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Description  |
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a synthetic vascular prosthesis having an
antithrombogenic hydrogel layer on the inner surface of the prosthesis and
also to a method for manufacturing such a prosthesis.
2. Description of the Prior Art
Synthetic vascular prostheses that are currently in practical use are all
of the neointima formation type, so that after implantation into a living
body, thrombi are immediately formed on the inner surface of the
prosthesis. When the thrombi are developed to cover the inner walls of the
synthetic vascular prostheses in a certain thickness, further thrombus is
not formed, thus ensuring the flow of blood. Subsequently, the neointima
grow whereby the synthetic vascular prosthesis acquires the
antithrombogenic property, thus performing the function of a blood vessel.
The synthetic vascular prosthesis of this type, however, has a
disadvantage that it is not applicable to a small prosthesis having an
inner diameter of about less than 4 mm. This is because the prosthesis is
plugged by the thrombi prior to the formation of the neointimae, thus
preventing an effective patency of the prosthesis.
On the other hand , research and development have recently been made on a
synthetic vascular prosthesis of the type which has an antithrombogenic
property by itself and thus does not need the formation of the neointima.
These synthetic vascular prostheses are generally divided into two kinds.
In one kind, a living body-derived anticoagulant such as heparin,
urokinase or the like is impregnated in, or is fixed through covalent
bonds or ionic bonds to, a synthetic vascular prosthesis substrate so as
to impart the antithrombogenic property thereto. In the other kind, a
hydrogel layer is formed on the inner surface of a synthetic vascular
prosthesis so as to prevent direct contact between a substrate of the
prosthesis and proteinous and cellular components in the blood, thereby
acquiring the antithrombogenic property. The prosthesis of this kind is
disclosed in, for example, Japanese Patent Publication No. 60-242857.
In the former instance, however, the impregnated anticoagulant will flow
away and be lost, or if fixed, the anticoagulant will gradually lose its
activity and efficacy. Therefore, an everlasting antithrombogenic property
cannot be obtained.
The latter kind where the hydrogel layer is formed on the inner surface of
the synthetic vascular prosthesis, is believed to be more suitable since
the antithrombogenic property can be maintained substantially permanently.
Further, the synthetic vascular prosthesis of this kind is applicable to a
small-diametered portion of the blood vessel as the neointimae need not be
formed.
It is known that a hydrogel layer has a good antithrombogenic property and
is formed by graft polymerization on the inner surface of a tubular base
member which is made of elastomer, typically polyurethane. The base member
should be porous in order to render the prosthesis flexible and to
facilitate a joining operation of the synthetic vascular prosthesis to a
natural vessel by suture. The porous base member, however, permits the
hydrogel to impregnate therethrough, which is not desirable because it
promotes calcification throughout the base member and reduces the
flexibility of the prosthesis. It has thus been proposed to provide a
thin, non-porous, dense layer between the inner surface of the base member
and the hydrogel layer, so that the hydrogel may be prevented from
infiltrating into the base member. However, fabrication of the hydrogel
layer on such a dense layer requires complicated operations such as plasma
treatment of the inner surface of the dense layer under vacuum to generate
radicals, graft polymerization of a hydrophilic monomer (acrylamide or the
like) on the inner surface, and removal of the resultant homopolymer not
grafted. In addition, expensive apparatuses such as a vacuum pump, a high
frequency generator and the like are necessary for the plasma treatment.
Furthermore, the provision of a dense layer increases the stiffness of the
prosthesis and reduces the compliance. The compliance, of which
measurement will be described later, is a value which indicates a
variation in inner capacity of the prosthesis when an internal pressure is
exerted thereon. A larger value results in a larger variation in the inner
capacity when the internal pressure is constant. Generally, the compliance
of the synthetic vascular prosthesis is small compared with that of a
natural blood vessel. The difference in compliance between the synthetic
vascular prosthesis and the natural vessel, tends to develop an aneurysm
at the joint or in osculated portion or to break the prosthesis thereat.
Accordingly, an object of the present invention is to provide a synthetic
vascular prosthesis which has a satisfactory strength and compliance as
well as a good antithrombogenic property.
Another object of the invention is to provide a method for manufacturing a
synthetic vascular prosthesis of the type set forth above by relatively
simple operation.
SUMMARY OF THE INVENTION
According to the invention, there is provided a synthetic vascular
prosthesis which comprises a hollow tubular base member having a multitude
of continuous cells or pores and formed of an elastomer material, and a
hydrogel layer formed on the inner surface of the base member. The outer
portion of the hydrogel layer is partially embedded in the inner portion
of the base member at the pores to thereby achieve anchoring adhesion
between the hydrogel layer and the base member.
This synthetic vascular prosthesis can be fabricated according to the
method of the invention which includes the steps of dissolving an
elastomer material in a solvent, adding an inorganic salt to the solution
and adjusting the viscosity of the solution, subjecting the solution to
extrusion into a hollow tube, and cutting the tube to a predetermined
length to form a tubular base member. After the solvent is removed from
the base member which is in turn solidified, the inorganic salt in the
inner portion of the base member is removed by dissolution with an acid to
form a porous inner portion. A hydrogel material is subsequently coated on
the inner surface of the base member so as to form a hydrogel layer on the
base member, with the hydrogel material partially infiltrating into the
pores of the porous inner portion. Thereafter, the inorganic salt in the
outer portion of the base member is removed by dissolution with an acid,
thereby forming a porous outer portion having continuous pores.
Other objects, features and advantages of the invention will be apparent
from the following detailed description thereof when taken in conjunction
with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view for use in explanation of a step for forming a
porous inner portion of a tubular base member according to the invention;
FIG. 2 is a schematic illustrative view showing how to measure compliance;
and
FIG. 3 is a schematic view showing one example of a synthetic vascular
prosthesis according to the invention.
DETAILED DESCRIPTION OF THE INVENTION
As described above, the synthetic vascular prosthesis of the invention
includes a hollow tubular base member having a multitude of continuous
pores and made of an elastomer, and a hydrogel layer formed on the inner
surface of the tubular base member. The outer portion of the hydrogel
layer is partially embedded in the inner portion of the base member at the
pores thereof, thereby achieving an anchoring adhesion between the
hydrogel layer and the base member.
The elastomers used above include, for example, polyurethanes, polyurethane
ureas, their blends with silicone polymers, silicone polymers and other
elastic polymers. In view of the durability in a living body, the
polyurethanes or polyurethane ureas are preferably of the polyether type
and are more preferably polyether-segmented polyurethanes or
polyether-segmented polyurethane ureas.
The hydrogel layer is preferably made of polyvinyl alcohol having a degree
of polymerization of from 500 to 10,000 and degree of saponification of
not less than 80%, or ethylene-vinyl alcohol copolymers having a high
content of vinyl alcohol. This is because these polymers are not dissolved
in cold water and are likely to form a hydrogel, and they have a good
antithrombogenic property and good durability.
When the hydrogel layer is partially embedded in the base member, the
thickness of the embedded portion may be determined depending upon
physical properties and porosity of the elastomer material from which the
base member is made.
In accordance with the method of the invention, the synthetic vascular
prosthesis is fabricated by the steps which comprise dissolving an
elastomer material in solvent, adding an inorganic salt to the resultant
solution and appropriately adjusting the viscosity of the solution to a
desired level, extruding the solution into a hollow tube, and cutting the
tube to a predetermined length to obtain a tubular base member.
Thereafter, the solvent in the base member is removed and the base member
is dried for solidification, and then the inorganic salt only in the inner
portion of the base member is removed by dissolution with an acid to form
an inner porous portion. A hydrogel layer is subsequently formed by
coating a hydrogel material on the inner surface of the base member so
that the hydrogel material is partly infiltrated into the pores in the
inner porous portion. Finally, the remaining, outer portion of the base
member is subjected to dissolution of the inorganic salt to form an outer
porous portion having continuous pores.
The elastomer material used in this method may be selected from those
mentioned before. The solvents particularly for the polyether-segmented
polyurethanes or polyether-segmented polyurethane ureas include, for
example, tetrahydrofuran, dimethylformamide, and the like.
The inorganic salts added to the solution of the elastomer material may be
any salts which are capable of dissolving out with an acid such as
hydrochloric acid, sulfuric acid, acetic acid and the like. Examples of
the salts are calcium carbonate, magnesium oxide and magnesium hydroxide,
and these salts may be used alone or in combination. In view of the
formation of the continuous pores, the amount of the salts is preferably
not less than 500 parts by weight per 100 parts by weight of the
elastomer.
The extruder used for the extrusion process is favorably a screw extruder
or a ram extruder having a circular die corresponding to the shape of the
final product. Viscosity of the solution is so controlled as to adapt for
the extrusion molding with these extruders by means of, for example,
evaporation of the solvent.
The present invention is more particularly described below by way of
example, in which a method of fabricating a synthetic vascular prosthesis
is first described and then, the prosthesis per se is described.
EXAMPLE
100 parts by weight of polyether-segmented polyurethane were dissolved in
600 parts by weight of tetrahydrofuran to obtain a viscous polymer
solution. 450 parts by weight of calcium carbonate having an average
particle size of 1.7 micrometers and 90 parts by weight of magnesium oxide
having an average particle size of 2 micrometers were added to the
solution and kneaded, during which a part of the tetrahydrofuran was
allowed to escape by vaporization. As a result, there was obtained a paste
which had a viscosity of about 1.25 g/10 minutes when measured at room
temperature by means of a melt indexer using a cylinder diameter of 9.55
mm, an orifice diameter of 2.096 mm and a load of 2160 g. The paste was
supplied to a screw extruder and extruded from a circular die having an
inner diameter of 3 mm and an outer diameter of 4 mm. While withdrawing
with a takeup machine, the extruded product was cut into a length of about
50 to 60 cm to obtain a tubular base member A. The tubular base member was
immersed in a water tank to remove the solvent for solidification,
followed by sufficient drying.
In FIG. 1, there is shown a step of forming an inner porous portion B (FIG.
3) in the inner surface of the base member A. In this step, after the base
member A was cut at opposite ends, 3N hydrochloric acid was supplied from
a container 1 by means of a pump 2 and passed through the base member A
for about 1 minute. As a result, the calcium carbonate and magnesium oxide
which were present in the inner portion of the base member A, were removed
by dissolution in the acid to form an about 20 micrometer thick inner
porous portion B. Then, after the base member A was washed with water and
dried, it was held upright with one end thereof being immersed in an
aqueous solution of 5% polyvinyl alcohol having a degree of polymerization
of 1700 and a degree of saponification of not less than 99%. The aqueous
solution was then passed through the base member A by applying a suction
force to the upper end thereof, and this sucking operation was repeated
three times. The base member A was again dried, resulting in forming a
hydrogel layer C (FIG. 3) having a total thickness of 25 to 30 micrometers
a part of which, i.e. 15 to 20 micrometers thickness, was embedded in the
inner porous portion B of the base member A.
Thereafter, the tubular base member A was entirely immersed in a sealed
autoclave filled with 3N hydrochloric acid and the calcium carbonate and
magnesium oxide present in the outside of the inner porous portion B were
dissolved out under reduced pressure, thereby forming an outer porous
portion D (FIG. 3) having continuous pores. After repetition of rinsing
with dilute hydrochloric acid and washing with water, the base member was
dried by a vacuum-freeze drying method at a reduced pressure of less than
2 mmHg for 12 hours in order to keep the porous condition.
The synthetic vascular prosthesis having the hydrogel layer C obtained in
this example had a section as shown in FIG. 3, with an inner diameter of
about 3.00 mm and an outer diameter of 3.7 mm. The prosthesis had at the
inside thereof the hydrogel layer C, which was composed of a smooth
sub-layer with a thickness of about 10 micrometers on the base member A
and an embedded sub-layer in the inner porous portion B of the base member
A with a thickness of about 15 to 20 micrometers, thus a total thickness
of the layer C being about 25 to 30 micrometers. The remaining portion of
the prosthesis, i.e. the outer porous portion D, had a thickness of about
320 micrometers with an average pore size of 6 to 10 micrometers and
porosity of about 80%.
The thus obtained synthetic vascular prosthesis of the invention felt
somewhat rigid in a dry condition because the hydrogel layer was made of
polyvinyl alcohol. However, when wetted sufficiently, the polyvinyl
alcohol became softened as a hydrogel (hydrous gel), exhibiting a
compliance and flexibility close to those of natural blood vessels.
The compliance and flexibility were measured according to the following
methods.
Measurement of Compliance:
The compliance is measured by a method shown in FIG. 2. A microsyringe
dispenser 4 is used for supplying a predetermined amount of a
physiological saline solution into a synthetic vascular prosthesis 3 every
operation. The variation in inner pressure of the prosthesis 3 is detected
with a pressure sensor 5 and recorded with a recorder 7 through an
amplifier 6. The compliance of the prosthesis can be obtained according to
the following equation (1) using the variation in inner pressure relative
to the amount of the physiological saline solution injected into the
prosthesis:
C=V/Vo - - - - -(1)
in which V is an increment of the inner volume of the prosthesis when the
inner pressure increases from 50 mmHg to 150 mmHg, and Vo is an inner
volume of the prosthesis at an inner pressure of 50 mmHg.
Measurement of Flexibility:
The measurement of the flexibility was effected using the "Olsen" type
flexibility measuring instrument.
When the modulus of elasticity in bending of a prosthesis is taken as E and
the moment of inertia of the prosthesis is taken as I, the value EI can be
obtained by the use of the Olsen type flexibility measuring instrument.
This value was used as a standard for the flexibility.
The physical characteristics of the synthetic vascular prosthesis of the
invention determined by these methods are shown in Table 1, along with a
comparative synthetic vascular protheses which was provided with a
polyether-segmented polyurethane inner layer (a dense layer) having a
thickness of 50 micrometers between a base member and a hydrogel.
TABLE 1
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C (Compliance)
Flexibility (g .multidot. cm.sup.2)
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Comparative 0.056 2.0
Example
Example of the
0.164 1.1
Invention
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As will be apparent from the foregoing, the synthetic vascular prosthesis
according to the invention has a hydrogel layer having a good
antithrombogenic property, which is embedded into pores of the inner
porous portion of the base member, so that an intimate bonding between the
hydrogel layer and the base member is ensured through anchoring adhesion.
Since the hydrogel layer becomes softened in use, the compliance and
flexibility of the prosthesis of the invention are close to those of
natural blood vessels, remarkably reducing a danger of development of an
aneurysm and a breakage of the prosthesis at a sutured portion. Further,
the fact that the hydrogel layer is not embedded into the full thickness
of the base member, prevents calcification and serves to maintain the
flexibility of the prosthesis.
Moreover, the formation of pores in the base member according to the method
of the invention is carried out in two stages, the first stage involving
the formation of pores only in the inner portion of the base member.
Subsequently, a hydrogel-forming material is coated on the inner portion.
Thus, the formation of the pores and the coating can be carried out
relatively simply.
Although the invention has been described with reference to the preferred
embodiments thereof, many modifications and alterations may be made within
the spirit of the invention.
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Description |
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