U.S. patent number RE36,370 [Application Number 08/777,360] was granted by the patent office on 1999-11-02 for resorbable vascular wound dressings.
Invention is credited to Shu-Tung Li.
United States Patent |
RE36,370 |
Li |
November 2, 1999 |
Resorbable vascular wound dressings
Abstract
The present invention is related to prostheses, their methods of
manufacture and methods for repairing vascular lesions using such
prostheses. Natural polymers such as collagen are processed and
fabricated to form tubular resorbable vascular wound dressings with
unique physico-chemical and mechanical properties for repairing
selected vascular segments, and for delivering therapeutic agents
at selected sites within vessels and at the anastomoses.
Inventors: |
Li; Shu-Tung (Oakland, NJ) |
Family
ID: |
26724412 |
Appl.
No.: |
08/777,360 |
Filed: |
December 27, 1996 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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821384 |
Jan 13, 1992 |
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Reissue of: |
046895 |
Apr 15, 1993 |
05376376 |
Dec 27, 1994 |
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Current U.S.
Class: |
424/443; 424/445;
606/108; 606/153; 606/154; 623/1.1; 623/23.64; 623/901 |
Current CPC
Class: |
A61B
17/11 (20130101); A61F 2/82 (20130101); A61F
2/958 (20130101); A61F 2/95 (20130101); A61F
2250/0067 (20130101) |
Current International
Class: |
A61B
17/11 (20060101); A61F 2/06 (20060101); A61B
17/03 (20060101); A61F 2/00 (20060101); A61F
013/00 () |
Field of
Search: |
;424/443,445
;606/108,153,154 ;623/1,12,901 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Brouillette; D. Gabrielle
Attorney, Agent or Firm: Fish & Richardson P.C.
Parent Case Text
This application .Iadd.is a Reissue of Ser. No. 08/046,895, filed
Apr. 15, 1993, U.S. Pat. No. 5,376,376, which .Iaddend.is a
continuation of prior U.S. application Ser. No. 07/821,384, filed
Jan. 13, 1992, now abandoned.
Claims
What is claimed is:
1. A self-expandable vascular wound dressing for treating a blood
vessel comprising a conduit having walls comprised of type I
collagen matrix material having pores with an average diameter of
from about 0.1 .mu.m to about 150 .mu.m, a density of from about
0.05 g/cm.sup.3 to about 0.8 g/cm.sup.3, and an inwardly converging
tapered inner diameter.
2. The wound dressing of claim 1 having a wall thickness of from
about 0.05 mm to about 0.30 mm at its ends and from about 0. 1 mm
to about 1.5 mm at its center.
3. The wound dressing of claim 2 having an inner diameter of from
about 2 mm to about 30 mm.
4. The wound dressing of claim 1 having a compliance of from about
2.0% radial change per mm Hg.times.10.sup.-2 to about 7.0% radial
change per mm Hg.times.10.sup.-2.
5. The wound dressing of claim 1 having a swelling capacity of from
about 0.5 g/g to about 15 g/g.
6. The wound dressing of claim 1 having a shrinkage temperature of
from about 55.degree. C. to about 85.degree. C.
7. The wound dressing of claim 1 having a relaxation recovery time
of from about 1 second to about 30 seconds in an aqueous
solution.
8. The wound dressing claim 1 further containing medicaments
comprising antibiotics, aspirin, coumadin, polyanionic
polysaccharides, prostaglandins, plasminogen activators,
glycoproteins, wound healing agents, type II through type XII
collagens, and mixtures thereof.
9. The wound dressing of claim 1 which is resorbable in vivo in
about 30 days to about 120 days.
10. A self-expandable vascular wound dressing for treating a blood
vessel comprising a conduit having walls comprised of type I
collagen matrix material having pores with an average diameter of
from about 0.1 .mu.m to about 150 .mu.m and an inwardly converging
tapered inner diameter; said walls having a thickness of from about
0.05 mm to about 0.30 mm at its ends and from about 0.1 mm to about
1.5 mm at its center; said conduit having an inner diameter of from
about 2 mm to about 30 mm, a density of from about 0.05 g/cm.sup.3
to about 0.8 g/cm.sup.3, a compliance of from about 2.0% radial
change per mm Hg.times.10.sup.-7 to about 7.0% radial change per mm
Hg.times.10.sup.-2, and a swelling capacity of from about 0.5 g/g
to about 15 g/g.
11. The wound dressing of claim 10 having a shrinkage temperature
of from about 55.degree. C. to about 85.degree. C.
12. The wound dressing claim 10 having a relaxation recovery time
of from about 1 second to about 30 seconds in an aqueous
solution.
13. The wound dressing of claim 10 further containing medicaments
comprising antibiotics, aspirin, coumadin, polyanionic
polysaccharides, prostaglandins, plasminogen activators,
glycoproteins, wound healing agents, type II through type XII
collagens, and mixtures thereof.
14. The wound dressing of claim 10 which is resorbable in vivo in
about 30 days to about 120 days. .Iadd.
15. A self-expandable vascular wound dressing for testing a blood
vessel comprising a folded conduit leaving walls comprised of type
I collagen matrix material having pores with an average diameter of
from about 0.1 .mu.m to about 150 .mu.m and a density of from about
0.05 g/cm.sup.3 to about 0.8 g/cm.sup.3. .Iaddend..Iadd.16. The
wound dressing of claim 15 having a wall thickness of from about
0.05 mm to about 0.30 mm at its ends and from about 0.1 mm to about
1.5 mm at its center. .Iaddend..Iadd.17. The wound dressing of
claim 16 having an inner diameter of from about 2 mm to about 30
mm. .Iaddend..Iadd.18. The wound dressing of claim 15 having a
compliance of from about 2.0% radial change per mm
Hg.times.10.sup.-2 to about 7.0% radial chance per mm
Hg.times.10.sup.-2. .Iaddend..Iadd.19. The wound dressing of claim
15 having a swelling capacity of from about 0.5 g/g to about 15
g/g. .Iaddend..Iadd.20. The wound dressing of claim 15 having a
relaxation recovery time of form about 1 second to about 30 seconds
in an aqueous solution. .Iaddend..Iadd.21. The wound dressing of
claim 15 having a shrinkage temperature of from about 55.degree. C.
to
about 85.degree. C. .Iaddend..Iadd.22. The wound dressing of claim
15 further containing medicaments comprising antibiotics, aspirin,
coumadin, polyanionic polysaccharides, prostagladins, plasminogen
activators, glycoproteins, wound healing agents from type II
through type XII, and mixtures thereof. .Iaddend..Iadd.23. The
wound dressing of claim 15 which is resorbable in vivo in about 30
days to about 120 days. .Iaddend.
Description
FIELD OF INVENTION
This invention pertains to the field of interventional therapeutic
approaches and surgical approaches to blood vessel repair and
regeneration. More specifically, the present invention relates to
the bioresorbable, biocompatible, non-thrombogenic, porous tubular
vascular wound dressings comprised of collagen based material,
which vascular wound dressings are used to repair damaged or
diseased blood vessel segments so as to provide a segment of
tubular vascular wound dressing to mechanically support the damaged
or diseased vessel, to facilitate the regeneration of the host
vessel, and to provide a means to deliver therapeutic agents at the
selected sites. Methods of manufacturing the resorbable vascular
wound dressings and methods of using the resorbable vascular wound
dressings are disclosed.
BACKGROUND OF THE INVENTION
Prior to 1980, the most effective means of repairing diseased blood
vessels was by surgery. A comprehensive review of the prior art of
vascular surgery can be found in "Vascular Surgery" edited by
Wesley S. Moore, Grune & Stratton, Inc. 1983. In one of the
disclosed surgical procedures, a vascular graft (either biological
or synthetic) is used to bypass the lesion to allow blood flow from
the proximal to the distal end. Typically, in coronary artery
repair procedures, an autogenous saphenous vein graft is used as a
bypass graft to restore the normal blood flow in the heart. As
surgical procedures of this kind are generally traumatic, requiring
weeks of hospitalization and extensive surgical costs, alternative
treatment methods have been sought. Percutaneous transluminal
angioplasty (PTA) has since emerged to be the most popular method
as the least traumatic interventional therapeutic approach for
repairing atherosclerotic coronary and peripheral artery diseases
in the past decade. There were approximately 300,000 angioplasty
procedures for coronary artery diseases in the U.S. alone for 1988
(BBI Newsletter vol 13, No. 5, Table 4, Page 86, 1989). Despite the
growth and acceptance of angioplasty, its overall success has been
limited by vessel reclosures (abrupt reclosure and restenosis).
Overall, vessel reclosure occurred in one third of cases over the
past ten years. With the anticipated increase in angioplasty
procedures in the coming years, a correspondingly greater number of
patients will be affected as a result of vessel reclosure. The
impact of vessel reclosure is therefore of major importance in
terms of patient morbidity, repeat procedure risk, and increased
health costs. It has been estimated that a reduction in the
restenosis rate or 33% to 25% could save $300 million in overall
healthcare costs. As such, an effective, reliable and safe method
of reducing and perhaps preventing vessel reclosure is most
welcome.
Many different approaches have been taken in an attempt to prevent
post-angioplasty vessel reclosure. One such approach has been the
use of an intravascular stent to mechanically keep the lumen open.
One such stent is disclosed in U.S. Pat No. 4,733,665, where an
intravascular stent comprising of an expandable stainless steel
wire mesh tube is used to prevent post angioplasty restenosis and
vessel reclosure. The stent is positioned over an inflatable
balloon secured to a catheter and is advanced to the stenosed
region. The balloon is inflated, thereby expanding the stent into
contact with the vessel wall. The elastic limit of the wire mesh is
exceeded when the balloon is expanded, so that the stent retains
its expanded configuration. U.S. Pat No. 4,503,569 discloses a
shape memory alloy stent which is advanced to a stenosed region on
a catheter. The stent has the form of a coil spring. After the
stent is in place, the stent is heated with a hot fluid causing the
shape memory alloy to expand into contact with the blood vessel.
Stents for blood vessel repair are also disclosed in U.S. Pat. Nos.
4,553,545 and 4,732,152. A plastic graft for repair of vascular
system is disclosed in U.S. Pat. No. 4,740,207. U.S. Pat. No.
4,577,631 discloses a Dacron graft that is coated with an adhesive
which may be activated by ultraviolet or ultrasonic energy after
placement in the aorta. As most of these stents and grafts have
been developed based on mechanical requirements, and are fabricated
from metals, alloys, or plastics and remain in the blood vessel
indefinitely, they generally have many disadvantages and
limitations in fulfilling the requirements of an acceptable
intravascular prosthesis which is in constant contact with the
blood and is subjected to continuous pulsatile pressure in the
body. The disadvantages of the prior art intravascular stents and
grafts are discussed below.
Firstly, the selection of a blood compatible material is most
critical in applications in contact with blood. Metals have high
surface energy and are not blood compatible which may therefore
induce acute thrombosis when implanted as an intraluminal or
intravascular stent or graft. In addition, metals are
non-resorbable and are subject to corrosion. Even the best
stainless steel cannot be guaranteed that they will not corrode
under the long term implantation conditions.
Secondly, compliance mismatch resulting in intimal hyperplasia and
graft reclosure has been documented in many vascular grafting
procedures. Metals are known to be non-compliant and it is not
surprising that some chronic reclosure of the metal stent may be
attributed to intimal hyperplasia formation. In fact, anastomotic
hyperplasia as a result of compliance mismatch is still one of the
major hurdles in developing a small diameter vessel for coronary
bypass surgeries.
Furthermore, complete circumferential contact with the vessel
endoluminal surface is critical for stent safety and efficacy.
Incomplete expansion of the metal stent may be fatal. The
continuous insult to the surrounding tissue due to pulsatile
actions of the vessels may induce long term untoward effects.
Moreover, metal stents have a fixed range of expansion within a
blood vessel. In some cases the stent may be too small in diameter,
even after expansion, to be affixed to the vessel wall, and in
other cases, the stent may expand to such a diameter that the
vessel is damaged or raptured. In either case, improperly sized or
positioned prior art stents require surgery for removal. The heat
expandable metal, nitinol, has the additional disadvantage of
incomplete expansion as a result of inadequate thermal exposure
during deployment or from variabilities in stent material. Still
further, migration of stents has been observed with prior art
stents. Stent migration may be fatal. Stent migration may be due to
under expansion, gradual change in metal properties, and the body's
own defense to foreign material.
To circumvent some of the disadvantages of metal stents, Slepian,
M. J. and Schindler, A. (Circulation, 78, Suppl IV: II-409, 1988)
selected a synthetic polymeric material, linear aliphatic polyester
for stent fabrication. This material is slowly degradable and has
certain thermal properties that may be used to seal and pave the
lumenal sites in situ. The investigators used a dual balloon
deployment approach and melted the polymer in situ at 60.degree. C.
followed by balloon compression directed flow of the melt polymer
for vessel sealing and subsequently cooling the material to
solidify the polymer seal or pave. This approach has been referred
to as polymeric endoluminal paving and sealing (PEPS) in the prior
art. This PEPS approach may have several potential disadvantages.
The high temperature may have an unknown effect on the local tissue
and cells. The melting and recrystallization within a vessel may
not be a predictable event in such a life-sustaining process.
Further, the long term effects of the degraded products are
unknown. The adhesion of the polymer film with the tissue also
increases the risk of fragmentation of the material which may cause
potential embolization.
There are many advantages of using type I collagen material for
intravascular stent or wound healing applications which can not be
simulated by metals and synthetic polymers. Type I collagen
molecule is a triple helix and has a unique protein configuration
that is a coiled coil of three polypeptide chains or alpha chains.
Two of the alpha chains are identical and are called alpha 1 chains
and the third chain is slightly different in amino acid composition
and is called alpha 2 chain. Each alpha chain twists in a
left-handed helix with three residues per turn, and three chains
are wound together in a right-handed superhelix to form a rod-like
molecule about 1.4 nanometer in diameter and 300 nanometer long The
alpha chains each contain about 1,050 amino acid residues and the
molecular weight of a type I collagen molecule is about 300,000
daltons. In each alpha chain within the triple helix every third
amino acid residue is a glycine. Collagen is characterized by a
high content of proline and hydroxyproline residues, the absence of
tryptophane, a minor amount of aromatic amino acid, and a
significant amount of dicarboxylic and dibasic amino residues. At
both ends of the collagen molecule three are terminal peptide
sequences known as telopeptides which are globular and are not
triple helical in structure and which lack glycine at every third
residue. These telopeptides are the primary sites of intermolecular
crosslinking in the molecule. Some of the advantages of using type
I collagen for the applications of the present invention are
briefly summarized below.
Firstly, type I collagen is hypo-immunogenic. Antibodies against
type I collagen molecule of one species cannot be raised in the
second species without the use of Freund's Complete Adjuvant. The
immunogenicity is reduced when collagen is in the fiber form.
Chemical crosslinking further reduces the immunogenicity to a
non-detectable level. In other words, purified type I collagen
fibers are highly biocompatible.
Secondly, type I collagen is biodegradable and the rate of
biodegradation can be controlled by chemical means such as by
crosslinking with glutaraldehyde, formaldehyde or other
bifunctional crosslinking agents. There are a number of cells
(macrophages, polymorphonuclear leukocytes and fibroblasts) that,
during wound healing, secrete the enzyme collagenases which cleave
collagen at 1/4 position from the C-terminal end of the molecule.
The two short triple-helices are not stable at body temperature and
are denatured to random coiled peptides which are then degraded
into amino acids and small peptides by proteases in the body. The
amino acids and peptides are metabolized, presumably through the
normal pathways similar to the resorption of host collagen during
remodeling of the wound.
Further, type I collagen molecule has about 250 amino and guandino
groups (positively charged groups at pH 7.4) and about 250 carboxyl
groups (negatively charged groups at pH 7.4). These side chain
functional groups are reactive and can be modified by chemical
means to change its physico-chemical, mechanical and biological
properties. For example, native type I collagen fibers are
thrombogenic. However, the thrombogenicity of the collagen can be
significantly reduced when the collagen molecule is modified to a
negatively charged protein.
Still further, type I collagen can be prepared either as a solution
or as a highly swollen fibrillar dispersion such that medicaments
in the form of small molecular drugs, peptides and macromolecules
can be incorporated into the collagen fibers to form a composite
material that would function as a vehicle for slow systemic release
or as a local delivery system of the medicaments.
Repair of other tissues such as skin, nerve and meniscus cartilage
has been attempted using type I collagen containing material. For
example, Yannas et. al. fabricated an endothermal implant using
collagen-glycosaminoglycan composite material (U.S. Pat No.
4,060,081). Li used a semipermeable, resorbable type I collagen
conduit for peripheral nerve repair (U.S. Pat. No. 4,963,146).
Stone used biocompatible, resorbable type I
collagen-glycosesinoglycan matrices to regenerate meniscus
cartilage (U.S. Pat No. 5,007,934).
A collagen wound healing matrix is disclosed in U.S. Pat. No.
5,024,841. This wound healing matrix is made from atelocollagen
(pepsin solubilized skin collagen) and is not chemically
crosslinked. As such, it does not possess the unique
physico-chemical and mechanical properties that are critically
required for the specific vascular applications of the present
invention.
However, even with the various foregoing technologies which have
been applied to repair damaged or diseased anatomical structures, a
device successful as a vascular wound dressing and constructed from
totally resorbable natural materials, or analogs thereof, has not
been developed in the prior art.
Accordingly, it is an object of the present invention to provide
improved vascular wound healing devices, which provide structural
support to the damaged or diseased vessel segment, allowing normal
blood flow.
It is another object of the present invention to provide vascular
wound dressings which are biocompatible, bioresorbable,
hemocompatible, and compliant.
It is a further object of the present invention to provide vascular
wound dressing devices which when released at the selective sites
inside a blood vessel will self expand to adhere to the vessel wall
via hydration of the material.
It is a yet another object of the present invention to provide a
means to deliver medicaments to the selective sites either
intravascularly or extravascularly for therapeutic
applications.
It is still another object of the present invention to provide a
means to manufacture the vascular wound dressings.
It is yet a further object of the present invention to provide a
means to repair the damaged or diseased blood vessel.
SUMMARY OF THE INVENTION
By means of the present invention, resorbable vascular wound
dressings for blood vessel repair have been discovered which
eliminate or substantially reduce many of the disadvantages and
problems associated with the prior attempts at vessel repair in
angioplasty procedures. In addition, by means of the present
invention, a method is provided to deliver medicaments to the
selected sites inside or outside a blood vessel. More specifically,
by means of the present invention, resorbable wound dressings have
been discovered which prevent or substantially reduce the risk of
post-angioplasty vessel reclosure, which vascular wound dressings
are tubular, compliant, self-expandable, low-profile,
biocompatible, hemocompatible and bioresorbable.
The resorbable vascular wound dressings of the present invention
are generally dry, porous matrices of type I collagen containing
fibers in a cylindrical form with varying inside and outside
diameters. In a preferred form of the invention, the fibers are
randomly oriented throughout the matrix to provide radial
compliance to the wound dressings.
The matrices may also include selected medicaments for local
therapeutic applications. Therapeutic medicaments include
anti-platelet agents such as aspirin and the like, anti-coagulant
agents such as coumadin and the like, antibiotics, anti-thrombus
deposition agents such as polyanionic polysaccharides including
heparin, chondroitin sulfates, hyaluronic acid and the like,
urokinase, streptokinase, plasminogin activators and the like,
wound healing agents such as transforming growth factor beta (TGF
beta) and the like, glycoproteins such as laminin, fibronectin and
the like, various types of collagens.
In particular, the self-expandable vascular wound dressing of the
present invention comprises a conduit having walls comprised of
type I collagen matrix material having pores with an average
diameter of from about 0.1 um to about 150 um and an inwardly
converging tapered inner diameter.
Further, the invention includes a method for fabricating resorbable
vascular wound dressings.
This method comprises:
a) forming an aqueous dispersion containing type I collagen;
b) coacervating the collagen with a coacervating agent;
c) placing the coacervated collagen fibers into a coaxial
cylindrical mold;
d) freeze drying the fibers in the mold to form a dried collagen
matrix conduit;
e) spraying the freeze dried collagen matrix conduit with water
mist;
f) compressing the water mist treated collagen matrix conduit;
g) compressing the ends of the collagen matrix conduit to form an
inwardly converging tapered inner diameter; and then
h) crosslinking the compressed collagen matrix conduit with a
crosslinking agent.
Still further, the invention includes a method for treating a
damaged or diseased blood vessel with resorbable vascular wound
dressings. The method includes delivering the resorbable vascular
wound dressing in a folded configuration to the selected site via a
conventional catheter and releasing the resorbable vascular wound
dressing at the selected site where the wound dressing self expands
to its original configuration and adhere to the vessel wall. In
particular, this method comprises:
a) inserting a delivery catheter containing the wound dressing
through a percutaneous site into an artery;
b) guiding the wound dressing to the selective intravascular site
with a guide wire; and then
c) releasing the vascular dressing at the intravascular site.
Moreover, the invention includes a method for delivering resorbable
vascular wound dressings at the anastomotic sites inside or outside
a blood vessel during vascular surgery. In particular, the method
for delivering a vascular wound dressing at the anastomotic site
inside a blood vessel comprises:
a) inserting vascular wound dressing into the lumens of a host
vessel and a vascular graft at the anastomotic sites; and then
b) aligning the host vessel and the vascular graft and suturing the
graft to the host vessel at both the proximal and distal ends of
the graft.
Further, the method for delivering a vascular wound dressing at the
anastomotic site outside a blood vessel comprises:
a) inserting the host vessel or the vascular graft into the
vascular wound dressing;
b) performing anastomosis of the host vessel and vascular
graft;
c) pulling the wound dressing to cover the anastomotic sites at
both the proximal and distal ends.
Particularly, the resorbable vascular wound dressings of the
present invention are constructed such that the walls are
substantially porous to permit nutrient diffusion for promoting
endothelialization, facilitating tissue ingrowth and hastening
anchorage with the host vessel. Further, the lumenal surface is
non-thrombogenic and effectively prevents thrombus deposition.
Still further, the resorbable wound dressings have a compliance
similar to the host vessel for compliance match, reducing the
potential risk of intimal hyperplasia formation. Moreover, the
resorbable wound dressings have low profile walls which further
reduce flow disturbances at the dressing vessel junctions. The
porous walls of the resorbable vascular wound dressings provide an
initial scaffold for host vessel regeneration.
Thus, in a preferred embodiment of the present invention, the
resorbable vascular wound dressings of the present invention have
the following physical characteristics and physico-chemical
properties:
______________________________________ Physical Characteristics
______________________________________ Inside Diameter (mm) 2-30
Pore size (um) 0.1-150 Wall Thickness (mm) Distal Ends 0.15-0.30
Center 0.10-1.5 Density (g/cm.sup.3) 0.05-0.80 Length (cm) 0.5-15
______________________________________
______________________________________ Physico-chemical Properties
______________________________________ Compliance (% radial
change/mm Hg .times. 10.sup.2) 2.0-7.0 Swelling Capacity (g/g)
0.5-15 Thermal Stability (.degree. C.) 55-85 Relaxation Recovery
Time (second) 1-30 ______________________________________
The invention will next be described in connection with certain
illustrated embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects of this invention, the various
features thereof, as well as the invention itself, may be more
fully understood from the following description, when read together
with the illustrated embodiments.
FIG. 1 shows a perspective view of a resorbable vascular wound
dressing made in accordance with the present invention.
FIG. 2 shows a longitudinal cross-sectional view of the resorbable
vascular wound dressing.
FIG. 3 shows a cross-sectional view of a delivery catheter having a
resorbable vascular wound dressing folded over a balloon inside a
protective sheath within a blood vessel in accordance with the
present invention.
FIG. 4 shows a cross-sectional view of a deployed resorbable
vascular wound dressing inside a blood vessel.
DESCRIPTION OF THE INVENTION
It has been discovered that the resorbable vascular wound dressings
having specific characteristics can be fabricated from type I
collagen containing material and can be introduced to the lesion
site either intraluminally via a catheter or at the anastomatic
sites during surgery, which wound dressings will eliminate or
substantially reduce many of the disadvantages of the prior art
metal and synthetic polymeric devices for vascular repair. Each
unique characteristic and property of the resorbable vascular wound
dressings and their advantages over the prior art are summarized
below.
Firstly, the resorbable vascular wound dressings of the present
invention have walls comprised of type 1 collagen material which is
biocompatible and is further chemically modified for blood contact
applications.
Secondly, walls of the resorbable vascular wound dressings of the
present invention are porous having pores from about 0.1 um to
about 150 um that are tortuously arranged to facilitate anchorage
of the walls with the host tissue via cellular infiltration. The
porous nature of the wound dressing also allows nutrient diffusion
through the walls, thus facilitating endothelialization.
Further, the resorbable vascular wound dressings of the present
invention have low profile walls at the distal ends as shown in
member 11 of FIG. 1 and member 21 of FIG. 2. The walls are tapered
such that the inner diameter X at the ends of the dressing are
greater than the inner diameter Y at the center portions of the
dressing. By means of this construction, the blood flows with
minimal disturbance, thus reducing the risk of blood stasis and
eddy current which may damage the blood cells and cause subsequent
accumulation of thrombus. In particular, the walls of the present
invention have a thickness from about 0.1 mm to about 1.5 mm in the
center part of the wound dressing and from about 0.05 mm to about
0.3 mm at the ends of the wound dressing.
The density of the resorbable vascular wound dressings of the
present invention may vary from about 0.05 g/cm.sup.3 to about 0.8
g/cm.sup.3, where "g/cm.sup.3 " is a unit connoting the number of
grams of wound dressing in a cubic centimeter of matrix, to
accommodate various mechanical and therapeutic requirements of the
wound dressings. For example, a lower density wound dressing may be
more advantageous in applications where a rapid diffusion of
therapeutic agents is required.
The resorbable vascular wound dressings of the present invention
have a compliance which is in the range of normal blood vessels.
Compliance match between the host vessel and the implant is
important. Compliance mismatch at the host vessel-implant junctions
may result in turbulent blood flow and thrombus deposition, leading
to smooth muscle proliferation and eventual occlusion. The
resorbable vascular wound dressings of the present invention have a
compliance from about 2.0% radial change per mm Hg.times.10.sup.-2
to about 7.0% radial change per mm Hg.times.10.sup.-2, preferably
from about 4.0% radial change per mm Hg.times.10.sup.-2 to about
6.0% radial change per mm Hg.times.10.sup.-2. The resorbable
vascular wound dressings of the present invention are hydrophilic
which facilitates cell infiltration for rapid anchorage to the host
vessel wall. The swelling capacity of the resorbable vascular wound
dressings may vary from about 0.5 g/g wound dressing to about 15
g/g wound dressing, preferably from about 2 g/g wound dressing to
about 10 g/g wound dressing.
The rate of resorption of the resorbable vascular wound dressings
of the present invention may be advantageously designed for a
specific lesion site application. For example, slower in vivo
resorption may be more advantageous in applications where
mechanical support function of the device is critical. The rate of
in vivo resorption can be controlled by chemical means such as by
using bifunctional intermolecular crosslinking agents such as
glutaraldehyde, formaldehyde or the like. The in vivo rate of
resorption is correlated with thermal shrinkage temperature of the
material. The thermal shrinkage temperature of the resorbable wound
dressings of the present invention is from about 55.degree. C. to
about 85.degree. C., preferably from about 60.degree. C. to about
75.degree. C. The vascular wound dressings having a shrinkage
temperature of from about 55.degree. C. to about 85.degree. C. is
resorbable in vivo in about 30 days to about 120 days.
Referring now to FIGS. 3 and 4, the resorbable vascular wound
dressing 31 of the present invention can be folded over the balloon
32 at the tip of a catheter 33, to facilitate delivery via a guide
wire 38 to the specific lesion site 34 within a blood vessel 35.
Upon release of the device via a pull of the string 37 to remove
the protective sheath 36, the wound dressing unfolds and self
expands to its full original geometry 41 when in contact with blood
42 within a blood vessel. This self expandability of the wound
dressings is of particular importance in using the wound dressings
for intravascular applications. The relaxation recovery time, which
is defined as the time required for the wound dressing to transform
from the folded geometry to the expanded geometry, is short for the
wound dressings of the present invention. The relaxation recovery
time of the resorbable wound dressings of the present invention is
from about 1 second to about 30 seconds, preferably from about 3
seconds to about 10 seconds. Generally, in preparing the resorbable
vascular wound dressings of the present invention, a collagenous
tissue is first subjected to purification and chemical modification
procedures.
In particular, the collagen material of the present invention may
be prepared by the following methods.
First, a native source of type I collagen, such as skin, tendon,
ligament, or bone is first cleaned of fat, fascia and other
extraneous matter and washed. The cleaned and washed collagen
containing material is then comminuted by slicing or grinding
followed by extensive washing in water to remove soluble blood
proteins.
The comminuted material is then subjected to a defatting treatment
using fat solubilizing agents such as low molecular weight
alcohols, including ethanol and propanols, ethers, such as ethyl
ether, petroleum ether, or a mixture of ether and alcohol at
approximately equal volumes. The defatted material is washed to
remove the residual alcohol and/or ether.
The defatted and washed collagen containing material is then
extracted with a neutral salt solution at a concentration of about
1M and a temperature of from about 4.degree. C. to about 25.degree.
C. by means well known in the art. Neutral salt solution of high
ionic strength weakens the electrostatic interactions between the
collagen and non-collagenous materials. Such neutral salts include
sodium chloride, potassium chloride and the like. By doing so, the
neutral salt soluble non-collagenous materials are removed. The
collagen material is then washed with deionized, distilled
water.
The salt extracted collagen containing material is further purified
by a process which subjects the collagen containing material to two
extreme pH extractions in the presence of a structure stabilizing
salt. The swelling at pH from about 2 to about 3 is accomplished by
means well known in the art, such as with a suitable acid. Such
acids include hydrochloric acid, acetic acid, lactic acid, or the
like. The salt used may be sodium chloride, ammonium sulfate,
sodium sulfate, or the like. Preferably, the acid extraction is
performed at 4.degree. C. to minimize the bacteria growth. The acid
weakens the ionic interactions between collagen and acidic
non-collagenous proteins which are solubilized and removed. After
extensive washing with deionized, distilled water, the collagen is
extracted with a basic solution at a pH above 13 by means well
known in the art. Such bases include sodium hydroxide, potassium
hydroxide, calcium hydroxide, and the like. The alkaline condition
weakens the ionic interactions between collagen and basic
non-collagenous materials which are solubilized and removed. The
alkaline treatment also reduces the isoionic point due to partial
deamidation of the glutamine and asparagine residues of collagen.
The alkaline extracted collagen material is then extensively washed
with deionized, distilled water to remove the residual base and to
lower the pH to from about 5 to about 7.
The base extracted collagen is then chemically modified to
partially acetylate the epsilon-amino groups of collagen to remove
the positively charged epsilon-amino groups so as to further lower
the isoionic point for hemocompatibility. Methods for acetylating
the epsilon-amino groups of collagen are well known in the art such
as by reacting with acetic anhydride in the presence of half
saturated sodium acetate at a pH of about 8.0. Alternatively, the
hemocompatibility may be enhanced by increasing the total number of
negatively charged groups by subjecting the collagen to
succinylation with succinic anhydride at a pH of about 8.0. By
doing so, additional negative charged carboxyl groups are attached
to the side chains of lysine residues.
The thusly prepared type I collagen material maintains fibrillar
structure, contains minimal non-collagenous impurities and is well
suited for additional processing for the preparation of the
resorbable vascular wound dressings of the present invention.
However, it must be appreciated that other types of collagen such
as type II collagen, type III collagen and the like from the
natural tissues may also be prepared for the intended use of the
present invention.
In preparing a resorbable vascular wound dressing of the present
invention, the purified and chemically modified collagen is first
used for the preparation of a dispersion in a manner well known in
the art. One such preparation of collagen dispersion is taught in
U.S. Pat No. 3,157,524 which is incorporated herein by reference as
if set out in full. In particular, the collagen dispersion of the
present invention may be prepared by the following method.
The purified type I collagen is first swollen with an acid solution
such as hydrochloric acid, phosphoric acid, lactic acid, acetic
acid and the like. Regardless of which acid is used, the pH of the
acid collagen dispersion is in the range of from about 2 to about
3.
The swollen collagen is then homogenized by any conventional means
such as a homogenizer or blender so as to further dissociate the
fibers. The homogenized collagen dispersion is then filtered to
remove unswollen aggregates by means well known in the art such as
by filtering through a stainless steel mesh or the like under
vacuum.
In one embodiment of the present invention, if the resorbable
vascular wound dressing is further intended to function as a
medicinal delivery vehicle, then in addition to the type I
collagen, various medicaments may optionally be present in the
dispersion such as aspirin, coumadin, antibiotics, polyanionic
polysaccharides such as heparin, hyaluronic acid, chondroitin
sulfates and the like, growth factors such as transforming growth
factor beta (TGF beta) and the like, prostaglandins, plasminogen
activators, urokinase, streptokinase, glycoproteins such as
fibronectin, laminin and the like, type II through type XII
collagens.
The resorbable vascular wound dressings may be formed from the
collagen dispersion by the following embodiments depending on the
size and mechanical requirements of the wound dressings.
In one preferred embodiment of the present invention, the collagen
fibers in the dispersion is first coacervated by adjusting the pH
to its isoionic point using a base well known in the art, such as
with a sodium hydroxide, ammonium hydroxide or the like. The
coacervated fibers are fully phase separated from the water and are
removed using tongs into a perforated centrifuge tube. The excess
water associated with the hydrated fibers is removed by centrifuge
at a low velocity using a commercial centrifuge. The partially
dehydrated fibers are then fitted into a cylindrical mold which
mold contains a rod in the center of the cylinder. The diameter of
the rod defines the diameter of the lumen of the resorbable
vascular wound dressing. The molded collagen fibers are then
subjected to a freeze drying procedure using a commercial freeze
dryer, which procedure is well know in the art. Typically, the
collagen fibers are first frozen at a temperature below -20.degree.
C. from about 4 hours to about 8 hours, followed by drying at
-10.degree. C. for about 24 hours to about 48 hours and then at
20.degree. C. for about 4 hours to about 8 hours at a vacuum from
about 50 um Hg to about 300 um Hg. The thusly formed tubular porous
matrix is allowed to stand overnight at room temperature to relax
the fibers due to excessive vacuum treatment. The collagen fibers
in the matrix prepared this way are randomly oriented so as to
provide mechanical strength and compliance in both the longitudinal
and radial directions. This is of particular importance in small
diameter (less than 6 mm) vessel repair applications where
compliance match of the wound dressing to the host vessel must be
considered for efficacy. The freeze dried matrix with the rod
attached is then inserted into a stirrer which rotates the matrix
at a velocity of from about 20 rpm to about 700 rpm, preferably
from about 40 rpm to about 400 rpm. A stream of water mist is
sprayed onto the surface of the matrix from a distance of from
about 6 inches to about 18 inches for about 5 seconds to about 30
seconds while the matrix is being rotated. Any commercial water
sprayer such as the Compressed Air Sprayer from Consolidated
Plastics Company, Inc. may be used for this purpose. The spray of
water mist facilitates the compression process similar to the
garment and laundry industries which are common in every household
practice.
The water mist treated tubular porous matrix is subjected to dual
rotational compression in order to reduce the wall thickness. The
first rotational compression step is carried out by means well
known in the art such as by rotation while compressing against a
smooth solid wall such as a glass surface or a plastic surface or
by compressing the porous cylinder between two smooth solid
surfaces during rotation. Preferably, the outside diameter of the
compressed matrix may be defined by the predetermined gap distance
of the two solid plates. Specifically, depending upon the internal
diameter of the wound dressing, the thickness of the wall may be
made according to the following formula: ##EQU1## Where O.D. equals
the gap distance between the plates. Preferably, the wall thickness
is from about 0.1 mm to about 1.5 mm.
The second compression step is carried out at the two ends of the
tube to further reduce the profile of the wound dressing at the
distal ends so as to form the desired taper. This is carried out by
inserting a tapered plug (a frustum of a right circular cone) at
each end of the tubular matrix. Depending upon the I.D. and O.D. of
the tubular matrix, the upper base of the frustum of the right
circular cone has a diameter equal to the I.D. of the tubular
matrix and the other end, lower base of the frustum of the right
circular cone, has a diameter which is about 0.1 mm to about 0.6 mm
smaller than the O.D. such that the inside diameter at the distal
ends of the final compressed vascular wound dressing has a wall
thickness of from about 0.05 mm to about 0.3 mm.
Alternatively, the central rod of the mold may be cone shaped (a
frustum of a right circular cone with the lower base pointing
outward) at each end which dictates the size of the lumen and the
wall thickness at the central portion and the ends of the
resorbable vascular wound dressing upon completion of the
compression step of the freeze dried matrix. The I.D. at the center
and at the ends and the wall thickness of the resorbable vascular
wound dressing may be defined by the diameter of the mandrel, the
size of the upper base and the lower base of the frustum of the
right circular cone and the gap distance between the two compressed
plates.
The thusly compressed tubular matrix is then subjected to a
crosslinking step by methods well known in the art, such as by
contacting the matrix to a bi-functional crosslinking agent
including formaldehyde, glutaraldehyde, carbodiimides and the like
in the vapor phase or in the liquid phase. Crosslinking controls
the in vivo stability of the vascular wound dressings and also
fixes the geometrical configuration which provides the self
expandability of the wound dressings when the dressings are
mechanically deformed and in contact with an aqueous solution.
Preferably, the crosslinking is performed in the vapor phase.
Particularly, when crosslinking is performed in the vapor phase,
the crosslinking may be achieved through vapors of formaldehyde,
glutaraldehyde or the like at a relative humidity of from about 75%
to about 100% and at a temperature of from about 20.degree. C. to
about 30.degree. C.
Alternatively, the crosslinking may be achieved through an
endothermic chemical condensation of the intermolecular side chains
of collagen at a temperature between 95.degree. C. to 110.degree.
C. and a vacuum between about 10 um Hg to about 100 um Hg for about
24 hours, known in the art as dehydrothermal crosslinking.
In another embodiment of the present invention where the radial
mechanical strength of the resorbable vascular wound dressing is
important, it may be desirable to have the mandrel wound with a
resorbable filament such as a collagen filament or a polyglyconate,
a polylactate, a polyglyconatepolylactate co-polymer filament or
the like. The resorbable filament incorporates into the walls of
wound dressings to provide additional rigidity to the vascular
wound dressing for mechanical support requirement.
Alternatively, the rigidity of the wall may be further increased by
aligning the fibers in the circumferential direction. This may be
accomplished by first inserting the filament wound mandrel into a
mechanical stirrer and rotating the mandrel at a speed from about
10 rpm to about 60 rpm so as to slowly wrap the partially
dehydrated fibers onto the coiled filament. The filament
impregnated fibers may be further dehydrated by slowly rotating
against a smooth surface such as glass before freeze drying.
The extent of crosslinking of the vascular wound dressing can be
measured by the hydrothermal shrinkage temperature of the wound
dressing, i.e. the temperature at which the wound dressing in an
aqueous environment begins to shrink due to unfolding of the
collagen triple helix. The method for measuring the shrinkage
temperature of a collagen material is well known in the art.
Typically, a segment of a vascular wound dressing is first
equilibrated in a 0.2M phosphate buffered solution bath at pH 7.4
at about 25.degree. C. for about 10 minutes to about 30 minutes.
The length of the wound dressing is determined by a cathetometer.
The temperature of the solution is then raised by heating the
solution at a rate of about 1.degree. C. per minute. The length of
the wound dressing is continuously recorded. The shrinkage
temperature is defined as that temperature at which 50% reduction
in the wound dressing length is reached. Alternatively, shrinkage
temperature may be measured by a commercial apparatus such as a
differential scanning calorimeter. Generally, the degree of
crosslinking is such that the shrinkage temperature of the
resorbable vascular wound dressing is in the range of from about
55.degree. C. to about 85.degree. C., preferably from about
60.degree. C. to about 75.degree. C. Such wound dressings are
crosslinked to such an extent they are completely resorbed within 1
to 4 months when in the body.
By virtue of having made the resorbable vascular wound dressings in
accordance with the above procedure, the dressing has a low profile
wall at the distal and proximal ends to minimize the blood flow
disturbance, a compliance match with the host vessel to minimize
the hyperplasia, and a porous wall to facilitate cell infiltration
whereby promoting adhesion of the wound dressing to the host vessel
to prevent dressing migration. Further, such a wound dressing will
facilitate wound healing and host vessel regeneration, permit
nutrient exchange, and facilitate endothelialization. Moreover,
such a wound dressing can be mechanically deformed and it
subsequently returns to its original configuration when in contact
with an aqueous solution. More specifically, in order to accomplish
this desired selectivity, the vascular wound dressings have the
following physical characteristics: wall thickness from about 0.1
mm to about 1.5 mm in the center of the wound dressing and from
about 0.05 mm to about 0.3 mm at the ends of the wound dressing;
inside diameter from about 2 mm to about 30 mm; length from about
0.5 cm to about 15 cm; pores in the range of from about 0.1 um to
about 150 um; density from about 0.05 g/cm.sup.3 to about 0.8
g/cm.sup.3. Further, in order to accomplish this desired
selectivity, the vascular wound dressings have the following
physico-chemical properties: compliance from about 2.0% radial
change per mm Hg.times.10.sup.-2 to about 7.0% radial change per mm
Hg.times.10.sup.-2, preferably from about 4% radial change per mm
Hg.times.10.sup.-2 to about 6% radial change per mm
Hg.times.10.sup.-2 ; swelling capacity from about 0.5 g/g to about
15 g/g, preferably from about 2.0 g/g to about 10 g/g; thermal
shrinkage temperature from about 55.degree. C. to about 85.degree.
C., preferably from about 60.degree. C. to about 75.degree. C.;
relaxation recovery time from about 1 second to about 30 seconds,
preferably from about 3 seconds to about 10 seconds.
The resorbable vascular wound dressings made in accordance with the
present invention possess unique properties not only to function as
a intravascular stent to prevent or significantly reduce
post-angioplasty vessel reclosure, but to repair vascular lesions
resulting from annurysms and to deliver specific therapeutic agents
to selective sites inside a blood vessel or at the anastomotic
sites for therapeutic applications.
Specifically, in applications as a coronary artery wound dressing
after angioplasty procedures, the low profile wall and the
compliance of the intracoronary wound dressing of the present
invention significantly reduce the risk of blood flow disturbance
at the dressing-host vessel junction and minimize the risk of
intimal hyperplasia. When in the presence of an anti-thrombogenic
and an anti-smooth muscle cell proliferation agent such as heparin
and the like, the slow release of the heparin and the like at the
wound dressing surface further protects the surface from thrombus
adhesion and intimal hyperplasia formation, while the dressing is
slowly replaced by the regenerated host tissue.
In peripheral and aortic artery repair where the diameter of the
vessel is in the range from about 6 mm to about 30 mm, mechanical
support may be obtained by incorporating a resorbable supporting
filament into the walls, such as collagen, polyglyconate,
polylactate and the like.
In use, the resorbable vascular wound dressings of the present
invention may be advantageously delivered to the selected site of
an artery via a catheter to be used after the angioplasty
procedure. Again referring to FIGS. 3 and 4, the vascular wound
dressing is folded over the balloon at the tip of a percutaneous
transluminal angioplasty (PTA) catheter covered with a tubular
protective sheath which is attached to a string (FIG. 3). The
sheath and the string may be made of any hemocompatible material
including silicone and polyurethane. Upon positioning of the wound
dressing at the lesion site via a guide wire and removing of the
protective sheath via the pull of the string, the vascular wound
dressing self expands as it rehydrates to conform to the walls of
the treated vessel. The balloon may be inflated to bring the
vascular wound dressing into its maximal expansion within the
artery. The balloon is then deflated and the catheter is removed
upon the completion of the procedure, leaving the expanded vascular
wound dressing at the selected site as shown in FIG. 4.
In another use, the resorbable vascular wound dressing may be
folded over the balloon and delivered to the lesion site during the
angioplasty procedure. Upon the removal of the protective sheath
via the pull of the string, the balloon is inflated to push the
vascular wound dressing to its maximum dimension, thereby opening
the vessel for normal blood flow. The balloon is deflated and the
catheter is removed, leaving the wound dressing at the lesion
site.
In a further use, the resorbable vascular wound dressings of the
present invention may be advantageously used to deliver medicaments
inside a blood vessel. The vascular wound dressing incorporated
with the medicaments may be advanced to the selected site of a
vessel. Upon the removal of the protective sheath via the pull of
the string, the vascular wound dressing self expands to adhere to
the host vessel wall, leaving the desired medicaments at the
specific site. Furthermore, if so desired, a radiopaque material
such as BaSO.sub.4 may be incorporated into the vascular wound
dressing for easy visualization.
In still another use, the resorbable vascular wound dressings of
the present invention incorporated with medicaments may be
advantageously delivered to the anastomotic sites either inside a
vessel or outside a vessel during surgery to protect the
anastomotic sites from hyperplasia formation.
While there have been shown and described what are at present
considered the preferred embodiments of the present invention, it
will be obvious to those skilled in the art that various changes
and modifications may be made without departing from the spirit and
scope of the invention as defined by the appended claims.
The above and other objectives, advantages and features of the
present invention will be better understood from the following
non-limiting descriptions of theoretical and actual examples of
producing and using the vascular wound dressings of the present
invention.
EXAMPLE 1
Preparation of the Purified, Chemically Modified Collagen
Fibers
The fat and fascia of bovine flexor tendon are carefully removed
and washed with water. The cleaned tendon is frozen and comminuted
by slicing into 0.5 mm slices with a meat slicer. The tendon is
first defatted with isopropanol (tendon:isopropanol=1:5 V:V) for 8
hours at 25.degree. C. under constant agitation. The extractant is
decanted and an equal volume of isopropanol is added and the tendon
slices is extracted overnight at 25.degree. C. under constant
agitation. The defatted tendon is extensively washed with
deionized, distilled water to remove the residual isopropanol. The
tendon is then extracted with 10 volumes of 1M NaCl for 24 hours at
4.degree. C. under agitation. The salt extracted tendon is washed
with deionized, distilled water to remove the salt. The salt
extracted collagen is then extracted in 10 volumes of 0.05M lactic
acid solution, in the presence of 0.35M sodium sulfate at pH 2.5
for 24 hours at 4.degree. C. under constant agitation. The
partially swollen collagen is deswelled by slowly adding 1M NaOH to
fully coacervate the collagen fibers. The coacervated fibers are
collected with a stainless steel strainer. After washing with
deionized, distilled water, the fibers are extracted with 10
volumes of 0.75M NaOH for 24 hours in the presence of 1M Na.sub.2
SO.sub.4 at 25.degree. C. under constant agitation. The alkaline
extracted collagen is collected with a strainer, neutralized with
0.1M HCl and washed with deionized, distilled water.
The thusly purified collagen is then chemically modified with
acetic anhydride in the presence of half saturated sodium acetate
at room temperature. Acetic anhydride is slowly added through a
burette to the sodium acetate solution while the pH of the solution
is continuously monitored and adjusted with 1M NaOH solution to 8.
The reaction is continued for 2 hours. The partially acetylated
collagen is then washed with deionized, distilled water, freeze
dried and stored dry until use.
EXAMPLE 2
Preparation of Resorbable vascular wound Dressings
An aliquot of the purified fibers prepared in Example 1 is
suspended in 0.05M lactic acid solution. The amount of fibers and
acid solution used is such that a 1.0% (w/v) of collagen suspension
is formed. The swollen fibers are then homogenized in a stainless
steel blender for 60 seconds. The dispersed collagen fiber material
is filtered through a 40 um stainless steel mesh with vacuum using
a filter flask.
5 grams of homogenized, filtered collagen dispersion is weighed
into a beaker. 0.3% NH.sub.4 OH is slowly added to coacervate the
fibers. The coacervated fiber is first dehydrated to the extent
that it will fit into a coaxial cylindrical mold of 1.2 cm
diameter, 2 cm long and a 0.4 cm rod in the center of the mold.
The collagen containing mold is then subjected to a freeze drying
procedure using a Virtis commercial freeze dryer. The freeze dried
tubular collagen sponge matrix is equilibrated at room temperature
overnight. The mandrel with the collagen matrix is then fit into a
stirrer. A stream of water mist is sprayed onto the collagen matrix
from a distance of 12 inches while the rod is spinning at 200 rpm.
The water mist treated collagen matrix is allow to stand for 10
minutes and the collagen matrix is then subjected to a rotational
compression procedure using two plates with a gap distance of 0.46
cm. The compressed tubular collagen matrix is then subjected to a
second compression procedure by inserting frustums of a right
circular cone at the ends of the tubular matrix to reduce the wall
thickness at the ends to about 0.1 mm. The compressed tubular
collagen matrix is then crosslinked in a formaldehyde crosslinking
chamber at 25.degree. C., at 95% relative humidity and excess
formaldehyde vapor for 60 minutes. The crosslinked collagen matrix
is evacuated to remove residual formaldehyde and the individual
vascular wound dressings are packaged for sterilization.
EXAMPLE 3
Preparation of Resorbable Vascular Wound Dressings Incorporated
with Heparin.
A collagen dispersion is prepared in accordance with Example 2.
Heparin solution (collagen:heparin=50:1 w/w) is slowly added to the
dispersion while mixing. The thoroughly mixed collagen/heparin gel
is then processed in accordance with Example 2.
EXAMPLE 4
Preparation of Resorbable Vascular Wound Dressings Containing
Coiled Filament al Support
A polyglyconate filament such as a maxon suture is first wound onto
a 0.4 cm O.D. mandrel. The subsequent process is identical to the
Example 2.
EXAMPLE 5
Method of Use of a Resorbable Vascular Wound Dressing with a PTA
Balloon Catheter During Peripheral Vessel Angioplasty Repair.
A PTA balloon catheter with a vascular wound dressing folded over
the balloon is inserted through the femoral artery via a
percutaneous puncture site. The balloon with the wound dressing is
guided to the selected vessel site via a guide wire. The protective
sheath is removed by pulling the attached string. The balloon is
inflated until a full resistance is reached at about 5 psi to about
7 psi. The balloon is deflated and the catheter removed, leaving
the vascular wound dressing in its expanded form.
EXAMPLE 6
Method of Use of a Resorbable Vascular Wound Dressing With a PTA
Catheter for Post Peripheral Vessel Angioplasty Vessel Repair.
A PTA catheter with a self expandable vascular wound dressing, made
in accordance with the present invention, folded at the tip of the
catheter is inserted through the femoral artery via a percutaneous
puncture site. The wound dressing is guided to the selected vessel
site via a guide wire. The protection sheath is removed by pulling
the attached string. The folded wound dressing self expands to
adhere to the vessel wall. The catheter is then removed.
EXAMPLE 7
Method of Use of a Resorbable Vascular Wound Dressing With a PTCA
Balloon Catheter During Coronary Angioplasty Vessel Repair.
A percutaneous transluminal coronary angioplasty (PTCA) catheter
with a resorbable vascular wound dressing folded over the balloon
made in accordance with the present invention is inserted through
an artery via a percutaneous puncture site. The balloon with the
wound dressing is guided to the selected site within a coronary
artery via a guide wire. The protection sheath is removed via a
pull of the string. The balloon is inflated until a full resistance
is reached at about 5 psi to about 7 psi, corresponding to a fully
expanded vascular wound dressing. The balloon is then deflated and
catheter removed, leaving the expanded wound dressing at the repair
site.
EXAMPLE 8
Method of Use of a Resorbable Vascular Wound Dressing With a PTCA
Catheter for Post Angioplasty Coronary Vessel Repair.
A PTCA catheter with a folded vascular wound dressing at the tip of
the catheter, made in accordance with the present invention, is
guided to the lesion site within a coronary artery. The protection
sheath is removed by pulling the string to free the wound dressing.
The dressing self expands to adhere to the vessel wall. The
catheter is then removed.
EXAMPLE 9
Method of Use of a Resorbable Vascular Wound Dressing At the
Anastomotic Sites Within a Vessel.
The vascular wound dressing of the present invention is used at
anastomotic sites in conjunction with a vascular surgery procedure.
The vascular wound dressings made in accordance with the present
invention are inserted from both the proximal and distal ends to
the host vessel and the vascular graft. The outside diameter of the
vascular wound dressing is chosen to fit the inside diameter of the
host vessel and the graft. The vascular wound dressing adheres to
the vessel walls of both the host vessel and the graft at the
anastomotic sites.
EXAMPLE 10
Method of Use of a Resorbable Vascular Wound Dressing at the
Anastomotic Sites Outside the Vessel.
Vascular wound dressings made in accordance with the present
invention are inserted from the proximal and distal ends of the
anastomotic sites outside the vessel walls. The inside diameter of
the vascular wound dressing is chosen to fit the outside diameter
of the host vessel and the graft. Upon completion of the
anastomotic procedure, the vascular wound dressings are pulled to
cover the anastomotic sites.
EXAMPLE 11
Characterization of the Resorbable Vascular Wound Dressings
The properties of vascular wound dressings are characterized
below:
a) Density (g/cm.sup.3)
The apparent density of the vascular wound dressing made in
accordance with the Example 2 is determined by first weighing the
wound dressing to obtain the weight. The volume of the wound
dressing is then determined from the following formula:
where
OD=outside diameter of the dressing (cm)
ID=inside diameter of the dressing (cm)
h=length of the dressing (cm).
The density (g/cm.sup.3) is then calculated from the weight and
volume of the vascular wound dressing.
The density of the vascular wound dressings of the present
invention is from about 0.05 g/cm.sup.3 to about 0.8
g/cm.sup.3.
b) Compliance (% radial change per mm Hg.times.10.sup.-2)
A balloon is inserted into the lumen of a vascular wound dressing
made in accordance with the Example 2. The outside diameter of the
dressing is measured with a cathetometer. The balloon is inflated
and the pressure inside the balloon is recorded. The outside
diameter of the pressurized wound dressing is then measured. The
average compliance is calculated as percent change in diameter per
mm Hg.times.10.sup.-2. ##EQU2## Where OD.sub.f =final outside
diameter of the wound dressing (mm)
OD.sub.0 =initial outside diameter of the wound dressing (mm)
P.sub.f =final pressure inside the balloon (mm Hg)
P.sub.0 =initial pressure inside the balloon (mm Hg)
The compliance of the present invention is from about 2.0% radial
change per mm Hg.times.10.sup.-2 to about 7.0% radial change per mm
Hg.times.10.sup.-2.
c) Pores (um)
The pore structure as seen by scanning electron micrographs of
cross-sectional areas of the vascular wound dressing made in
accordance with Example 2 are measured. The porous structure of the
vascular wound dressings of the present invention is such that long
axis of the pores are aligned circumferentially and the short axis
of the pores arc perpendicular to the circumference. The pore size
is calculated as the average between the long axis and the short
axis of each pore.
It is determined that the vascular wound dressings of the present
invention have pores in the range of from about 0.1 um to about 150
um.
d) Swelling (g/g)
The swelling is measured by the amount of solution uptake per unit
weight of the vascular wound dressing made in accordance with the
Example 2. The dry weight of the wound dressing is first
determined. The wound dressing is next immersed in a buffered
solution, pH 7.4 at 25.degree. C. for one hour. The wet weight is
then determined. The swelling (g/g) of the wound dressing is
calculated as the difference of the wet weight and the dry weight
of the wound dressing divided by the dry weight of the wound
dressing.
The swelling of the wound dressings of the present invention is
from about 0.5 g/g to about 15 g/g.
e) Shrinkage Temperature (.degree. C.)
A segment of the vascular wound dressing is immersed in a buffered
solution bath, pH 7.4. The length is recorded with a cathetometer.
The temperature of the solution is raised at a rate of 1.degree.
C./minute. The temperature and the length of the samples are
continuously recorded until sample shrinks and a constant length
maintained. The shrinkage temperature is defined as the temperature
where 50% change of the sample length occurs. The shrinkage
temperature of the wound dressings of the present invention is from
about about 55.degree. C. to about 85.degree. C.
f) Wall Thickness (mm)
The wall thickness of the vascular wound dressing is measured with
a micrometer. The wall thickness of the wound dressing is in the
range of from about 0.1 mm to about 1.5 mm in the center of the
dressings and in the range of from about 0.05 mm to about 0.3 mm at
the distal ends of the dressings.
g) Relaxation Recovery Time (second)
The vascular wound dressing is first mechanically deformed by
folding to a compact configuration similar to that folded at the
tip of a catheter. The mechanically deformed wound dressing is then
soaked in a phosphate buffered saline solution, pH 7.4 at
25.degree. C. The time which takes for the deformed wound dressing
to return to the original configuration is recorded as the
relaxation recovery time.
The wound dressings of the present invention have a relaxation
recovery time in the range from about 1 second to about 30
seconds.
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