
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08350223 |
Dec 6, 1994 |
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08350223 |
Dec 6, 1994 |
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08235300 |
Apr 29, 1994 |
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60032682 |
Dec 10, 1996 |
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Current U.S.
Class: |
623/1.13 |
Current CPC
Class: |
A61F 2002/072 20130101;
A61F 2002/9583 20130101; A61F 2/82 20130101; A61F 2220/0075
20130101; A61M 29/02 20130101; A61F 2/95 20130101; A61F 2/958
20130101; A61F 2220/0008 20130101; C08L 89/06 20130101; A61F
2002/075 20130101; A61L 33/18 20130101; A61F 2250/0067 20130101;
A61F 2/07 20130101; A61L 31/10 20130101; A61M 25/0045 20130101;
A61F 2/86 20130101; A61L 31/005 20130101; A61F 2240/001 20130101;
A61L 31/10 20130101; A61F 2/885 20130101; A61F 2220/005 20130101;
A61F 2/90 20130101; A61F 2/91 20130101 |
Class at
Publication: |
623/1.13 |
International
Class: |
A61F 002/06 |
Claims
1. A prosthetic device for repairing the inner linings of damaged
or diseased vertebrate vessels, said device comprising a
cylindrical shaped expandable member having a luminal and exterior
surface, wherein expansion of said member increases the
circumference of said member; and a layer of submucosal tissue
fixed to the luminal or exterior surface of said member.
2. The device of claim 1 wherein the cylindrical shaped member is a
vascular stent having a lumen sized for receiving a catheter.
3. The device of claim 1 wherein the submucosal tissue comprises
intestinal submucosa delaminated from both the tunica muscularis
and at least the luminal portion of the tunica mucosa of a
warm-blooded vertebrate.
4. The device of claim 3 wherein the submucosal tissue covers both
the exterior and the luminal surface of the stent.
5. The device of claim 4, wherein said layer of submucosal tissue
comprises a narrow sheet of submucosal tissue wrapped
longitudinally about the luminal and exterior surface of the stent
a plurality of times to form loops of submucosal tissue wherein
each loop partially overlaps another loop of submucosal tissue.
6. The device of claim 4, wherein the layer of submucosal tissue
comprises a plurality of narrow sheets of submucosal tissue having
a first end and a second opposite end wrapped longitudinally about
the luminal and exterior surface of the stent, wherein the first
and second opposite ends of each sheet of submucosal tissue are
bonded together to form loops of submucosal tissue and wherein each
loop of submucosal tissue partially overlaps another loop of
submucosal tissue.
7. The device of claim 2 wherein the means for expanding the stent
comprises a releasable spring mechanism that biases the prosthetic
device to a minimal circumference.
8. The device of claim 2 wherein the layer of submucosal tissue
comprises fluidized submucosal tissue coated onto the surface of
the stents.
9. The device of claim 2 wherein the submucosal tissue covering the
stent is provided with a plurality of slits that upon expansion of
the expandable member provide fluid communication between the lumen
of the stent and the exterior of the stent.
10. A method for repairing the inner linings of damaged or diseased
vertebrate vessels, said method comprising the steps of: inserting
a catheter into a vessel, wherein said catheter has a graft
construct comprising submucosal tissue of a warm blooded vertebrate
removably fixed to its distal end; positioning the graft construct
at a site within the vessel in need of repair; biasing the graft
construct against the luminal surface of the vessel to fix the
graft construct to the luminal surface; and removing the
catheter.
11. The method of claim 10 wherein the catheter is a
balloon-expandable catheter and the step of biasing the graft
construct comprises inflating the balloon.
12. The method of claim 10 wherein graft construct further
comprises a stent, and the submucosal tissue covers at least a
portion of the exterior surface of the stent.
13. The method of claim 10 wherein the vessel is a blood
vessel.
14. An improved vascular stent for expanding obstructed vessels,
said stent formed as an expandable tube having an exterior and
luminal surface, the improvement comprising fixing a layer of
submucosal tissue to the external surface of the stent.
15. The improved vascular stent of claim 14 further comprising a
layer of submucosal tissue covering the luminal surface of the
stent.
16. The improved vascular stent of claim 14 wherein a strip of
submucosal tissue is wrapped longitudinally about the luminal and
exterior surfaces of the stent a plurality of times to form loops
of submucosal tissue and wherein each loop of submucosal tissue
partially overlaps an adjacent loop of submucosal tissue.
17. The improved vascular stent of claim 14 wherein the layer of
submucosal tissue is formed as a tube of submucosal tissue, wherein
the tube is provided with a plurality of longitudinal slits.
18. The improved vascular stent of claim 17 wherein the
longitudinal slits are approximately uniform in shape and are
located equidistant from one another.
19. The device of claim 14, wherein the layer of submucosal tissue
comprises a pluraltiy of narrow sheets of submucosal tissue having
a first end and a second opposite end wrapped longitudinally about
the luminal and exterior surface of the stent, wherein the first
and second opposite ends of each sheet of submucosal tissue are
bonded together to form loops of submucosal tissue and wherein each
loop of submucosal tissue overlaps with another loop of submucosal
tissue.
20. The improved vascular stent of claim 14 wherein the stent
comprises a wire that is coiled and shaped in the form of an
incomplete tube, and the submucosal tissue is fixed to the stent by
braiding a plurality of narrow sheets of submucosal tissue around
the wire forming the stent.
Description
FIELD OF THE INVENTION
[0001] This invention relates to an intestinal tissue covered
prosthesis useful in promoting the resurfacing and repair of
damaged or diseased tissue structures. More particularly this
invention is directed to stents having a layer of submucosal tissue
covering a surface of the stent, and their use in repairing damaged
or diseased physiological vessels, particularly blood vessels.
BACKGROUND AND SUMMARY OF THE INVENTION
[0002] The most common cause of vascular disease in the Western
world is atherosclerosis, in which cholesterol and fibrous tissue,
often together with calcium precipitates, gradually build up within
the inner layers of the arterial wall, diminishing the cross
sectional area available for blood flow. There are two essential
abnormalities of such atherosclerotic lesions that cause
complications. The first is the narrowing of the lumen, which
produces a chronic limitation of blood flow distally. The second is
the abnormally raised, roughened inner surface of the artery, the
physical properties of which tend to induce platelet adhesion and
clot formation at the diseased site. Thrombosis can produce sudden
cessation of blood flow with disastrous consequences for downstream
organs such as the brain, heart muscle, kidney, or lower
extremities. The eroded, abnormal intimal surface of sclerotic
vessels causes additional complications including fragmentation of
atherosclerotic material with downstream embolization and
hemorrhage or dissection of blood into the plaque itself causing
sudden expansion of the lesion and occlusion of the vessel.
[0003] Percutaneous transluminal angioplasty (PTA), first performed
25 years ago by Dotter and Judkins, is the technique of opening
narrowed or occluded blood vessels by passing guide wires and
catheters through the stenotic or occluded portion of the blood
vessel. Dotter's original PTA method involved inserting
increasingly larger catheters over a guidewire to progressively
dilate the vessel. Later modifications utilized graduated catheters
with gradually tapering tips, which created more lateral
compression and less longitudinal shearing action. These early PTA
procedures were limited by the requisite stiffness of the catheters
and by the large puncture wounds required for the procedure.
[0004] In 1974, PTA procedures were revolutionized by the
introduction of balloon catheter angioplasty. A balloon catheter
has an expandable sac that can be expanded and contracted in a
controlled manner in response to inflation pressure. Balloon
catheter angioplasty involves positioning the balloon catheter at a
stenotic site and inflating the sac to a predetermined size to open
the stenotic or occluded portion of the blood vessel. The sac is
then deflated and the catheter removed leaving a larger lumen.
Standard balloon angioplasty, with or without the use of stents,
produces a torn vessel with myointimal flaps and exposed fissures.
These provide thrombogenic surfaces and sites for hemodynamic
dissection. Furthermore, although the use of the stents in PTA
procedures gives highly predictable immediate angiographic results,
those stents all suffer the disadvantage that they have limited
long term efficacy. Despite holding the vessel open, the natural
reparative processes at a stent-dilated vessel result in healing
tissues growing around the stent structure and eventually occluding
the lumen of the vessel. In addition to PTA procedures, alternative
techniques for removing atherosclerotic plaques include laser
angioplasty and mechanical arthrectomy devices, which can vaporize,
melt, or remove plaque material. However all such systems leave an
abnormal, thrombogenic surface.
[0005] Angioplasty is now known to damage the vessel wall by
tearing and stretching, and this form of controlled injury opens
the vessel lumen and increases blood flow acutely in nearly all
cases. However, abrupt vessel closure during or immediately
following PTA and late restenosis continues to limit the
effectiveness of the procedure. To enhance the efficacy of PTA
procedures catheters have been fitted with vascular stents.
[0006] Stents are three dimensional implantable structures that
(upon delivery to an intra vessel position) physically hold a blood
vessel open. Vascular stents are typically formed to fit on the end
of conventional catheters for delivery of the stent to a
predetermined intravascular location. A number of stents for
coronary use are commercially available. They differ in
physicochemical characteristics and the mode of implantation.
Ideally, a stent should be flexible, thrombo-resistant, low in
profile, radiopaque, limit the expansion of repair tissues into the
lumen of the vessel, and have an easy, reliable delivery system.
Currently available expandable stents can be categorized as "self
expandable stents" and "balloon expandable stents." Self-expanding
stents utilize a spring mechanism to constrain the stent to a
compressed shape. Upon removal of the constraint, the stent expands
to a predetermined dimension. Balloon expandable stents are
expandable members formed to fit over a balloon catheter and
capable of being expanded in response to controlled inflation of
the balloon catheter. Inflation of the balloon results in plastic
deformation of the stent beyond its elastic limits so that the
stent remains in its expanded state upon subsequent deflation and
removal of the balloon catheter. Preferably stents used in
conjunction with PTA are "expandable stents" having an initial
collapsed state that allows the stent to be delivered to the
desired intravascular location with minimal longitudinal shearing
action. Upon delivery to the desired location the stent is expanded
to fix the stent at that location and to physically hold the vessel
open.
[0007] The present invention utilizes a natural collagenous matrix
comprising submucosal tissue in combination with known angioplastic
techniques to eliminate complications that derive from the residual
abnormal, thrombogenic surfaces produced by current available
angioplastic techniques such as ordinary balloon angioplasty, laser
angioplasty, and transluminal mechanical arthrectomy. The
collagenous matrices for use in accordance with the present
invention comprise highly conserved collagens, glycoproteins,
proteoglycans, and glycosaminoglycans in their natural
configuration and natural concentration. On preferred collagenous
matrix comprises warm-blooded vertebrate submucosa.
[0008] In accordance with the present invention the submucosa is
isolated from warm-blooded vertebrate tissues including the
alimentary, respiratory, intestinal, urinary or genital tracts of
warm-blooded vertebrates. The preparation of intestinal submucosa
is described and claimed in U.S. Pat. No. 4,902,508, the disclosure
of which is expressly incorporated herein by reference. Urinary
bladder submucosa and its preparation is described in U.S. Pat. No.
5,554,389, the disclosure of which is expressly incorporated herein
by reference. Stomach submucosa has also been obtained and
characterized using similar tissue processing techniques. Such is
described in U.S. patent application No. 60/032,683 titled STOMACH
SUBMUCOSA DERIVED TISSUE GRAFT, filed on Dec. 10, 1996. Briefly,
stomach submucosa is prepared from a segment of stomach in a
procedure similar to the preparation of intestinal submucosa. A
segment of stomach tissue is first subjected to abrasion using a
longitudinal wiping motion to remove the outer layers (particularly
the smooth muscle layers) and the luminal portions of the tunica
mucosa layers. The resulting submucosa tissue has a thickness of
about 100 to about 200 micrometers, and consists primarily (greater
than 98%) of acellular, eosinophilic staining (H&E stain)
extracellular matrix material.
[0009] Preferred submucosal tissues for use in accordance with this
invention include intestinal submucosa, stomach submucosa, urinary
bladder submucosa, and uterine submucosa. Intestinal submucosal
tissue is one preferred starting material, and more particularly
intestinal submucosa delaminated from both the tunica muscularis
and at least the tunica mucosa of warm-blooded vertebrate
intestine.
[0010] As a tissue graft, submucosal tissue undergoes remodeling
and induces the growth of endogenous tissues upon implantation into
a host. It has been used successfully in vascular grafts, urinary
bladder and hernia repair, replacement and repair of tendons and
ligaments, and dermal grafts. The preparation and use of submucosa
as a tissue graft composition is described in U.S. Pat. Nos.
4,902,508; 5,281,422; 5,275,826; 5,554,389; and other related U.S.
patents. When used in such applications the graft constructs appear
not only to serve as a matrix for the regrowth of the tissues
replaced by the graft constructs, but also promote or induce such
regrowth of endogenous tissue. Common events to this remodeling
process include: widespread and very rapid neovascularization,
proliferation of granulation mesenchymal cells,
biodegradation/resorption of implanted intestinal submucosal tissue
material, and lack of immune rejection. The use of submucosal
tissue in sheet form and fluidized forms for inducing the formation
of endogenous tissues is described and claimed in U.S. Pat. Nos.
5,281,422 and 5,275,826, the disclosures of which are expressly
incorporated herein by reference.
[0011] The present invention is directed to an improved prosthetic
device for repairing the intima surface of damaged or diseased
vessels. The prosthetic devices of the present invention can also
be used in traditional PTA procedures to open narrowed or occluded
vessels. In one embodiment the prosthetic device comprises a
cylindrical shaped expandable member having a luminal and exterior
surface, and a layer of submucosal tissue fixed to the exterior or
luminal surface of the member. The expandable member is typically a
stent wherein expansion of the stent increases the circumference of
said member, thus fixing the device at a predetermined location
within the vessel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a cross-sectional view of a balloon catheter
carrying a submucosa tissue coated stent in accordance with this
invention.
[0013] FIG. 2 is a sectional view of a submucosa covered stent
positioned on a mandrel.
[0014] FIG. 3a-3c are perspective views of a stent, wrapped
longitudinally with one or more sheets of submucosal tissue. FIG.
3a illustrates a stent, wrapped longitudinally with a single sheet
of submucosal tissue. FIG. 3c and FIG. 3d illustrate a stent
wrapped with three separate sheets of submucosal tissue, each sheet
forming a single loop of submucosal tissue, wherein the stent is
shown in its condensed state (FIG. 3c) or in its expanded state
(FIG. 3d).
[0015] FIG. 4a and 4b are perspective views of a tube of submucosa
having a plurality of longitudinal slits formed in the walls of the
tube. FIG. 4a shows the tissue in its compact state and FIG. 4b
shows the tissue in its expanded state.
[0016] FIG. 5a-5d illustrates the construction of one embodiment of
a submucosa covered stent.
[0017] FIG. 6a illustrates a stent wire covered with a narrow sheet
of submucosal tissue and FIG. 6b and FIG. 6c illustrate a stent
formed from the submucosa tissue covered wire of FIG. 6a.
[0018] FIG. 7 illustrates an alternative embodiment of a submucosa
covered wire for forming stents in accordance with this
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention is directed to an improved vascular
stent composition and a method for repairing the inner linings of
damaged or diseased vessels. The method comprises the step of
applying a new, non-thrombogenic intimal surface of submucosal
tissue over the former damaged or diseased intima. The term
"vessel" as used herein is defined as including any bodily canal,
conduit, duct or passageway, including but not limited to blood
vessels, bile ducts, the esophagus, the trachea, the ureter and the
urethra. In one embodiment the vessel is expanded to increase the
lumen of the vessel simultaneously with the application of a layer
of submucosal tissue. Applicants have discovered that the applied
submucosal tissue layer provides a non-thrombogenic surface that
induces the formation of a new endothelium and inhibits restenosis
of a vessel after expansion of the vessel.
[0020] Submucosal tissue suitable for use in the present invention
comprises naturally associated extracellular matrix proteins,
glycoproteins, proteoglycans, glycosaminoglycans and other factors
in their natural configuration and natural concentration.
Submucosal tissue can be prepared from a variety of natural sources
including the alimentary, respiratory, intestinal, urinary or
genital tracts of warm-blooded vertebrates.
[0021] In one embodiment of the present invention the submucosal
tissue comprises intestinal submucosa delaminated from both the
tunica muscularis and at least the luminal portion of the tunica
mucosa. In another embodiment the intestinal submucosal tissue
comprises the tunica submucosa and basilar portions of the tunica
mucosa including the lamina muscularis mucosa and the stratum
compactum which layers are known to vary in thickness and in
definition dependent on the source vertebrate species.
[0022] The preparation of intestinal submucosal tissue for use in
accordance with this invention is described in U.S. Pat. No.
4,902,508. A segment of vertebrate intestine, preferably harvested
from porcine, ovine or bovine species, but not excluding other
species, is subjected to abrasion using a longitudinal wiping
motion to remove the outer layers, comprising smooth muscle
tissues, and the innermost layer, i.e., the luminal portion of the
tunica mucosa. One preferred source of intestinal submucosa is the
small intestine of mature adult pigs weighing greater than 450 lbs.
The submucosal tissue is rinsed several times with saline and
optionally sterilized.
[0023] The submucosal tissue of the present invention can be
sterilized using conventional sterilization techniques including
glutaraldehyde tanning, formaldehyde tanning at acidic pH,
propylene oxide treatment, gas plasma sterilization, gamma
radiation, electron beam radiation, and peracetic acid
sterilization. Sterilization techniques which do not adversely
affect the mechanical strength, structure, and biotropic properties
of the submucosal tissue is preferred. For instance, strong gamma
radiation may cause loss of strength of the sheets of submucosal
tissue. Preferred sterilization techniques include exposing the
graft to peracetic acid, 1-4 Mrads gamma irradiation (more
preferably 1-2.5 Mrads of gamma irradiation) or gas plasma
sterilization; peracetic acid sterilization is the most preferred
sterilization method.
[0024] Submucosal tissue treated with peracetic acid exhibits
little if any significant post-implantation calcification. The
treatment is typically conducted at a pH of about 2 to about 5 in
an aqueous ethanolic solution (about 2 to about 10% ethanol by
volume) at a peracid concentration of about 0.03 to about 0.5% by
volume. Typically, the submucosal tissue is subjected to two or
more sterilization processes. After the submucosal tissue is
sterilized, for example by chemical treatment, the tissue may be
wrapped in a plastic or foil wrap and sterilized again using
electron beam or gamma irradiation sterilization techniques.
[0025] The submucosal tissue specified for use in accordance with
this invention can also be in a fluidized form. The preparation of
fluidized forms of submucosa tissue is described in U.S. Pat. No.
5,275,826, the disclosure of which is expressly incorporated herein
by reference. Fluidized forms of submucosal tissue are prepared by
comminuting submucosa tissue by tearing, cutting, grinding, or
shearing the harvested submucosal tissue. Thus pieces of submucosal
tissue can be comminuted by shearing in a high speed blender, or by
grinding the submucosa in a frozen or freeze-dried state to produce
a powder that can thereafter be hydrated with water or a buffered
saline to form a submucosal fluid of liquid, gel or paste-like
consistency.
[0026] The comminuted submucosa formulation can further be treated
with an enzymatic composition to provide a homogenous solution of
partially solubilized submucosa. The enzymatic composition may
comprise one or more enzymes that are capable of breaking the
covalent bonds of the structural components of the submucosal
tissue. For example, the comminuted submucosal tissue can be
treated with a collagenase, glycosaminoglycanase, or a protease,
such as trypsin or pepsin at an acidic pH, for a period of time
sufficient to solubilize all or a major portion of the submucosal
tissue protein components. After treating the comminuted submucosa
formulation with the enzymatic composition, the tissue is
optionally filtered to provide a homogenous solution.
[0027] The viscosity of fluidized submucosa for use in accordance
with this invention can be manipulated by controlling the
concentration of the submucosa component and the degree of
hydration. The viscosity can be adjusted to a range of about 2 to
about 300,000 cps at 25.degree. C. Higher viscosity formulations,
for example, gels, can be prepared from the submucosa digest
solutions by adjusting the pH of such solutions to about 6.0 to
about 7.0.
[0028] Submucosal tissue can be stored in a hydrated or dehydrated
state. Lyophilized or air dried submucosa tissue can be rehydrated
and used in accordance with this invention without significant loss
of its biotropic and mechanical properties.
[0029] Submucosal tissue can be used in accordance with the present
invention in combination with standard PTA devices to form
prosthetic devices suitable for use in PTA procedures. Applicants
anticipate that the use of the present tissue graft constructs
comprising submucosal tissue will enhance the repair of damaged or
diseased vessels and thus improve the effectiveness of PTA
procedures. The method of repairing vessels in vivo through the use
of the disclosed devices comprises the steps of contacting the
intima surface of the vessel with submucosal tissue and holding the
submucosal tissue in place to provide a new intima surface.
Advantageously, the implanted layer of submucosal tissue induces
the growth of new endothelium without stenosis, and therefore the
submucosal tissue is preferably held in contact with the site in
need of repair for a time sufficient to induce the formation of a
new intima surface. In preferred embodiments the tissue graft
construct is permanently located within a blood vessel or other
structure and is ultimately replaced by endogenous cell growth.
[0030] In one embodiment of the present invention submucosal tissue
is used in combination with known angioplastic techniques and
devices to provide an improved composition and method for repairing
damaged or diseased portions of vessels. The improvement method
comprises fixing a graft construct comprising submucosal tissue
onto the surface of a catheter and delivering the tissue graft
construct to a predetermined intra-vessel location. It is
anticipated that the vessel walls of any bodily vessel, conduit,
canal or body cavity that is accessible to a catheter, can be
repaired using the method described in the present invention.
[0031] Conventional catheters can be used to position the
submucosal graft constructs to an intra-vessel location for contact
with a diseased or damaged surface of the vessel. In accordance
with one embodiment, the catheter is a balloon catheter, and the
balloon portion is covered with submucosal tissue. Upon positioning
of the submucosal tissue covered catheter within a vessel,
inflation of the balloon presses the submucosal tissue against the
intima surface of the vessel. Subsequent deflation of the balloon
portion allows the removal of the catheter, leaving the submucosal
tissue positioned in contact with the intima surface of the
vessel.
[0032] The submucosal tissue is preferably combined with additional
elements to enhance the retention of the submucosal tissue layer on
the original intima surface including, use of anchoring projections
(such as plastic or metal pins), adhesives, stents, or other
fixation devices known to those skilled in the art. In preferred
embodiments the submucosal tissue is held in contact with the
intima surface through the use of a stent.
[0033] In accordance with one embodiment an improved stent is
provided for opening obstructed or occluded vessicles. The improved
stent comprises a conventional expandable stent, wherein the
exterior surface of the stent is covered with submucosal tissue.
Upon deployment of the submucosal tissue covered stent, the
submucosal tissue covers the original intima surface of the vessel
to provide a smooth, non-thrombogenic surface. For example, in one
embodiment the exterior surface of a stent is covered with
submucosal tissue and a catheter is used to position the stent to a
predetermined location in a blood vessel. The stent is expanded,
and thereby expands the lumen of the vessel, and the submucosal
tissue is pressed against the luminal surface of the vessel thus
covering the arteriosclerotic lesions and the surface of blood
vessels damaged through the angioplasty procedure.
[0034] Table 1 provides a list of several stents suitable for use
in accordance with the present invention, however the list is not
exhaustive and additional stents known to those skilled in the art
can be used in accordance with the present invention.
1TABLE 1 Design and Characteristics of Stents in Clinical
Evaluation Filament Filament Stent Stent Surface Stent
Configuration Composition Thickness (mm) Diameter (mm) Length (mm)
Area (%) Radiopaque Self-expanding Wallset Wire-mesh Stainless
0.07-0.10 3.5-6.0 21-45 18.5-20 No Steel Balloon- expandable
Palmaz- Slotted tube Stainless 0.08 3.0-4.0 15 10 No Schatz Steel
Gianturco- Incomplete Stainless 0.15 2.0-4.0 20 10 No Roubin coil
Steel Wiktok Helical coil Tantalum 0.125 3.0-4.0 15-17 5-10 Yes
Streker Woven wire Stainless 0.07 2.0-3.5 15-25 -- No steel/ Yes
tantalum
[0035] In one embodiment, a prosthetic device utilizing a stent
incorporates a conventional balloon angioplasty catheter around
which are placed, in order, an expandable vascular stent, and a
layer of submucosal tissue. Alternatively the stent can be
sandwiched between two layers of submucosal tissue (i.e., one layer
covering the luminal surface of the stent and one layer covering
the external surface of the stent). The submucosal tissue is
immobilized onto the stent through the use of adhesives, sutures,
interweaving the tissue with the stent struts or other fixation
techniques known to those skilled in the art.
[0036] The graft constructs of the present invention can be
utilized in combination with conventional prosthetic devices known
to those skilled in the art as being useful for vessel repair. For
example the submucosal tissue constructs of the present invention
are fixed onto the distal end of a prosthetic device, such as a
catheter, using a variety of techniques including: frictional
engagement, applying the tissue onto the surface of the prosthetic
device followed by drying the material, suturing the tissue to the
device, and other means known to those skilled in the art.
[0037] In one preferred embodiment, the graft construct comprises
an expandable cylindrical shaped member that has submucosal tissue
covering at least the external surface of the member. In this
embodiment the lumen of the cylindrical member is sized for
receiving the distal end of a catheter, and more preferably the
expandable member is formed to frictionally engage the exterior
surface of the distal end of the catheter. The expansion of the
expandable member increases the circumference of the cylindrical
shaped member thus fixing the submucosal tissue against the luminal
surface of the vessel and allowing for the removal of the catheter
after deployment of the graft construct.
[0038] In one embodiment the catheter comprises a balloon-type
catheter and the expandable member comprises a stent that is
expanded to a fixed enlarged size by the inflation of the balloon
catheter. In this embodiment, inflation of the submucosal
tissue/stent-covered balloon catheter accomplishes several
therapeutic objectives, almost simultaneously. First, as in
conventional balloon angioplasty, the lumen is forcibly dilated to
reverse narrowing caused by an atherosclerotic plaque. Second, the
vascular stent maintains the expanded caliber of the vessel,
providing a degree of rigid support and maintaining a circular,
isodiametric cross-sectional profile. In addition the stent, in
combination with intra-arterial pressure, holds the submucosal
tissue against the intima surface of the vessel covering any
cracks, fissures, or tears in the vessel that result during balloon
inflation. Such defects in blood vessels are highly thrombogenic
when exposed to the blood stream. The new submucosal tissue also
provides a barrier between the metallic stent and vascular smooth
muscle, inhibiting late re-stenosis. Finally, the submucosal tissue
layer covers the old, diseased inner lining of the vessel (tunica
intima), substituting a smooth, non-thrombogenic surface, into
which healthy new endothelial cells can grow, ultimately replacing
the submucosal tissue with new endothelium.
[0039] Commercially available stents that are best suited for use
in accordance with the present invention are metallic (typically
stainless steel or tantalum) and are carried in a collapsed form
over a conventional balloon angioplasty catheter. When the balloon
is inflated the stent is deployed and expanded to its working, in
vivo size. However, other types of stents, such as self-expanding
stents, can also be used in accordance with the present invention
to resurface damaged or diseased body vessels.
[0040] One submucosal tissue covered stent construct suitable for
use in the present invention comprises a stent having one or more
pieces of submucosal covering the exposed external surfaces of the
stent. Upon implantation into a host the submucosal tissue is held
between the stent and the diseased vessel wall. In one preferred
embodiment the stent is positioned to the desired location in the
vessel through the use of a balloon-type catheter. In this
embodiment shown in FIG. 1, a single lumen angioplasty catheter 1
having an inflatable balloon 2, which is semi-rigid or rigid upon
inflation, carries a vascular stent 3 covered with small intestinal
submucosa 4. This embodiment of the invention is intended for
segments of vessels without significant side branches, such as the
renal arteries, the common carotid arteries, or the popliteal
arteries. Because of the absence of significant side branches, the
lack of perforations in the submucosal tissue will not pose
problems for tissue perfusion.
[0041] In another embodiment (FIG. 2) the submucosal tissue 12
overlays both the luminal surface 18 and the exterior surface 20 of
the stent 10 to covered all stent surfaces with submucosal tissue
12. Such a submucosal tissue covered stent is prepared in
accordance with one embodiment by first preparing a tubular
submucosal tissue construct, longer than the stent (preferably
twice as long as the stent). A mandrel 26 of the appropriate size
is inserted into the lumen of a tube of submucosal tissue and the
stent 10 is then fashioned around the submucosal tissue 12. The
leading edge 14 and trailing edge 16 of submucosal tissue 12 are
inverted, brought back over the exterior surface 20 of the stent 10
and sutured together, as shown in cross-section in FIG. 2. In this
embodiment, wherein both the luminal inward and exterior 20
surfaces of the stent are covered with submucosal tissue, a lumen
28 is formed between the outer and inner layers of the submucosal
tissue. The lumen 28 can optionally be filled with fluidized
submucosal tissue, growth factors, a heparin containing composition
or other components to assist the repair of the damaged or diseased
vessel.
[0042] The tube of submucosal tissue used to prepare the submucosa
covered stents of the present invention can be prepared in
accordance with procedures described in U.S. Pat. No. 5,902,508. In
one embodiment a tube of submucosa tissue is prepared from
intestinal submucosa that has been delaminated from both the tunica
muscularis and at lest the luminal portion of the tunica mucosa.
The appropriate sized lumen of the tube of submucosa can be
prepared by inserting a glass rod/mandrel, having the appropriate
diameter, into the lumen of the tube of submucosa and gathering up
the redundant tissue and suturing longitudinally along the gathered
material.
[0043] Alternatively, a sheet of submucosa can be used to form the
tube of submucosal tissue. In one embodiment the sheet of
submucosal tissue is rolled up around the distal end of the
catheter and the opposing lateral ends are situated to form a tube
that frictionally engages the catheter. Alternatively the graft
construct can be formed to define a tube of submucosa having a
diameter approximately the same as the catheter by wrapping the
submucosal tissue around an appropriately sized mandrel. The formed
tube of submucosal tissue can then be fixed onto the distal end of
a catheter. The tube of submucosal tissue is held in its
cylindrical shape by sutures, adhesives, compressing the tissue
under dehydration conditions, heat treating the tissue, the use of
crosslinking agents or any combination thereof. In one embodiment
multiple strips of submucosal tissue are overlapped with one
another as they are wrapped onto the mandrel to form a
multi-layered tube of submucosal tissue. In accordance with the
present invention the submucosal tissue can be wrapped onto the
mandrel in a variety of different orientations, provided that no
gaps exist between the seams of overlapped tissue that would expose
the surface of the mandrel.
[0044] In one embodiment a submucosal tissue covered stent
construct is formed by wrapping the stent with one or more strips
of submucosal to cover both the luminal and the exterior surfaces
of the stent. For example, a single long narrow sheet of submucosal
tissue 36 can be wrapped longitudinally along the exterior surface
of the stent 38 starting at one end of the stent, running along the
exterior surface to the second end of the stent and then running
along the luminal surface, from the second end back to the first
end (See FIG. 3a). The longitudinal wrapping is continued forming
continuous loops of submucosal tissue that cover the luminal and
exterior surfaces of the stent 38. In one preferred embodiment the
strip of submucosal tissue is wrapped longitudinally so that each
loop overlaps with the previously underlying strip. The overlapped
region may range from about 20% up to about 75%. The width of the
individual strips and the amount of overlap will vary according to
the size and type of stent selected. In addition, the stent can
optionally be covered with additional strips of submucosal tissue
to increase the thickness of the submucosal layer. The appropriate
parameters (width of the sheet of submucosal tissue and percent
overlap) will be selected to ensure that upon deployment of the
stent 38 the stent surface will not become exposed. Accordingly,
upon expansion of the circumference of the stent the individual
loops of overlapped submucosal tissue will slide over one another
to allow for the increased size of the stent without exposing the
surface of the stent
[0045] In one embodiment the luminal and exterior surfaces are
covered by a single strip of submucosal tissue, wherein the strip
of submucosal tissue has a width less than the circumference of the
stent. The strip of submucosal tissue is longitudinally wrapped
about the exterior and luminal surfaces to form loops of submucosal
tissue that cover the entire surface of the stent. Preferably the
loops of submucosal tissue will overlap with each other to such an
extent that the stent can be expanded to its in vivo working size
without exposing the surface of the stent.
[0046] In another embodiment (FIG. 3b) both the luminal surface an
the exterior surface of the stent are covered by a plurality of
separate sheets of submucosal tissue, each of which are wrapped
longitudinally about the exterior and luminal surface of the stent
to form loops of submucosal tissue. As shown in FIG. 3b and 3c
three sheets of submucosal tissue each having a first end 70 and a
second end 72 are longitudinally wrapped around the luminal and
exterior surface of the stent and the first and second ends (70 and
72, respectively) are sutured together to form 3 separate loops of
submucosal tissue. In the collapsed form shown in FIG. 3b the stent
has a collapsed luminal diameter CD and the three sheets of
submucosal tissue overlap one another by an overlap region,
OR.sub.1. When the stent is deployed the diameter of the stent
lumen is expanded to a second diameter, ED, wherein ED is greater
than CD. (See FIG. 3c). The sheets of submucosa slide past one
another to account for the increase in the circumference of the
expanded stent and the overlapped region decreases in size to a
distance OR.sub.2 wherein OR.sub.1, is greater than OR.sub.2.
Hence, both the inward and outward facing surfaces of the stent
remain covered with submucosal tissue, and both the blood and
underlying vascular wall "see" only submucosal tissue.
Alternatively in one embodiment the individual loops of submucosal
tissue shown in FIG. 3c and FIG. 3d cover only the exterior surface
of the stent, and the two opposite ends of each sheet of submucosal
tissue are looped around the first and second end coil,
respectively, of the stent and sutured.
[0047] Applications involving the repair of vessels that have
several branches (such as the left anterior descending coronary
artery, that has several smaller, but metabolically significant
side branches) requires modification of the basic device. In
accordance with FIG. 4a and 4b, a sleeve of submucosal tissue 30 is
placed over a stent, and the tissue covered stent is placed over an
angioplasty balloon. Staggered rows of longitudinal slits 32 are
cut in the submucosal tissue, as shown in FIG. 4a. When the
balloon-stent unit is expanded, the submucosal tissue opens to form
a submucosal tissue mesh 34, through which blood can pass from the
central lumen into side branches (FIG. 4b).
[0048] The mesh provides a matrix for in growth of native
endothelial tissue, however high blood flow rates through the open
spaces in the mesh where vessel side branches exist will tend to
retard thrombosis, maintaining the opening in the submucosal mesh.
Occasional obstruction of a side branch by the substance of the
mesh can occur, but by optimizing mesh size, blood flow to the side
branches will be preserved.
[0049] Attachment of the slit submucosal tissue to the coils of the
underlying stent is accomplished by the placement of sutures
through adjacent slits in the tissue and around individual stent
coils to form gathers of submucosal tissue. As the balloon stent
complex is expanded in vivo, the meshwork opens to the pre-planned
final diameter, and the gathers are drawn taut.
[0050] Alternatively, a slitted tube of submucosal tissue can be
used to cover both the exterior and luminal surface of the stent to
repair vessels that have several branches. In this embodiment, a
slitted sheet of tubular submucosal tissue, twice as long as the
stent, is laid down over the surface of a mandrel, and a stent is
fashioned around it. Then the leading and trailing edges of slitted
submucosal tissue are everted, brought back over the exterior
surface of the stent and sutured together to secure the submucosal
tissue around both the blood-facing and tissue-facing surfaces of
the stent. In this case suturing the submucosal tissue to the
individual coils of the stent is not necessary, the single suture
line is sufficient to secure the submucosal tissue in place. The
stent can be fixed onto the distal end of a balloon type catheter
and when the balloon stent complex is expanded in vivo, the
meshwork opens to allow blood to pass from the central lumen into
side branches.
[0051] Deployment of a submucosal tissue-covered stent, corrects
two resultant abnormalities of atherosclerotic occlusive disease in
one simple mechanical treatment. First, angioplasty with stent
placement reverses the chronic stenosis caused by atherosclerotic
plaque material. Second, resurfacing with anchored submucosal
tissue covers the old, complication prone, diseased surface with a
smooth, fresh, biocompatible surface that is resistant to
thrombosis, fragmentation, and dissection. Furthermore, submucosal
tissue can be dried, stored, and rehydrated without loss of
mechanical strength or thromboresistance. Thus submucosal tissue
can be applied to angioplasty catheters, and stored in conventional
sterile packages., and rehydrated at the time of use by immersion
in sterile saline.
EXAMPLE 1
Preparation of a Submucosal Tissue Covered Stent
[0052] A segment of intestinal tissue (the proximal jejunum) from
the donor species of choice is collected within 1 to 3 hours of
death. The submucosal tissue, prepared as described in U.S. Pat.
No. 4,902,508, is sized to make the diameter of the implant less
than or equal to the normal caliber of expected recipient blood
vessel (i.e., isodiametric). A sterile glass rod having the same
diameter as that of the target vessel is selected and placed into
the graft lumen. This reduced diameter allows for the initial 10 to
20% dilation that occurs after exposure to the systemic circulation
and eventual isodiametric size. Redundant tissue is then gathered
and the desired lumen diameter achieved by using either two
continuous suture lines or a simple interrupted suture line with
5-0 polypropylene suture material with a swaged, tapercut needle.
The material is then fixed onto the pre-made stent-and-balloon
catheter and the cut longitudinal ends are tucked under the ends of
the stent or otherwise secured to the stent, for example by
suturing the submucosa to the individual coils of the stent (See
FIG. 1). The preferred stent design is one that does not change
length during deployment, and thus does not create longitudinal
folds or wrinkles in the submucosal tissue.
EXAMPLE 2
[0053] Submucosal tissue can be fixed onto a stent by interweaving
the submucosal tissue onto the individual coils of a wire stent as
shown in FIG. 5a. First the stent 43 is made from a single wire 44
that is bent back and forth to form a coil, as shown in FIG. 5a A
sheet of dry submucosal tissue sheet 42 is then interweaved with
the zig-zag shaped stent wires as shown in FIG. 5a. A first end of
the submucosal tissue 46 is sutured to one end of the stent wires
46, whereas the opposite free end 48 extends beyond the unsutured
end of the stent wires as shown in FIGS. 5a and 5c. Then the
submucosal tissue-coated stent wires are bent into a cylindrical
shape to form an incomplete tube, as shown in FIGS. 5b, 5c and 5d.
FIG. 5b is an exploded view illustrating the interweaving of the
coiled stent with the submucosal tissue. FIG. 5c illustrates the
complete construct and FIG. 5d provides a sectional view of the
submucosal tissue covered stent. Note that the opposite free end 48
extends beyond the coils of the stent 40 so that when the stent is
expanded in the blood vessel, there is enough submucosal tissue to
fully cover the stent. FIG. 5b shows how the stent wires
interweave.
EXAMPLE 3
[0054] In an alternative embodiment the submucosal tissue is fixed
to the stent by spiral wrapping sheets of submucosal tissue on a
stent wire (See FIG. 6a), then forming the stent, as shown in FIG.
6b and 6c. The stent is made by starting with a straight stent wire
50 which is covered with submucosal tissue. The wire is covered
with two or more strands of dry submucosal tissue 52 by braiding as
shown in FIG. 6a. When covered in this way, the submucosal tissue
is wetted and allowed to dry. Therefore the strands of submucosal
tissue form a braided sleeve that covers the wire. Alternatively
the stent wire can be coated with a fluidized form of submucosal
tissue and allowed to dry. The wire is bent into a stent as shown
in FIGS. 6b and 6c.
[0055] The submucosal tissue can also be fixed onto the stent wire
without first cutting a prepared tube of submucosa into narrow
sheets of submucosa. After preparing a tube of submucosal tissue as
described in U.S. Pat. No. 4,902,508, the stent wire 62 is passed
through the lumen of the prepared tube of submucosal tissue 60
(FIG.7). The tube of submucosal tissue 60 will then be stretched by
pulling the two ends away from each other, to decrease the diameter
of the prepared tube of submucosal tissue, thereby forming a
closely fitting covering for the stent wire, as shown in FIG. 7.
The gut-covered stent wire is then coiled as in FIG. 6b to form the
expandable stent.
EXAMPLE 4
Implantation of Submucosa Covered Stents within Dogs
[0056] Five dogs (hounds, approximately 40 to 60 lbs) will undergo
a laparotomy under general anesthesia (Pentothal I.V. and
Isoflurane gas maintained at 2%) with placement of a 2-4 cm, small
intestinal submucosa coated, 11.5 Fr. biliary stent. The stents
will be Cotton Leung Biliary Stents manufactured by Wilson-Cook
Medical, Inc. of Winston-Salem, N.C. Sterilized small submucosa is
prepared in accordance with Example 1 in tubular form and having a
length greater than the length of the stent. The submucosal tissue
is positioned within the luminal space of a stent so the two ends
of the submucosal tissue extend past the ends of the stent. The two
ends of the submucosal tissue will then be everted and pulled back
over the exterior portion of the stent and sutured at the midline
of the stent. Thus both the exterior and luminal surface of the
stent will be covered with the submucosal tissue.
[0057] This submucosal tissue covered stent is then deployed in the
bile duct of the dogs using the following procedure which entails a
laparotomy in the dog under general anesthesia. A midline incision
from umbilicus to xiphisternum will be performed with dissection to
and opening of the peritoneum performed in accordance with
procedures known to those skilled in the art. The common bile duct
will be identified and followed to the duodenum. A duodenotomy will
be performed and the major papilla identified. After dilation of
the papilla, a 24 cm submucosal tissue coated 11.5 Fr biliary stent
will be placed into the common bile duct with the distal portion of
the stent protruding through the papilla and draining into the
duodenum. The duodenotomy and abdominal wall incisions will be
closed and the animal allowed to recover from anesthesia in an
intensive care cage. The dogs will be monitored by the Medical
Research Lab Animal Technicians and be allowed food and water
approximately 24 hours post-operatively. Post-operative analgesia
(torbutrol) will be administered as required.
[0058] No drains will be placed in the animals and the
post-operative recovery needs are expected to be those encountered
with exploratory laparotomy alone. Animals will be observed for
signs of sepsis, jaundice, bowel obstruction, etc. and euthanized
at this time if necessary. Euthanasia will be by Socumb euthanasia
solution, I.V., 1 ml/10 lbs. Dogs with uneventful post-operative
courses will be euthanized at approximately 12 weeks; the biliary
stent will be recovered at the time of postmortem examination of
the abdomen with appropriate specimens of adjacent organs submitted
for pathological examination.
* * * * *