U.S. patent application number 11/366700 was filed with the patent office on 2006-07-20 for bioresorbable sealants for porous vascular grafts.
This patent application is currently assigned to Meadox Medicals, Inc.. Invention is credited to Jennifer DePreker, David J. Lentz, Gary L. Loomis, Antonio Moroni.
Application Number | 20060159720 11/366700 |
Document ID | / |
Family ID | 24867600 |
Filed Date | 2006-07-20 |
United States Patent
Application |
20060159720 |
Kind Code |
A1 |
Lentz; David J. ; et
al. |
July 20, 2006 |
Bioresorbable sealants for porous vascular grafts
Abstract
A bioresorbable sealant composition useful for impregnating
implantable soft-tissue prostheses includes at least two
polysaccharides in combination to form a hydrogel or sol-gel. The
sealant compositions may optionally include a bioactive agent
and/or be cross-linked subsequent to application of these
compositions to the substrate surface.
Inventors: |
Lentz; David J.; (Randolph,
NJ) ; Loomis; Gary L.; (Morristown, NJ) ;
Moroni; Antonio; (Morris Plains, NJ) ; DePreker;
Jennifer; (Rochelle Park, NJ) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Assignee: |
Meadox Medicals, Inc.
|
Family ID: |
24867600 |
Appl. No.: |
11/366700 |
Filed: |
March 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09108692 |
Jul 1, 1998 |
|
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11366700 |
Mar 2, 2006 |
|
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08713801 |
Sep 13, 1996 |
5851229 |
|
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09108692 |
Jul 1, 1998 |
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Current U.S.
Class: |
424/425 ; 514/54;
623/1.43 |
Current CPC
Class: |
A61L 27/34 20130101;
A61L 27/52 20130101; A61L 27/20 20130101; A61L 27/26 20130101; A61L
33/0064 20130101 |
Class at
Publication: |
424/425 ;
623/001.43; 514/054 |
International
Class: |
A61F 2/02 20060101
A61F002/02; A61K 31/715 20060101 A61K031/715 |
Claims
1. A device comprising: an implantable soft tissue prosthesis and a
hydrogel comprising a combination of at least two different
polysaccharides.
2. The device of claim 1, wherein said prosthesis is porous.
3. The device of claim 1, wherein said hydrogel is impregnated on a
surface of said prosthesis.
4. The device of claim 1, wherein said prosthesis is tubular having
an inner surface and an outer surface.
5. The device of claim 4, wherein said hydrogel is impregnated on
said inner surface of said prosthesis.
6. The device of claim 1, wherein said polysaccharides are selected
from the group consisting of algin, carboxymethyl cellulose,
carrageenan, furcellaran, agarose, guar, locust bean gum, gum
arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl
cellulose, hydroxyalkylmethyl cellulose, pectin, partially
de-acetylated chitosan, starch, starch derivatives, amylase,
amylopectin, hyaluronic acid and its derivatives, heparin, xanthan,
and combinations thereof.
7. The device of claim 1, wherein said combination of
polysaccharides is selected from the group consisting of alginic
acid/pectin, alginic acid/chitosan, carrageenan type I/locust bean
gum, carrageenan type I/pectin, carrageenan type II/locust bean
gum, carrageenan type II/pectin, carrageenan type II/guar gum,
carrageenan type IV/locust bean gum, locust bean gum/xanthan, guar
gum/locust bean gum, guar gum/xantham, chitosan/heparin and
agar/guar gum.
8. The device of claim 1, wherein said hydrogel further comprises
an anticoagulant.
9. The device of claim 8, wherein said anticoagulant is selected
from the group consisting of heparin, prostaglandin, urokinase,
streptokinase, sulfated polysaccharide, albumin, and combinations
thereof.
10. The device of claim 1, wherein said prosthesis is impregnated
with said hydrogel by a method selected from the group consisting
of submersion and injection.
11. The device of claim 1, wherein said hydrogel further comprises
an ion selected from the group consisting of K.sup.+, Ca.sup.2+,
Mg.sup.2+and combinations thereof.
12. The device of claim 1, wherein said prosthesis comprises a
porous material comprising a synthetic or natural polymer.
13. The device of claim 1, wherein said prosthesis comprises a
porous material selected from the group consisting of polyester,
expanded poly(tetrafluoroethylene), nylon, polypropylene,
polyurethane, polyacrylonitrile, and combinations thereof.
14. The device of claim 8, wherein said hydrogel provides
controlled release of said anticoagulant.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 09/108,692, filed on Jul. 1, 1998, which is a divisional of
U.S. Application No. 08/713,801, now U.S. Pat. No. 5,851,229, all
of which are incorporated herein by reference.
FIELD OF INVENTION
[0002] The present invention generally relates to sealants for
porous implantable devices. More particularly, the present
invention is directed to porous implantable vascular grafts
impregnated with hydrogel or sol-gel mixtures of polysaccharides
that render such grafts blood-tight. Another aspect of the
invention is directed toward providing timed-released delivery of
therapeutic agents impregnated within the interstitial spaces of
such grafts. Methods of providing these grafts are also
provided.
BACKGROUND OF THE INVENTION
[0003] In general, it is important that implantable tubular devices
designed to carry fluids be fluid-tight and nonthrombogenic while
at the same time accommodating to tissue ingrowth. This is
especially true for implantable vascular prostheses. In order to
accommodate tissue ingrowth, such a prosthesis may be porous. Most
textile porous endoprostheses and grafts, however, are not
naturally blood-tight and, unless preclotted or coated with a
biocompatible water-tight coating, substantial bleeding may occur
through the walls of the graft. Accordingly, a balance must be
struck between maintaining a blood-tight surface and promotion of
tissue ingrowth into such vascular grafts. In particular, vascular
grafts made of porous materials must be substantially blood-tight
during the initial introduction of the vascular graft into the body
of a patient in order to reduce blood loss to the patient. As the
graft site heals, however, tissue ingrowth into the graft must be
encouraged. Thus, it is desirable to have graft materials which are
both blood-tight and yet encourage tissue ingrowth. Such
characteristics, however, require the graft to have two different
physical structures.
[0004] For example, vascular graft materials that promote tissue
ingrowth and healing must be porous enough to allow cells and
nutrients to migrate into the graft. Such cellular ingrowth is
vital for the long term patency of the graft. Nylon, polyester,
polytetrafluoroethylene (PTFE), polypropylene, polyurethane,
polyacrylonitrile, etc. are known in the art as materials for
making such vascular grafts. PTFE and polyester are widely used
today because they are inert materials that have low
thrombogenicity in the body. In particular,
polyethyleneterephthalate is most commonly used in making textile
vascular grafts and endoprostheses.
[0005] For the surgeon, the porosity of such graft materials is an
essential factor to consider. In particular, the porosity of such
materials contributes to the long-term patency and overall
performance of a graft. In addition, ease of handling, anastomosis
and flexibility usually increase as the porosity of a graft
material increases. Also, the healing process, i.e., the ability of
connective tissue cells to infiltrate the graft increases as the
porosity of the graft material increases.
[0006] The ability of such porous graft materials to promote tissue
ingrowth etc., however, comes at a price. Untreated, such a graft
is not blood-tight. Thus, when the graft is implanted, bleeding
through the pores in the surface of the graft is a significant
problem. Alternative methods have been developed for reducing blood
loss through leakage of the vascular graft. For example, less
porous materials have been used as vascular grafts. Such materials,
however, suffer from their inability to support endothelialization
of the lumen and tissue ingrowth into the graft. Accordingly, such
textile graft materials are not practical because their patency is
short-lived.
[0007] Alternatively, porous vascular graft materials have been
pretreated with blood prior to introduction of the graft into the
body. Such a pretreatment introduces clotting factors throughout
the graft that help to reduce bleeding during surgery by causing
blood to become clotted before significant loss of blood to the
patient occurs. Generally, these grafts are immersed in, or flushed
with, fresh blood of the patient in order to preclot the surfaces
of the graft. These methods are limited because they are time
consuming, require blood transfusions from the patient, and
increase the amount of blood loss from the patient. Thus, such
methods are not available in emergency medical situations where the
patient has lost a large amount of blood or where time is a
critical factor. In addition, such methods cannot be used
effectively with patients who are taking anticoagulants, such as
heparin or warfarin.
[0008] A considerable amount of research has centered around
developing materials that are initially blood-tight and then
gradually become more porous in order to facilitate healing and
tissue ingrowth into the implanted graft. Much of this research has
focused on coating the surfaces of porous graft materials with
extracellular matrix (ECM) proteins in order to render such graft
materials blood-tight, but which, over time biodegrade and promote
tissue ingrowth into the graft. For example, collagen, albumin,
gelatin, elastin, and fibrin have all been used as bioresorbable
sealants for porous vascular grafts.
[0009] In addition, gels, hydrogels and sol-gels have also been
described as biocompatible, biodegradable materials. A gel is a
substance with properties intermediate between the liquid and solid
states. Gels deform elastically and recover, yet will often flow at
higher stresses. They have extended three-dimensional network
structures and are highly porous. Accordingly, many gels contain a
very high proportion of liquid to solid. The network structures can
be permanent or temporary and are based on polymeric molecules,
basically formed from a colloidal solution on standing. Thus, a
hydrogel may be described as a gel, the liquid constituent of which
is water. By way of contrast, a sol is a colloidal solution, i.e.,
a suspension of solid particles of colloidal dimensions in a
liquid. See, Larouse Directory of Science and Technology 470, 543
(1995).
[0010] By way of example, U.S. Pat. No. 5,209,776 ('776 patent)
issued to Bass et al. discloses a composition for bonding separated
tissues together or for coating the surface of tissues or
prosthetic materials in order to form a water-tight seal thereon.
The composition of the '776 patent includes a first protein
component that is preferably a collagen and a second
protein-supporting component that can be a proteoglycan, a
saccharide or a polyalcohol. In this composition, the second
component is adapted to support the first component by forming a
matrix, sol or gel with the first component. Thus, the matrix, sol
or gel formed is a hybrid composition that includes a protein
component and a protein-supporting component that can be a protein,
a saccharide or a polyalcohol. The protein component provides the
sealing or bonding function, while the protein-supporting component
forms a supporting matrix for the protein.
[0011] In another example, U.S. Pat. Nos. 5,135,755 and 5,336,501
both issued to Czech et al. disclose hydrogels that may be used as
wound secretion absorbers or incorporated into wound dressings for
absorbing wound secretions. The hydrogel composition of these
inventions include 20-70% of at least one multivalent alcohol, for
example glycerol, 10-35% of at least one natural biopolymer
thickener agent, 0.05-10% of a cross-linking agent and 0-50% of
water or physiological saline.
[0012] The gel or hydrogel described in these patents can be
gelatin alone or gelatin in combination with a polysaccharide,
particularly an alginate. Thus, the hydrogel of these patents is a
protein hydrogel or a protein-polysaccharide hybrid hydrogel. In
addition to gelatin, collagens and pectins are also preferred
protein components in the hydrogel materials of these patents.
These patents all require conventional protein materials to provide
the sealing function and the hydrogels are used as carriers for the
proteins.
[0013] Such hybrid coating compositions described in the Bass and
Czech patents however, are not easily manufactured. For example,
the protein components of the hybrid coating compositions can
become denatured during the manufacturing, sterilizing or storing
of the hydrogel coated material (wound dressing as in Czech or an
implantable device as in Bass). Once denatured, these hybrid
coating compositions can lose their ability to function. Another
problem with such hybrid coating compositions is that the surface
of the substrate material, e.g., wound dressing or implantable
device, must be pretreated with, for example, plasma, in order to
effectively bind such compositions to the surface of, for example,
a vascular graft. In addition, such hybrid compositions are
deposited as coatings on the surface of a substrate material. Such
surface coatings are limited in that they are readily accessible to
the body's degradative enzymes and thus are swiftly degraded.
[0014] In an attempt to alleviate the problems incident with such
protein or protein hybrid coatings, U.S. Pat. No. 5,415,619 issued
to Lee et al. ('619 patent) describes a method of rendering a
porous vascular graft blood-tight by impregnating the surface
thereof with a polysaccharide or polysaccharide derivative.
Accordingly, the '619 patent uses the word "impregnate" to mean
physically adsorbing or chemically binding the polysaccharides to
the surface of a graft. Although this method alleviates the problem
of protein denaturation during the manufacturing, sterilizing and
storing of, for example, a vascular graft, the surface of such a
graft must be chemically or physically altered in order to bind the
polysaccharide coating to the surface thereof. For example, the
'619 patent describes chemically oxidizing the surface of a porous
vascular graft with a solution of sulfuric or perchloric acid prior
to impregnating the surface of the graft with a polysaccharide
solution. Alternatively, the '619 patent describes physically
altering the surface of such a graft by pretreatment with plasma or
corona discharge. In either case, the methods described in the '619
patent add additional unnecessary steps to such a process by
chemically or physically pretreating the surface of such vascular
grafts. [0015] Accordingly, it would be desirable to provide an
improved bioresorbable sealant for porous implantable prostheses,
such as vascular grafts, that renders the porous prosthesis
blood-tight upon introduction into the body and that is
bioresorbable over time such that tissue ingrowth is promoted. In
particular, it would be desirable to provide an improved
bioresorbable sealant for a porous vascular graft that renders such
a graft blood-tight and that does not require physical or chemical
modification of the surface of such a graft prior to incorporation
of the sealant.
SUMMARY OF THE INVENTION
[0015] In accordance with the present invention, an improved
bioresorbable sealant composition for implantable prostheses is
provided. In particular, the bioresorbable sealant composition
includes the combination of at least two polysaccharides which form
a hydrogel that imparts a substantially blood-tight barrier to the
implantable prostheses. Preferably the prosthesis is a soft tissue
prostheses used in the vascular system, such as a vascular graft or
endoprosthesis. Other tubular prostheses or soft-tissue prostheses
such as surgical mesh or hernia plugs are also contemplated.
[0016] The implantable prosthesis is preferably made from a
synthetic textile material that is woven or knitted into a tubular
prosthesis. Useful materials include for example, polyester,
poly(tetrafluoroethylene), nylon, polypropylene, polyurethane and
polyacrylonitrile, among others. In addition to knitted or woven
textile fabrics, the prosthesis may be formed from extrusion and
expansion techniques, such as with expanded
poly(tetrafluoroethylene) (ePFTE). Composites of these materials,
as well as others, are also contemplated.
[0017] In the present invention, useful polysaccharides include
algin, carboxymethyl cellulose, carrageenan, including carrageenan
type I, carrageenan type II, carrageenan type III, and carrageenan
type IV, furcellaran, agarose, guar, locust bean gum, gum arabic,
hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose,
hydroxyalkylmethyl cellulose, pectin, partially de-acetylated
chitosan, starch and starch derivatives including, amylose and
amylopectin, xanthan, casein, polylysine, hyaluronic acid and its
derivatives, heparin, their salts, and mixtures thereof.
[0018] As previously mentioned, the present invention requires the
combination of at least two polysaccharides, or a polysaccharide
and a protein to form a hydrogel. Numerous combinations of
polysaccharides may be used in this invention, such as, for
example: alginic acid/pectin, alginic acid/chitosan, carrageenan
type I/ locust bean gum, carrageenan type I/pectin, carrageenan
type II/locust bean gum, carrageenan type II/pectin, carrageenan
type II/guar gum, carrageenan type IV/locust bean gum, locust bean
gum/xanthan, guar gum/locust bean gum, guar gum/xanthan, and
agar/guar gum. Preferred combinations of polysaccharides which form
a hydrogel include carrageenan type II with Ca+.sup.2 ion and/or
locust bean gum, or carrageenan type IV, Ca+.sup.2 with or without
locust bean gum. Other preferred combinations include purified
agarose/guar gum, as well as chitosan/guar gum. Because natural
polysaccharides are constantly being isolated and characterized,
and new polysaccharides may be produced by molecular biology
techniques, other such polysaccharides are useful in the present
invention.
[0019] The present invention also contemplates incorporating a
therapeutic or bioactive agent into the hydrogel. In this way, the
hydrogel controllably releases the therapeutic agent while the
hydrogel is biodegraded or bioresorbed. One particularly useful
class of therapeutic agents is the anticoagulants. As used herein,
the anticoagulant agent may include any agent useful for such
purposes, but among those currently known as being useful are
heparin, sulfated polysaccharides, prostaglandin, urokinase,
hirudin streptokinase, their pharmaceutical salts and mixtures
thereof. Heparin is preferred because it is a polysaccharide and is
easily incorporated into a hydrogel. Furthermore, combinations of
heparin/chitosan are also known to form gels when combined as shown
in Table 2.
[0020] In the present invention, the hydrogel formed from
combinations of polysaccharides may be cross-linked in order to
form a tighter barrier and seal around, e.g., throughout the
interstitial spaces of, the porous device.
[0021] In another embodiment of the invention, a controlled release
material is provided that includes a hydrogel matrix formed from at
least two polysaccharides and an anticoagulant agent incorporated
within the matrix thereof. This material is impregnated within the
interstitial space between the inner and outer surfaces of a porous
implantable device.
[0022] In yet another embodiment of the present invention, there is
provided a sealant for an implantable porous luminal substrate. In
this embodiment of the invention, a porous substrate having an
inner and an outer surface with interstitial spaces defined
therebetween is provided. The sealant of this embodiment includes a
hydrogel that includes, in combination, at least two
polysaccharides. This sealant fills the interstitial space of the
porous substrate and imparts a substantially liquid-tight barrier
between the inner and outer surfaces of the porous material. The
sealant may also be a sol-gel which includes, in combination, at
least two polysaccharides.
[0023] In another embodiment of the present invention, the
prosthesis includes a tubular member that is impregnated with a
hydrogel that is defined by a mixture of a seed gum polysaccharide
and a sea weed extract polysaccharide dispersed in a glycerol-water
solution. Alternatively, this prosthesis includes a tubular member
that is impregnated with a hydrogel that is defined by a mixture of
a linear polysaccharide component and a branched polysaccharide
component dispersed in a glycerol-water solution.
[0024] A method for rendering an implantable porous tubular
substrate fluid-tight is also provided. The method includes
providing an implantable porous substrate having an inner and an
outer surface with an interstitial space defined therebetween;
providing a hydrogel or a sol-gel that includes at least two
polysaccharides; and impregnating the porous substrate with the
hydrogel or sol-gel to render the substrate fluid-tight.
[0025] In yet another embodiment of the present invention, there is
provided a bioresorbable sealant composition for use in a
soft-tissue prosthesis including, in combination, at least two
polysaccharides which when mixed together in an aqueous medium form
a hydrogel. This hydrogel forms a liquid-tight seal when applied to
the prosthesis as a sealant. A controlled-release, bioresorbable
sealant composition is also provided whereby in addition to the
combination of at least two polysaccharides, there is also included
a therapeutic or bioactive agent which is slowly released in the
body subsequent to implantation as the sealant gradually bioerodes
and tissue ingrowth increases.
[0026] Methods of preparing and using the aforementioned sealant
compositions and prostheses containing same are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
[0027] While this invention is satisfied by embodiments in many
different forms, there will be described herein in detail preferred
embodiments of the invention, with the understanding that the
present disclosure is to be considered as exemplary of the
principles of the invention and is not intended to limit the
invention to the embodiments illustrated and described.
[0028] The present invention relates to sealant compositions and
implantable soft tissue prostheses having such compositions
impregnated therein. In particular, the invention relates to
hydrogel or sol-gel sealant compositions which include the
combination of at least two polysaccharides. The sealant
compositions of the present invention form a substantially
liquid-tight, i.e., blood-tight seal on porous substrate surfaces,
and particularly the luminal surfaces of substrates such as on
vascular grafts. These sealant compositions biodegrade over time in
order to allow healing and endothelial cell ingrowth.
[0029] The implantable soft tissue prostheses of the present
invention can be formed of any porous material, including any
synthetic or natural polymer material, onto which a hydrogel or
sol-gel can effectively adhere. Thus, such porous materials may
include polyesters, expanded poly(tetrafluoroethylene), nylons,
polypropylenes, polyurethanes, polyacrylonitriles, polyolefins,
polycarbonates, highly cross-linked collagens, polylactides,
polyglycosides and combinations thereof. Woven or knitted grafts
made of such materials may also be used in this invention. In
addition, velour or double velour grafts may also be used.
[0030] For purposes of this invention, "hydrogel" and "hydrogel
matrix" both refer to a polymeric material that swells in water
without dissolving and that retains a significant amount of water
in its structure. Such a material has properties intermediate
between the liquid and solid states. Hydrogels also deform
elastically and recover, yet will often flow at higher stresses.
Thus, for purposes of this invention hydrogels are water-swollen,
three-dimensional networks of hydrophilic polymers.
[0031] By way of contrast, a sol-gel is a hydrogel in which part of
the structure is, in some way water-soluble. Thus, in a sol-gel
system, some portion of the material is water-extractable, although
the rate of solubilization may be low. Accordingly, for purposes of
this invention, "sealant" or "sealant matrix" both refer to either
a hydrogel or a sol-gel composition as described herein.
[0032] These sealant matrices can be made more stable by
cross-linking the component parts thereof. The sealant matrices of
the present invention can be cross-linked in several ways. For
example, formation of covalent bonds between one or more of the
polysaccharides in the matrix can produce generally irreversible
cross-linking. Alternatively, the sealant matrices of the invention
can be cross-linked by the formation of ionic bonds in at least one
of the polysaccharides. In another example, cross-links may be
formed in the sealant matrices of the invention through weaker
intermolecular interactions, such as, for example, hydrogen bonding
and specific van der Waals interactions. In yet another example of
cross-linking in the present invention, a semicrystalline
hydrophilic polymer can form a hydrogel when the amorphous regions
of such a polymer absorbs water and the water-insoluble crystalline
regions (crystallites) act as physical crosslinks.
[0033] These sealant cross-linking mechanisms may be either
intramolecular or intermolecular. Furthermore, such interactions
may occur between two or more polysaccharides or one polysaccharide
and one or more other hydrophilic polymers. It is difficult to
predict whether a particular combination of polysaccharides when
combined under various conditions will form a gel material which is
stable under physiological conditions, is compatible with an
appropriate plasticizer, and is suitable for rendering an
implantable graft blood-tight. Thus, Table 1 below is exemplary of
some the combinations of polysaccharides prepared according to the
present invention. These exemplary polysaccharides were evaluated
for their abilities to form stable gels in a physiological
phosphate buffer at pH 7.2. TABLE-US-00001 TABLE 1 POLYSACCHARIDE
GELS IMPREGNATED COMBINATIONS GRAFT AND INSOLUBLE PREPARED WITH
POROSITY POLYSACCHARIDE IN BUFFER GLYCEROL TESTED Low Viscosity
Alginic Acid + Pectin No No -- Med Viscosity Alginic Acid + Pectin
No -- -- High Viscosity Alginic Acid + Pectin Yes Yes -- Low
Viscosity Alginic Acid + Chitosan Yes -- -- Med Viscosity Alginic
Acid + Chitosan No -- -- Carrageenan Type I + Locust Yes Yes Yes
Bean Gum Carrageenan Type I + Pectin Yes Yes -- Carrageenan Type II
+ Locust Yes Yes Yes Bean Gum Carrageenan Type II + Pectin Yes Yes
-- 100% Guar Gum No Yes -- 100% Locust Bean Gum No Yes -- 100%
Purified Agar Yes Yes -- Guar Gum + Locust No Yes -- Bean Gum Guar
Gum + Xantham Yes Yes -- Gum Xantham Gum + Locust Yes Yes -- Bean
Gum Purified Agar + Guar Yes Yes Yes Gum
[0034] Accordingly, in the present invention, at least two
polysaccharides must be used to define such sealant matrices. In
particular, the following list of polysaccharides may be used
herein: heparin, algin, carboxymethyl cellulose, carrageenan,
including carrageenan type I, carrageenan type II, carrageenan type
III, and carrageenan type IV; furcellaran, agarose, guar, locust
bean gum, gum arabic, hydroxyethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, hydroxyalkylmethyl cellulose, pectin,
chitosan; starch and starch derivatives including, amylose and
amylopectin; xanthan, their salts, and mixtures thereof. Certain
proteins and polyamino acids may also be useful. Such a list is
illustrative and should not be construed to limit in any way the
scope of the invention.
[0035] Plasticizers and softeners may also be used in the present
sealant matrices. Examples of such reagents include glycerol,
sorbitol and diols, such as, polypropylene glycol; partially
esterfied citric acid, such as, mono-ethylcitrates; and lactic acid
esters, such as ethyl lactate may also be used in the present
sealant matrices. In the present invention, from about 0% to about
70% plasticizer may be used. It is critical, however, to monitor
the concentration of plasticizer in a particular sealant. Too much
plasticizer can cause a sealant-impregnated graft material to leak.
Such plasticizers, used in the proper concentration as indicated
above, are beneficial because they increase the softness and
flexibility of the impregnated implantable material.
[0036] Table 2 below summarizes some of the relevant chemical
properties and gel forming abilities of exemplary polysaccharides
of the present invention. TABLE-US-00002 TABLE 2 POLYSACCHARIDE
PROPERTIES AND GEL FORMING ABILITIES GEL FORMING ABILITY WITH
POLYSACCHARIDE PROPERTIES OTHER MATERIALS COMMENTS Agar Contains
some SO.sub.3H Guar gum Forms strong, rigid low solubility below
forms strong rigid gel, gels that melt at high 100.degree. C.
resistant to pH changes temperatures Algin Polyelectrolyte,
polyamino acids, such as, Elasticity of gels (salts of alginic
acid) contains COO.sup.-, poly(lysine), Ca.sup.+2 varies with
alginate forms pseudo plastic structure solutions Amylose Forms
dispersions in -- -- water that undergo retrogradation Carrageenan,
kappa Polyanion, contains K.sup.+, proteins, such as, k- Forms
firm, rigid gels SO.sub.3H, Na salt is casein, locust bean gum when
cooled soluble in cold water, other in hot water. Carrageenan, iota
Polyanion, contains K.sup.+, Mg.sup.+2, Ca.sup.+2, proteins, Forms
elastic, stable, SO.sub.3H, similar to k-casein, locust bean gum
syneresis free gels kappa carrageenan that are thermally but more
soluble reversible Carrageenan, lambda Polyanion contains K.sup.+,
proteins, milk Anticoagulant, SO.sub.3H, the most proteins, locust
bean induces connective soluble, non gelling gum tissue growth
Chitosan Contains-NH.sub.2 Hyaluronic acid, Stimulates Heparin,
Chondroitin macrophage Sulfate, Cellulose growth, anti- Sulfate,
and Sodium infective agent, Carboxymethyl immuno-enhancer,
Cellulose hemostatic, accelerates wound healing Furcelleran
Polyanion, contains Locust bean gum, K.sup.+, properties similar
some SO.sub.3H, fewer Ca.sup.+2, milk proteins to carrageenan than
the kappa carrageenans but more than Agar; forms flexible,
opalescent gels. Guar Gum Nonionic, disperses Borates, Xanthan Gum,
Viscosity increases ad swells in cold or Carrageenans, and after
being heated; hot water forms Agar gels are weaker high viscosity,
than locust bean cloudy pseudo gums plastic solutions Gum Arabic
acidic Gelatin Has a protective polysaccharide, colloid action
highly soluble, forms Newtonian solutions with low viscosity, even
at low concentrations Hydroxyethyl Nonionic, both Sodium
carboxymethyl Properties not Cellulose, form clear, smooth
cellulose affected by pH, Hydroxypropyl solutions and Newtonian at
low Cellulose impermeable films shear rates, pseudo plastic at high
shear rates Locust Bean Gum Nonionic, partially kappa carrageenan,
Viscosity increases soluble in cold Furcelleran, xanthan after
heating above water, fully soluble 85.degree. C. in hot water,
delayed viscosity Pectin Soluble in hot Sugar, Ca.sup.+2, pH < 3
Forms pseudo water, gels upon plastic solutions cooling Sodium
Polyanion, hydrates Casein, Soy Protein, -- Carboxymethyl rapidly
to form Guar Gum, HPC and Cellulose clear solutions Chitosan
Xanthan Gum Anionic, forms Locust Bean Gum Viscosity does not
viscous, strongly (thermally reversible change pseudo plastic gel),
Guar Gum significantly with solutions (weak), Methyl temperature or
pH Cellulose
[0037] As previously stated, the present invention utilizes in
combination at least two polysaccharides as component parts of the
sealant matrix. Such paired combinations of polysaccharides
include, but are not limited to the following combinations: alginic
acid/pectin, alginic acid/chitosan, carrageenan type I/locust bean
gum, carrageenan type I/pectin, carrageenan type II/locust bean
gum, carrageenan type II/pectin, carrageenan type II/guar gum,
carrageenan type IV/locust bean gum, locust bean gum/xanthan, guar
gum/locust bean gum, guar gum/xanthan, alginic acid/poly lysine,
agar/guar gum, proteins and polyamino acids.
[0038] It is known that ions, in particular, K.sup.+, Ca.sup.+2,
and Mg.sup.+2 synergistically interact with certain polysaccharides
to form gels. Accordingly, sealant impregnated grafts may be
contacted with a solution of such ions in order to increase the
strength of the gel. In the present invention, the sealant
impregnated grafts may be, for example, dipped, steeped, sprayed or
otherwise conventionally contacted with a solution of ions, such as
for example, K.sup.+, Ca.sup.+2, and Mg.sup.+2 ions, although other
ions may also be useful. Accordingly, the sealant matrices may
include for example, carrageenan type II, Ca.sup.+2 ion and locust
bean gum or carrageenan type IV, Ca.sup.+2 ion and locust bean
gum.
[0039] In another embodiment of the present invention, an
anticoagulant agent or other bioactive agents may be incorporated
into the sealant. In this way, as the sealant's polysaccharide
matrix biodegrades the bioactive agent, i.e. anticoagulant agent,
may be controllably released over time. Thus, the anticoagulant
agent augments the sealant's ability to prevent blood leakage
through, for example, the walls of a porous vascular graft. In the
present invention, the anticoagulant agent may be a prostaglandin,
a urokinase, a streptokinase, a sulfated polysaccharide, an
albumin, their pharmaceutical salts and mixtures thereof. Other
suitable anticoagulant agents may also be used. Preferably, the
anticoagulant agent is heparin or its pharmaceutical salt.
[0040] As the type and composition of the sealant matrix can vary,
so too can the type and structure of the porous implantable
material. For example, generally synthetic grafts fall into one of
two categories: textile grafts or extrusion grafts. Textile grafts
are manufactured out of extruded fibers, such as, for example,
Dacron polyester. Such fibers are made into yarns and are then
formed into tubular structures by knitting or weaving.
Alternatively, extrusion grafts are non-textile grafts manufactured
out of polymers, such as, for example, polytetrafluoroethylene,
that are extruded and mechanically stretched to produce a
microporous tube. In general, non-coated textile grafts have a
higher water permeation rate than non-textile extruded grafts.
Accordingly, how a graft is manufactured influences its
porosity.
[0041] For purposes of this invention, "porous" or "porosity"
refers to the relative amount of open or interstitial space in the
wall of, for example, a vascular graft. The tightness of the weave
or knit of a textile graft, or the degree of stretching of an
extruded graft influences its porosity. Other factors influencing
the porosity of a textile graft include the type of yarn used and
knitting or weaving configuration used. For example, graft
materials made of texturized fabrics that have additional yarns
added thereto give the fabric a plied or napped texture and are
called velour (single-sided) or double-velour (double-sided).
Traditionally, such velour grafts were less likely to bleed after
implantation because they had more surface area and were easier to
preclot.
[0042] By way of contrast, grafts formed of expanded PTFE (ePTFE)
have a fibrous structure which is defined by interspaced nodes
interconnected by elongated fibrils. The spaces between the node
surfaces that are spanned by the fibrils are defined as the
internodal distance (IND). The porosity of an ePTFE vascular graft
is controlled by varying the IND of the microporous structure of
the graft. An increase in the IND within a given structure results
in enhanced tissue ingrowth, as well as cell endothelialization,
along the inner surface thereof. This tissue ingrowth and
endothelialization promotes stability, enhances radial strength and
increases the patency of the graft.
[0043] Accordingly, either textile or extruded materials may be
used in connection with the sealants of the present invention. It
is critical, however, that the walls of the intended graft material
be sufficiently porous so that the polysaccharide hydrogel or
sol-gel can impregnate the interstitial spaces thereof. For
purposes of this invention, "impregnate" is intended to mean the
partial or complete filling of the interstitial space, e.g., the
pores or spaces between the inner and outer surface of, for
example, a vascular graft, in order to render such a graft
substantially blood-tight.
[0044] For purposes of this invention, the specific porosity of a
material can be measured with a Wesolowski Porosity tester. With
this apparatus, a graft is tied off at one end and the free end is
attached to a valve on a porometer so that the graft hangs freely
in a vertical position. Then, water is run through the graft for
one minute and all the water that escapes from the graft is
collected and measured. The specific porosity of the graft is then
calculated according to the following formula: P = V A ##EQU1##
where V is the volume of water collected in ml/min and A is the
surface area of the graft exposed to water in cm.sup.2. A specific
porosity of .ltoreq.1.0 ml/min/cm.sup.2 is considered an acceptable
amount of leakage for an implantable vascular graft. Accordingly,
for purposes of this invention, a substantially blood-tight graft
means a graft with a specific porosity, after impregnation with a
sealant of the present invention, of .ltoreq.1.0
ml/min/cm.sup.2.
[0045] In yet another embodiment of the present invention, an
anticoagulant agent or other bioactive agent dispersed within a
controlled release material is impregnated within the interstitial
space between the inner and outer surface of a porous implantable
device. The controlled release material is a hydrogel matrix
containing at least two polysaccharides as described hereinabove.
Thus, as the hydrogel is biodegraded by natural enzymes present in
the body, the anticoagulant agent is slowly released over time.
Accordingly, in addition to imparting a substantially blood-tight
seal to, for example, a vascular graft, the hydrogel matrix as it
biodegrades, also provides a support structure from which the
anticoagulant or bioactive agent is controllably released. In this
way, the controlled release of the anticoagulant enhances the
ability of this hydrogel composition to prevent blood loss to the
patient by coagulating any blood that evades the physical barrier
created by the hydrogel.
[0046] According to Kinam Park et al., Biodegradable Hydrogels For
Drug Delivery (Technomic Publishing Co. 1993), drug release in a
hydrogel system is influenced by various formulation variables
and/or physiochemical properties of the components in the system.
Thus, in addition to polymer degradation, release of the
anticoagulant is affected by the physical parameters of the
polymer, such as, water content, degree of crosslinking,
crystallinity, and phase separation. In addition, the
physiochemical properties of the anticoagulant, particularly its
solubility in the polymer and aqueous medium and the amount of drug
loaded into the hydrogel are also expected to have significant
effects on the release characteristics of the drug-polymer
composite. Accordingly, the release rate of the anticoagulant agent
will vary according to the variables disclosed hereinabove.
Providing the appropriate release rate, however, can be achieved by
one skilled in the art by adjusting these parameters.
[0047] Any conventional method for filling or impregnating the
interstitial spaces of the porous substrate can be used. For
example, a sealant mixture of the present invention was placed in a
glass container and a porous substrate, such as, for example, a
porous vascular graft, was submerged in the sealant mixture. A
vacuum was applied to the glass container until no bubbles remained
on the surface of the graft or in the solution. The vacuum forced
the sealant into the interstitial spaces of the graft. Then, the
graft was removed from the sealant mixture, excess sealant removed
or squeezed out and allowed to dry.
[0048] Alternatively, the graft may be filled with a sealant
composition according to the present invention and pressurized to
cause penetration of the composition into the pores of the graft
wall. For example, one end of a porous substrate, such as, for
example, a vascular graft, was tied off. The other end of the graft
was connected to the nozzle portion of a 60 cc syringe. The syringe
was filled with a composition of the present invention and the
composition was pushed through the syringe with a plunger. In this
way, the composition of the present invention impregnated, e.g.,
was forced into the interstitial spaces of the graft. Once the
graft was filled with the composition, the syringe was withdrawn
and excess sealant was removed from the graft. The graft was then
allowed to dry. This injection procedure may be repeated any number
of times as may be required to ensure effective impregnation of the
substrate, for example, up to six times. Other means of using force
to cause sealant penetration into the interstices of the graft wall
are also contemplated.
[0049] As previously described, the sol-gel of the present
invention is made from a partially water-extractable, e.g., water
soluble, material. The solubility rate of the sol-gel material of
the present invention is, however, very low. The sol-gel material
of the present invention is formed from at least two
polysaccharides as described herein above. Accordingly, such a
sol-gel sealant is optimally suited for providing blood-tight
barriers to porous graft materials because such a sealant provides
an initial blood-tight surface that is slowly biodegraded and/or
solubilized into biocompatible products to permit endothelial cell
proliferation into the graft from the surrounding tissue.
[0050] Gums, for example, seed gums, are polymeric substances that,
in an appropriate solvent or swelling agent, form highly viscous
dispersions or gels at low, dry substance content. In particular,
seed gum polysaccharides are water soluble polymers that produce
viscous aqueous dispersions. The seed gum polysaccharide family of
the present invention includes, for example, corn starch, guar gum
and locust bean gum, although other gum materials are also useful.
Similarly, the sea weed extract polysaccharides are also
water-soluble polymers that produce viscous aqueous dispersions.
Thus, all members of the sea weed extract polysaccharide family may
be used in the present invention, including, for example, algin,
carrageenan, including types I-IV, and agar.
[0051] In one embodiment of the present invention, the hydrogel
includes a combination of a linear polysaccharide component and a
branched polysaccharide component dispersed in a glycerol-water
solution. The linear polysaccharides of the present invention are
water-soluble polymers that produce viscous aqueous dispersions.
Thus, all members of the linear polysaccharide family may be used
in the present invention, including, for example, algin, starch
amylose and its derivatives, carrageenan, including types I-IV,
pectin, and cellulose derivatives. Similarly, the branched
polysaccharides of the present invention are water-soluble polymers
that produce viscous aqueous dispersions. Thus, all members of the
branched polysaccharide family may be used in the present
invention, including, for example, guar gum, xanthan, locust bean
gum, starch, amylopectin and its derivatives, and gum arabic.
[0052] The following examples are provided to further illustrate
methods of preparation of the sealant compositions and their
application to porous implantable substrates.
EXAMPLE 1
CARRAGEENAN TYPE I/LOCUST BEAN GUM
[0053] Several preparations of the sealant compositions of the
present invention were prepared in 600 ml beakers as described
herein.
[0054] Sealant Composition A: A solution of carrageenan type I
(SIGMA Chemical Co., St. Louis, Mo) was prepared by adding 4 gm of
carrageenan type I to 300 ml of water under constant mixing with a
Dyna-Mixer. The carrageenan type I used in this experiment is
predominantly of the kappa variety and contains lesser amounts of
the lambda variety. This carrageenan type I is of commercial grade
and is derived from various seaweeds. When this solution was smooth
and no lumps were visible, the mixing was stopped and 20 gm of
glycerol was added thereto and then stirred by hand.
[0055] Sealant Composition B: A solution of locust bean gum was
prepared by adding 3 grn locust bean gum to 300 ml water under
constant mixing with a Dyna-Mixer. When this solution was smooth
and no lumps were visible, the mixing was stopped and 20 gm of
glycerol was added thereto and then stirred by hand.
[0056] Sealant Composition C: Equal amounts (1:1 mixture) of
solutions A and B was prepared by hand mixing.
[0057] The ability of Solution C to make woven and knitted double
velour grafts water-tight was then assessed under the following
three conditions: (1) grafts were coated with a room temperature
sealant and then dried at room temperature; (2) grafts were coated
with a sealant at a temperature of 60.degree. C. and then dried at
room temperature; (3) grafts were coated with a room temperature
sealant and then dried at 60.degree. C. Each parameter was tested
in triplicate. For purposes of this invention, "room temperature"
means a temperature from about 22.degree. C. to about 25.degree.
C.
[0058] To impregnate each graft with one of the sealant
compositions, the following protocol was followed. Each graft was
attached to a 60 cc syringe. A sealant composition was then added
to the syringe and was then injected into the graft until the graft
was full and under pressure. The graft was then emptied, the excess
sealant removed by applying force thereto and allowed to dry.
Grafts dried at room temperature were allowed to dry from about 2
to about 4 hours. Grafts dried at 60.degree. C. were dried in an
oven from about 30 minutes to about 1 hour. This procedure was
repeated six times per graft. After the sixth treatment, the
ability of each sealant composition to seal the graft was tested by
measuring the water porosity, e.g., specific porosity, of the graft
as described hereinabove. Table 3 summarizes the results for each
of the grafts tested. TABLE-US-00003 TABLE 3 CARRAGEENAN TYPE
I/LOCUST BEAN GRAFT GRAFT GRAFT DIAMETER LENGTH WATER POROSITY**
SAMPLE (cm) (cm) (ml) (ml/min/cm.sup.2) Uncoated Woven 0.8 25 3550
56.5 Uncoated Knitted 0.8 25 3510 56.5 Woven 1* 0.8 27 200 3.68
Woven 2.sup.+ 0.8 27 750 13.80 Knitted Double 0.8 21 2750 52.10
Velour 1* Knitted Double 0.8 21 3200 60.60 Velour 2.sup.+ *Graft
impregnated with 23.degree. C. sealant and dried at room
temperature. .sup.+Graft impregnated with 60.degree. C. sealant and
dried at room temperature. **Porosity measured in accordance with
the Wesolowski test described herein.
[0059] As the data indicate, the sealant impregnated woven grafts
were significantly more water-tight than the knitted double velour
grafts. Both the woven and knitted grafts held more water when the
sealant was injected at 60.degree. C. It should be noted that all
grafts were soft and flexible after the final coating and were
manipulated easily without causing the sealant to crack. As the
specific porosity of all of the grafts were .gtoreq.1
ml/min/cm.sup.2, none of these preparations are suitable for
implanting into a host organism. Accordingly, a sealant composition
of carrageenan type II and locust bean gum was tried.
EXAMPLE 2
CARRAGEENAN TYPE II/LOCUST BEAN GUM
[0060] In another experiment, the sealant properties of a
carrageenan type II-locust bean gum hydrogel were assessed. The
protocol for this experiment was the same as in Example 1 except
that in Sealant Composition A, 4 gm of carrageenan type II (SIGMA
Chemical Co., St. Louis, Mo) was used instead of carrageenan type
I. The carrageenan type II used in this experiment is predominantly
of the iota variety. In addition, Sealant Composition A alone was
used to impregnate a woven graft. The results of the experiment are
indicated below in Table 4. TABLE-US-00004 TABLE 4 CARRAGEENAN TYPE
II/LOCUST BEAN GUM GRAFT GRAFT GRAFT DIAMETER LENGTH WATER
POROSITY** SAMPLE (cm) (cm) (ml) (ml/min/cm.sup.2) Uncoated Woven
0.8 25 3550 56.5 Uncoated Knitted 0.8 25 3510 56.5 Woven 1* 0.8 27
6 0.09 Woven 2.sup.+ 0.8 27 8 0.12 Woven 3.sup.# 0.8 27 1 0.01
Knitted Double 0.8 24 2600 43.13 Velour 1* Knitted Double 0.8 24
2650 43.96 Velour 2.sup.+ Knitted Double 0.8 21 1050 19.90 Velour
3.sup.# Woven 0.8 27 2000 29.49 (carrageenan type II alone)* Woven
0.8 28 300 4.27 (carrageenan type II alone).sup.# *Graft
impregnated with 23.degree. C. sealant and dried at room
temperature. .sup.+Graft impregnated with 60.degree. C. sealant and
dried at room temperature. .sup.#Graft impregnated with 23.degree.
C. sealant and dried at 60.degree. C. **Porosity measured in
accordance with the Wesolowski test described herein.
[0061] As the data indicate, the sealant impregnated woven grafts
were significantly more water-tight than the knitted double velour
grafts. There is no difference in porosity between grafts dried at
room temperature versus grafts dried at 60.degree. C. Both the
woven and knitted grafts held more water when the sealant was
injected at 60.degree. C. The woven grafts coated with carrageenan
type II alone were significantly more porous than grafts coated
with the carrageenan type II locust bean mixture. Drying the
carrageenan type II coated graft at 60.degree. C. significantly
improved water tightness as demonstrated in the porosity tests. All
grafts were soft and flexible after the final coating and were
manipulated easily without causing the sealant to crack. As the
data indicate, the carrageenan type II/locust bean gum sealant
impregnated woven grafts were substantially water tight, e.g., gave
specific porosity data of .ltoreq.1.0 ml/min/cm.sup.2. These data
indicate that such a graft-sealant combination is viable for
implanting into a host organism.
EXAMPLE 3
CARRAGEENAN TYPE IV/LOCUST BEAN GUM
[0062] In another experiment, the sealant properties of a
carrageenan type IV/locust bean gum hydrogel were assessed. The
protocol for this experiment was the same as in Example 1 except
that in Sealant Composition A, 4 gm of carrageenan type IV (SIGMA
Chemical Co., St. Louis, Mo) was used instead of carrageenan type
I. The carrageenan type IV used in this experiment is predominantly
of the lambda variety. The carrageenan type IV used in this
experiment was derived from Gigartina aciculaire and G. pistillata.
The results of this experiment are indicated below in Table 5.
TABLE-US-00005 TABLE 5 CARRAGEENAN TYPE IV/LOCUST BEAN GUM GRAFT
GRAFT GRAFT DIAMETER LENGTH WATER POROSITY** SAMPLE (cm) (cm) (ml)
(ml/min/cm.sup.2) Uncoated 0.8 25 3550 56.5 Woven Uncoated 0.8 25
3510 56.5 Knitted Woven 1* 0.8 27 5 0.07 Woven 2.sup.+ 0.8 28 5
0.07 Knitted Double 0.8 25 2050 32.60 Velour 1* Knitted Double 0.8
26 1550 23.70 Velour 2.sup.+ *Graft impregnated with 23.degree. C.
sealant and dried at room temperature. .sup.+Graft impregnated with
60.degree. C. sealant and dried at room temperature. **Porosity
measured in accordance with Wesolowski test described herein.
[0063] As the data indicate, the sealant impregnated woven grafts
were significantly more water-tight than the knitted double velour
grafts. There was no difference in porosity between the woven
grafts injected with 60.degree. C. sealant compared to woven grafts
injected with 23.degree. C. sealant. The knitted grafts, however,
held more water when the sealant was injected at 60.degree. C. It
should be noted that all grafts were soft and flexible after the
final coating and were manipulated easily without causing the
sealant to crack. As the data indicate, like the carrageenan type
II/locust bean gum sealant, the carrageenan type IV/locust bean gum
sealant was able to provide a substantially water-tight graft that
can be implanted into a host organism.
[0064] As Examples 1-3 demonstrate, carrageenan types II and IV
were more effective in sealing the grafts when used in combination
with locust bean gum than carrageenan type I. The sealants were
more effective when used with woven grafts than with knitted double
velour grafts primarily due to the larger porosity inherent in
knitted constructions. In grafts impregnated with carrageenan type
II and locust bean gum, there was no difference between grafts that
were dried at room temperature versus grafts dried at 60.degree. C.
Both the knitted and woven grafts injected with 60.degree. C.
sealant held more water in the porosity tests when compared to
similar grafts injected with 23.degree. C. sealant.
[0065] The woven grafts coated with carrageenan type II alone did
not give comparable results to the woven grafts coated with the
carrageenan type II and locust bean gum combination. The results in
Table 4, however, demonstrate that the carrageenan type II
impregnated grafts dried at 60.degree. C. allowed more sealant to
adhere to the graft and were less porous. Grafts coated with the
carrageenan type IV/locust bean gum combination were comparable to
the carrageenan type II/locust bean gum combination. The drying
method did not change the observed porosity characteristics. Grafts
coated with the carrageenan type I/locust bean gum combination,
however, were the most porous of the sealant mixtures tested in
Examples 1-3.
EXAMPLE4
AGAR/GUAR GUM
[0066] In an attempt to find an universally applicable sealant,
e.g., a sealant that renders both woven and knitted textile grafts
substantially blood-tight, it was decided to experiment with a
mixture including a combination of agar/guar gum. In this example,
the porosity of grafts impregnated with a hydrogel made from the
combination of purified agar and guar gum was tested. Two knitted
grafts and two double velour grafts were injected at 60.degree. C.
because it was found that the agar/guar gum sealant mixture formed
a gel at 40.degree. C. Each graft was injected six times as
described in Example 1. One of each type of graft was dried between
injections at room temperature from about 1 to about 2 hours
(denoted trial 1) and the other grafts were dried in an oven at
60.degree. C. from about 30 minutes to about 1 hour (denoted trial
2). Water porosity testing was performed on each graft as described
in Example 1 above. The results of the porosity testing for the
purified agar/guar gum sealant composition is presented hereinbelow
as Table 6. TABLE-US-00006 TABLE 6 AGAR/GUAR GUM TRIAL 1 GRAFT
GRAFT GRAFT DIAMETER LENGTH WATER POROSITY** SAMPLE (cm) (cm) (ml)
(ml/min/cm.sup.2) Uncoated Knitted 0.8 25 3510 56.5 Uncoated Woven
0.8 25 3550 56.50 Woven 1 0.8 24 3 0.049 Woven 2 0.8 24 3 0.049
Knitted 1 0.8 20 35 0.696 Knitted 2 0.8 19 165 3.45 **Porosity
measured in accordance with the Wesolowski test described
herein.
[0067] In another experiment, the purified agar/guar gum mixture
was tested again as described above but using a different batch of
knitted and double velour grafts. As indicated in Table 7 herein
below, the results between the two experiments are comparable.
TABLE-US-00007 TABLE 7 AGAR/GUAR GUM TRIAL 2 GRAFT GRAFT GRAFT
DIAMETER LENGTH WATER POROSITY** SAMPLE (cm) (cm) (ml)
(ml/min/cm.sup.2) Uncoated Knitted 0.8 25 3510 56.5 Uncoated 0.8 25
3550 56.5 Woven Woven #1 0.8 20 1 0.019 Woven #2 0.8 20 2 0.039
Knitted #1 1.0 16.5 11 0.212 Knitted #2 1.0 16.5 54 1.04 **Porosity
measured in accordance with the Wesolowski test described
herein.
[0068] As the results from tables 6 and 7 indicate, grafts dried at
room temperature were less porous than grafts dried at 60.degree.
C. It is thought that as heat removes water from the graft it
interferes with the gelling process and leads to the observed
higher porosity results. In addition, the grafts dried at room
temperature were more flexible than the graft dried at 60.degree.
C. The results indicate that the purified agar/guar gum sealants
are comparable to the carrageenan types II and IV/locust bean gum
sealant mixtures. In fact, the data from Tables 6 and 7 suggest
that the agar/guar gum sealant mixture, when dried at room
temperature, is well suited for rendering blood-tight both woven
and knitted grafts.
EXAMPLE 5
[0069] In this example, data is provided from various porosity
experiments conducted as described in Example 1. In this
experiment, the porosity of knitted and woven grafts were assessed
by changing various parameters including the polysaccharides used,
the concentration and ratio of the various polysaccharides, the
concentration of glycerol, as well as, the temperature of the
sealant and of the drying process. These data are summarized in
Table 8 herein below. TABLE-US-00008 TABLE 8 No. Of Drying Porosity
Glycerol Graft Injec- Tem- Value (ml/ Sealant Components Content
Type Coating Method tions perature min/cm.sup.2) Comments 1.0
Alginate/ None Knitted Vacuum -- 23.degree. C. Not tested Coating
Uneven, Brittle 100 ml water 12 mm Room Temp Sealant (Graft dipped
in 1% CaCl Solution after coating) 4.5 Alginate/300 ml 6 g Knitted
Injection 4 23.degree. C. 29.7 Coating Uneven, Gelation not
controlled water 8 mm Room Temp Sealant (Graft dipped in 1% CaCl
Solution after coating) 1.0 g Carrageenan Type None Knitted Vacuum
-- 23.degree. C. 47.4 Coating Uneven, Stiff, Brittle I/200 ml water
12 mm Room Temp Sealant 1.0 g Locust Bean 16.8 g Knitted Vacuum --
23.degree. C. 48.8 Graft flexible, not coated in crimps Gum/200 ml
water 16.8 g = 12 mm Room Temp Sealant 33.6 g Total 4.5 g
Carrageenan Type 4.5 g Knitted Vacuum -- 23.degree. C. 47.7 Coating
on graft broke under pressure of I/300 ml water 3.0 g = 12 mm Room
Temp Sealant porometer 3.0 g Locust Bean 7.5 g Total Knitted Vacuum
-- 23.degree. C. 47.7 Coating on graft broke under pressure of
Gum/300 ml water 12 mm 50.degree. C. Sealant porometer 5.0
Carrageenan Type I/ 40 g Knitted Injection 4 23.degree. C. 47.1
Grafts were very oily 300 ml water 40 g = 12 mm Room Temp Sealant
4.0 g Locust Bean 80 Total Gum/300 ml water 4.0 g Carrageenan Type
30 g Woven Injection 6 23.degree. C. 3.68 -- I/300 ml water 30 g =
8 mm Room Temp Sealant 3.0 g Locust Bean Gum 60 g Total Woven
Injection 6 60.degree. C. 13.8 -- 8 mm Room Temp Sealant Knitted
Injection 6 23.degree. C. 52.10 -- 8 mm Room Temp Sealant Knitted
Injection 6 60.degree. C. 60.60 -- 8 mm Room Temp Sealant 4.0 g
Carrageenan Type 20 g Woven Injection 3 23.degree. C. 37.3 --
II/300 ml water 20 g = 8 mm Room Temp Sealant 3.0 g. Locust Bean 40
g Total Woven Injection 4 23.degree. C. 32.2 -- Gum/300 ml. water 8
mm Room Temp Sealant 30 g Woven Injection 6 23.degree. C. 0.068
First woven graft to give porosity value 30 g = 8 mm Room Temp
Sealant less than 1.0. 60 g Total Woven Injection 6 23.degree. C.
0.064 -- 8 mm of 60.degree. C. Sealant Woven Injection 6 60.degree.
C. 0.102 -- 8 mm Room Temp Sealant 4.0 g. Carrageenan Type 30 g
Woven Injection 6 23.degree. C. 0.088 -- II/300 ml water 30 g = 8
mm Room Temp. Sealant 3.0 g. Locust Bean 60 g Total Woven Injection
6 23.degree. C. 0.014 -- Gum/300 ml water 8 mm 60.degree. C.
Sealant (Retrials) Woven Injection 6 60.degree. C. 0.118 -- 8 mm
Room Temp Sealant Knitted Injection 6 23.degree. C. 43.1 -- 8 mm
Room Temp Sealant Knitted Injection 6 23.degree. C. 19.9 -- 8 mm
60.degree. Sealant Knitted Injection 6 60.degree. C. 44.0 -- 8 mm
Room Temp Sealant 4.0 g Carrageenan 30 g Woven Injection 6
23.degree. C. 29.5 -- Type II 8 mm Room Temp Sealant Woven
Injection 6 60.degree. C. 4.27 -- 8 mm Room Temp Sealant 8.0 g
Carrageenan Type 30 g Woven Injection 4 23.degree. C. 0.015 Coated
Graft slightly inflexible II/300 ml water 30 g = 8 mm Room Temp
Sealant 60 g Total Woven Injection 5 23.degree. C. 0.015 Coated
Graft slightly inflexible 8 mm Room Temp Sealant Woven Injection 6
23.degree. C. 0.015 Coated Graft slightly inflexible 8 mm Room Temp
Sealant Knitted Injection 6 23.degree. C. 3.86 Coated Graft too
Stiff 8 mm Room Temp Sealant Knitted Injection 6 60.degree. C. 2.62
Coated Graft too Stiff 8 mm Room Temp Sealant 45 g Knitted
Injection 6 23.degree. C. 4.37 Coated Graft Flexible 45 g = 8 mm
Room Temp Sealant 90 g Total Knitted Injection 6 60.degree. C. 1.46
Coated Graft Flexible 8 mm Room Temp Sealant 2.0 g Carrageenan Type
15 g Woven Injection 6 23.degree. C. 0.07 -- IV/150 ml water 15 g =
8 mm Room Temp Sealant 1.5 g. Locust Bean 30 g Total Woven
Injection 6 60.degree. C. 0.07 -- Gum/150 ml water 8 mm Room Temp
Sealant Knitted Injection 6 23.degree. C. 32.6 -- 8 mm Room Temp
Sealant Knitted Injection 6 60.degree. C. 23.70 -- 8 mm Room Temp
Sealant 8.0 g Carrageenan Type 60 g Woven Injection 6 23.degree. C.
Not Tested Grafts felt very oily. Did not completely dry. IV/300 ml
water 60 g = 8 mm Room Temp Sealant Glycerol content too high. 120
g Total Woven Injection 6 60.degree. C. Not Tested Grafts felt very
oily. Did not completely dry. 8 mm Room Temp Sealant Glycerol
content too high. Knitted Injection 6 23.degree. C. 19.9 Grafts
felt very oily. Glycerol 8 mm Room Temp Sealant content too high.
Knitted Injection 6 60.degree. C. 25.8 Grafts felt very oily.
Glycerol 8 mm Room Temp Sealant content too high. 32 g Knitted
Injection 6 23.degree. C. 0.0468 First knitted graft to give
porosity level 46 g = 8 mm Room Temp Sealant less than 1.0 78 g
Total Knitted Injection 6 60.degree. C. 0.248 -- 8 mm Room Temp
Sealant 8.0 g Carrageenan Type 35 g Woven Injection 6 23.degree. C.
0 Graft did not leak any water in porosity test IV/300 ml water 35
g = 8 mm Room Temp Sealant 8.0 g Guar Gum/ 70 g Total Woven
Injection 6 60.degree. C. 0 Graft did not leak any water in
porosity test 300 ml water 8 mm Room Temp Sealant Knitted Injection
6 23.degree. C. 0.942 -- 8 mm Room Temp Sealant Knitted Injection 6
60.degree. C. 0.610 -- 8 mm Room Temp Sealant 3.0 g Purified
Agarose/ 30 g Total Woven Injection 6 23.degree. C. 0.049 -- 300 ml
water 8 mm 60.degree. C. Sealant Woven Injection 6 60.degree. C.
0.049 -- 8 mm 60.degree. C. Sealant Knitted Injection 6 23.degree.
C. 0.0696 -- 8 mm 60.degree. C. Sealant Knitted Injection 6
60.degree. C. 3.45 -- 8 mm 60.degree. C. Sealant Woven Injection 6
23.degree. C. 0.019 -- 8 mm 60.degree. C. Sealant Woven Injection 6
60.degree. C. 0.039 -- 8 mm 60.degree. C. Sealant Knitted Injection
6 23.degree. C. 0.212 -- 8 mm 60.degree. C. Sealant Knitted
Injection 6 60.degree. C. 1.04 -- 8 mm 60.degree. C. Sealant 5.0 g
Chitosan/300 ml 30 g Woven Injection 6 23.degree. C. 0 -- 0.1 M
Acetic Acid 30 g 7 mm Room Temp Sealant 7.0 g Guar Gum/300 ml Woven
Injection 6 60.degree. C. 0.021 -- water 7 mm Room Temp Sealant
Knitted Injection 6 23.degree. C. 0.162 -- 7 mm Room Temp Sealant
Knitted Injection 6 60.degree. C. 0.032 -- 7 mm Room Temp Sealant
Uncoated Graft Porosity Values: Woven 8 mm 56.5 ml/min/cm.sup.2
Knitted 8 mm 56.5 ml/min/cm.sup.2
[0070] These data indicate that sealant mixtures of carrageenan
type IV/guar gum, carrageenan type IV/locust bean gum, agarose/guar
gum and chitosan/guar gum sealant combinations are universally able
to provide substantially blood-tight barriers to both woven and
vascular grafts.
[0071] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *