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Description  |
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FIELD OF THE INVENTION
The present invention relates to a vessel prosthesis which is in itself
porous, but is sealed by impregnating with crosslinked gelatin and to a
process for the production thereof.
BACKGROUND OF THE INVENTION
Vessel prosthesis for replacing hollow organs in humans and animals and in
particular blood vessels have long been known. They are generally made
from textile material and in particular a knitted fabric (DE-A2-26 13 575
corresponding to U.S. Pat. No. 4,047,252, DE-A2-20 09 349 corresponding to
U.S. Pat. No. 3,945,052 and DE-A1-24 61 370 corresponding to U.S. Pat. No.
3,878,565). However they can also be made from non-textile materials
(EP-A1-0 106 496 and BG-A1-15 06 432). In general, the vessel prosthesis
are porous, so as to permit a growing in of the tissue for obtaining
conditions which are as natural as possible. However, since after the
implantation of the prosthesis, these pores frequently lead to undesirably
high body fluid loseses, it is desirable to seal said pores with a
material resorbable by the body and which is successively replaced by the
growing in tissue.
It is known from DE-A2-14 94 939 to use procollagen as the impregnating
agent, which is applied to the porous prosthesis in acid solution and then
rendered insoluble by increasing the pH-value.
The use of collagen for sealing is known from DE-A2-14 91 218, U.S. Pat.
No. 4,167,,045, DE-A1-34 03 127 and De-A1-35 03 126. The crosslinking of
collagen normally takes place with aldehydes, particularly formaldehyde.
It is also known to impregnate porous vessel prostheses with soluble
gelatin and to crosslink the same (DE-A2-14 94 939), crosslinking taking
place with the aid of thiol group-containing compounds with subsequent
oxidative crosslinking, accompanied by the formation of disulphide
bridges.
High demands are made on the characteristics of the impregnating coating,
which must adhere well to the prosthesis body, provide a good sealing
thereof, be ealstic and in particular not release any harmful products
during resorption. The known impregnated prostheses only partly fulfil
these requirements. In addition, they are far from easy to produce, or
expensive starting materials are required, which is prejudicial to
industrial manufacture.
OBJECT OF THE INVENTION
The object of the present invention is therefore to provide an impregnated
vessel prosthesis, which is easier to manufacture, has good mechanical
characteristcs and is completely tight, is not harmful for the receiver
organism and can be easily handled, particularly during implantation.
DESCRIPTION OF THE INVENTION
This problem is solved by a vessel prosthesis which is porous as such, but
is sealed by impregnating it with crosslinked gelatin and wherein the
gelatin is crosslinked with a diisocyanate.
Isocyanates react with the reactive nucleophilic groups of gelatin,
particularly the amino groups and also the hydroxyl groups, accompanied by
the formation of stable bonds and crosslinking products. Crosslinking with
diisocyanates is irreversible in contrast to crosslinking with aldehydes,
in which there is a state of equilibrium, so that aldehydes re-form and
are released again. At the end of the reaction there are no longer any
isocyanate residues and they are also not reformed from the crosslinking
product. A gelatin crosslinked with diisocyanate forms a tight
impregnation with good mechanical characteristics, so that in relation to
the porosity of the vessel prosthesis little gelatin and crosslinking
agent is required, but nevertheless a complete seal is obtained.
The crosslinking of biological material with diisocyanates is known per se.
Thus, DE-A2-27 34 503 describes a process for producing a collagen sponge,
in which a paste or slurry of partly decomposed collagen is mixed with
diisocyanate, shock-frozen to temperatures of -10.degree. to -30.degree.
C., left at temperatures below 0.degree. C., washed, subsequently treated
and then dried. This gives a soft, porous foam or sponge. In a process
known from DE-A2-30 20 611 Achilles' tendons are macerated and reduced to
fibers, after which the fibers are crosslinked using hexamethylene
diisocyanate emulsified in an aqueous saline solution and then inter alia
knittable yarns are produced from the crosslinked fibers. However, these
processes are in no way linked with the problem of the invention.
The vessel prosthesis which is porous as such can have a porosity of
approximately 2000 cm.sup.3 /min/cm.sup.2. As a result of the inventive
impregnating coating of gelatin mixed with diisocyanate, it is possible to
completely eliminate this porosity. The decomposition of the thus
crosslinked gelatin in the body is slowed down to coincide with the rate
at which the new tissue grows into the porous body of the vessel
prosthesis and ensures natural sealing.
The porous body of the vessel prosthesis can have the conventional
structure of a textile vessel prosthesis, e.g. a smooth warp knitted
fabric according to German Pat. No. 20 09 349, the structure of a onesided
velour prosthesis according to U.S. Pat. No. 38 78 565 or that of a double
velour prosthesis according to German Pat. No. 26 13 575. However, the
prosthesis can also be a porous, non-textile prosthesis, e.g. of stretched
polytetrafluoroethylene, as described in British Pat. No. 15 06 432. The
prosthesis structures bounding the pores are coated with a thin
crosslinked gelatin film for sealing purposes, the pores being closed by
thin gelatin membranes. As a result of the film-like coating of the
individual structural elements of the vessel prosthesis and the joining
thereof by membranes, a seal is obtained which differs from a coating
completely filling or covering the porosity. For example, in the case of
textile prostheses, individual fibers or fiber bundles or strands are
coated with a film of crosslinked gelatin and through the membranes are
interconnected over and beyond the cavities between the fibers or strands
and namely in different planes within the vessel prosthesis wall. As a
result of this fine structure the vessel prosthesis handling is improved
rather than impaired by the impregnation.
The good sealing of the vessel prosthesis when using only a little
impregnating material is also made possible in that gelatin is a material
present in the form of a homogeneous solution, as opposed to collagen
which is a heterogeneous fibrous material and is not therefore completely
tight in thin layer form. The weight rati of porous prosthesis body to
impregnating coating can be in the range 1:02. to 1:3, particularly
approximately 1:1, including the further additives optionally present in
the impregnating coating such as plasticizers. Hydrophilic plasticizers,
particularly glycerol and other known polyols are used with advantage, to
prevent a complete drying out of the impregnating coating and to improve
the elasticity thereof. The moisture content of the impregnating coating
in the dried state is preferably in the range 15 to 25% by weight,
especially 17 to 22% by weight, based on the weight of the crosslinked
impregnating coating.
The preferred crosslinking agent is hexamethylene diisocyanate. However, it
is also possible to use other diisocyanates, particularly aliphatic
diisocyanates with 4 to 12 carbon atoms and preferably 6 to 10 C-atoms. As
opposed to formaldehyde, it has been found that a greater chain length
crosslinking agent is more favorable for the elasticity of the product due
to the so-called spacer function of the bridges between the protein
chains.
The impregnating coating of the vessel prosthesis according to the
invention can in known manner contain therapuetically active materials or
other active substances. In a particularly preferred embodiment, these
materials or active substances are not merely mixed into the impregnating
coating and are instead bonded or enclosed in the support or carrier, so
that they are only released after time delay. To this end, the
impregnating coating and in particular the gelatin can contain
constituents which absorb or adsorb the active substances and only
gradually release the same. Particularly suitable constituents of this
type are exchangers, particularly ion exchangers. In a particularly
preferred embodiment of the invention at least part of the gelatin
comprises succinylated gelatin, which has such properties. As a result of
their basic functions aminoglycosides, such as gentamycin, can be well
held by such modified gelatins. As modified gelatin gelatinizes or gels
less well than normal gelatin, the modified gelatin proportion is normally
dependent on the gelability of the mixture and can be in the range 10 to
50% by weight with respect to the total gelatin quantity. Readily gelable
gelatins, such as edible gelatin is preferred (Bloom value 110 to 300,
preferably 240 to 280). When crosslinking with diisocyanate the modified
gelatin having the exchanger functions is also crosslinked in, so that the
therapeutically active material or the active substance adheres to the
actual gelatin structure.
The inventive process for producing the impregnated vessel prosthesis is
characterized in that a porous vessel prosthesis is impregnated with an
aqueous gelatin solution, the gelatin is allowed to gel and then carefully
dehydrated, particularly dried in air and then the preimpregnate obtained
is crosslinked with diisocyanate.
Diisocyanates react not only with gelatin, but also with compounds having
other polar groups, such as e.g. with water and alcohols, accompanied by
the formation of undesired by-products, such as insoluble urethane and
urea derivatives. Although, as a result of its tightness, the impregnating
coating does not allow a washing out of any by-products formed in the
coating, as is the case with the known porous fibrous products crosslinked
with diisocyanate, it has been found that the tendency of diisocyanates,
to form by-products does not have a harmful effect.
For impregnating the porous vessel prosthesis with the gelatin solution,
the vessel prosthesis is preferably immersed in the solution. As a result
of the application of a vacuum, the pores can be completely filled with
the gelatin solution. The gelatin concentration in the solution can vary
within wide limits and is preferably between 3 and 20, particularly betwen
5 and 15% by weight of the impregnating solution. However, it is important
that there is a homogeneous solution. Impregnation takes place at elevated
temperature, i.e. over 40.degree. C., in order to bring about gelling by
cooling. As in aqueous solution at temperatures over 60.degree. C.,
gelatin decomposes when left standing for a long time, the temperatures
should not be significantly above this. Therefore temperature ranges
between 45 and 70.degree. C., especially 55.degree. and 60.degree. C. are
preferred. The impregnating solution can also contain the plasticizer in
quantities up to 60% by weight, particularly 10 to 40% by weight. The
water content is normally 30 to 97% by weight, preferably 50 to 80% by
weight. As a function of the gelability of the gelatin or gelatin mixture,
the quantity ratios are so matched with one another that the gelatin is
dissolved at the impregnating temperature and the impregnating solution is
able to flow, but while ensuring that the gelatin gels on cooling to
approximately 20.degree. to 30.degree. C. During cooling the prostheses
impregnated with the gelatin solution are preferably moved in order to
obtain a uniform coating thickness of the gelled gelatin. For this
purpose, the prostheses can be rotated about their longitudinal axis or
subject to a tumbling movement after removal from the impregnating bath
and after briefly being left to drip.
It is important that the dehydration or dewatering of the gelled gelatin
coating or the drying thereof is performed in a careful manner, in order
to obtain a good uniformly structured impregnating coating. Air drying at
25 to 35, particularly approximately 30.degree. C. is suitable. The
relative humidity of the drying air is preferably between 30 and 50%,
particularly approximately 405. Particularly if the prosthesis are
immersed in the gelatin solution accompanied by the application of a
vacuum, a single impregnation or treatment is sufficient for obtaining a
complete tightness, accompanied by the advantage of the resulting low
material quantity and favorable mechanical characteristics.
Working takes palce with a diisocyanate excess for crosslinking the
gelatin, firstly to obtain a complete gelatin crosslinking and to make it
insoluble and secondly in view of the expected secondary reactions.
Working preferably takes place without influencing the pH-value. The
gelatin can be left at a normal pH-value, which is usually approximately
5.5. The crosslinking reaction can be performed in a pH range of 3.5 to
7.5. Acceptable reaction times of approximately 5 to 10 hours are
attainable during crosslinking at ambient temperature, without secondary
reactions having a disadvantageous effect and without special measures
having to be taken.
It is particularly advantageous for performing the crosslinking reaction to
use solutions of diisocyanate in polar organic solvents, which readily wet
the predried gelatin impregnating coating. Preference is given to solvents
which are miscible with water and plasticizer; isopropanol being
particularly suitable. Preferably the solvent makes up 30 to 95% by weight
of the crosslinking solution. The diisocyanate diffuses from the
crosslinking solution into the gelatin coating and reacts, accompanied by
crosslinking, with the gelatin. The diffusion of diisocyanate into the
gelatin coating preferably takes place both from the outside and from the
inside. For this purpose, the prostheses can advantageously be immersed in
the crosslinking solution. Although working takes placed with a
considerable diisocyanate excess, which is preferably more than 10 times
the stoichiometric quantity needed for crosslinking, the diisocyanate
concentration in the crosslinking solution is preferably under 3% by
weight, in order to suppress secondary reactions to the greatest possible
extent, because diisocyanate is also able to react with components of the
crosslinking solution. The diisocyanate concentration can be between 0.03
and 3% by weight, preferably between 0.05 and 0.5% by weight, preference
being given to roughly 0.1% by weight. The crosslinking solution
preferably also contains plasticizers and/or water in order to introduce
the plasticizer and water into the gelatin coating or prevent a washing
out of water and/or plasticizer from the gelatin coating during the
crosslinking reaction. The concentration of plasticizer, particularly
glycerol can be 0 to 60% by weight and in particular 10 to 20% by weight.
In extreme cases the water content can be up to 70% by weight, but is
normally much lower, namely between 3 and 30% by weight and particularly
between 5 and 10% by weight. It is important for the preferred embodiment
that the water content is so low that the diisocyanate is present in the
dissolved state in the crosslinking solution. Through a relative movement
between the crosslinking solution and vessel prosthesis it is possible to
ensure that the diisocyanate concentration on the prosthesis surface is
kept as high as possible. In a preferred embodiment the crosslinking
solution is constantly circulated or pumped around and is simultaneously
filtered. Insoluble by-products are continuously removed, so that deposits
on the vessel prosthesis and therefore contamination are avoided. The low
diisocyanate concentration permits a safe handling of the crosslinking
solution. The diisocyanate concentration constantly decreases during the
crosslinking reaction, so that safe disposal is possible at the end of the
reaction. However, process variants are possible in which working takes
place with a substantially constatn diisocyanate concentration.
In a particularly preferred embodiment of the invention the moisture
content and preferably also the plasticizer content of the dehydrated,
still uncrosslinked, but predried gelatin impregnating coating, together
with the water content and preferably also the plasticizer content of the
crosslinking solution are adjusted in such a way that they are
substantially in equilibrium with one another on immersing the predried
impregnated vessel prosthesis in the crosslinking solution. This makes it
possible to avoid undesired concentration changes, which could e.g. lead
to the leaching or swelling of the not yet crosslinked gelatin
impregnating coating.
At the end of crosslinking the gelatin impregnating coating is waterproof,
so that it can be washed with water, to which optionally a plasticizer is
added and then carefully dried. Sterilization takes place preferably by
per se known radiation.
SPECIFIC EXAMPLES
Further features and details of the invention can be gathered from the
following description of preferred embodiments. The individual features
can be realized alone or in the form of combinations.
EXAMPLE 1
Knitted double microvelour vessel prostheses of polyethylene terephthalate
fibers provided with a pleat are fixed in a frame and immersed in an
aqueous gelatin impregnating solution containing 7.5% by weight of gelatin
and 15% by weight of glycerol as the plasticizer in demineralized water
and at a temperature of 60.degree. C.
A vacuum is now applied to the gelatin solution to completely remove the
air enclosed in the textile prostheses. Following the rising of the air
bubbles, the prostheses are left for approximately 15 minutes in the
solution under reduced pressure and the latter is then raised to normal
pressure again. The prostheses are then removed from the impregnating
solution and are briefly allowed to drip. They are then cooled to normal
temperature, accompanied by a slight tumbling movement. Following the
gelling of the coating material, the coated prostheses are placed in a
climatic chamber and dried in air therein having a relative atmospheric
humidity of 40% at 30.degree. C. until the residual moisture content in
the impregnating solution is approximately 20%.
The predried prostheses are them immersed in a crosslinking solution
containing 0.1% by weight of hexamethylene diisocyanate, 15% by weight of
glycerol, 8.5% by weight of water and 76.4% by weight of isopropanol. The
coated prostheses are left for 8 hours at ambient temperature in this
solution, while the latter is simultaneously constantly pumped around and
filtered. At the end of crosslinking the prostheses are removed from the
crosslinking solution and washed in water with a 15% glycerol solution,
followed by careful drying again at 30.degree. C. and 40% relative
atmospheric humidity until there is a residual moisture content of 15 to
20%, based on the impregnating coating. The prostheses are then cut to the
nominal length, individually packed and sterilized by radiation.
The prostheses impregnated in this way are completely tight. The
impregnating coating is located in the textile fibrous structure and can
hardly be seen with the naked eye. The prosthesis has a bright white
appearance, is flexible and can be compressed and stretched in the axial
direction. Following implantation of the prosthesis, the crosslinked
coating material is resorbed at the rate of which the natural tissue
subsequently grows, without the decomposition products revealing any
harmful effects. The impregnating coating is also both immunologically and
toxicologically unobjectionable.
EXAMPLE 2
The procedure of example 1 is repeated, but the edible gelatin is replaced
by a mixture of 70% by weight of edible gelatin and 30% by weight of
succinylated gelatin. The crosslinked impregnating coating obtained in
this way contains additional acid radicals making the impregnating coating
suitable for storage, e.g. by diffusion and binding of therapeutic acitve
substances with basic characteristics. These therapeutic active substances
are only very slowly released following the implantation of the
prosthesis, so that e.g. infection protection is provided over a long
period.
EXAMPLE 3
Knitted vessel prosthesis of the double velour type formed from
polyethylene terephthalate fibres and having a pleat, are secured in a
frame as in example 1 and then impregnated with gelatin in an immersion
process. The aqueous impregnating solution contains 10% by weight of
gelatin and 20% by weight of glycerol, whilst having a temperature of
60.degree. C. As ain example 1, the textile prosthese are thoroughly
vented under reduced pressure. Following removal, they are briefly allowed
to drip and the frame is tumbled slightly during the gelling phase of the
impregnating solution. Following the separating of the coating mass, the
impregnated prostheses are transferred into a climatic chamber and, as in
exmaple 1, subject to careful intermediate drying until the residual
moisture content of the impregnating coating is approximatley 25%. The
predried prostheses are then introduced in the clamped state into a
crosslinking bath containing 0.2% by weight of hexamethylene diisocyanate,
50% by weight of glycerol, 43.3% by weight of isopropanol and 6.5% by
weight of water. As in example 1, the coated prostheses are left in the
crosslinking solution for 8 hours at ambient temperature. The subsequent
rinsing stage takes place in such a way that the clampled prostheses are
exposed for approximately 5 minutes to a 30% aqueous glycerol solution at
ambient temperature and in the circulating process. After drying the
impregnating coating of the thus produced prostheses has a residual
moisture content of approximately 22%.
The coated prosthesis according to example 1 contains
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9.5% by weight of water
22% by weight of glyceroI
18% by weight of crosslinked gelatin
i.e. 49.5% by weight impregnating coating and
50.5% by weight porous basic body.
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The prosthesis according to example 3 contains
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13% by weight of water
32% by weight of glycerol
16% by weight of crosslinked gelatin
i.e. 61% by weight impregnating coating and
39% by weight knitted porous prosthesis.
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Based on the total weight of the impregnating coating, the latter generally
contains
10 to 30% by weight water
10 to 60% by weight plasticizer and
20 to 60% by weight crosslinked gelatin.
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