CA1110402A - Vascular prosthesis having a composite structure and a process for producing same - Google Patents
Vascular prosthesis having a composite structure and a process for producing sameInfo
- Publication number
- CA1110402A CA1110402A CA306,564A CA306564A CA1110402A CA 1110402 A CA1110402 A CA 1110402A CA 306564 A CA306564 A CA 306564A CA 1110402 A CA1110402 A CA 1110402A
- Authority
- CA
- Canada
- Prior art keywords
- tubing
- polyethyleneimine
- water
- vascular prosthesis
- porous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/0005—Use of materials characterised by their function or physical properties
- A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
- A61L33/0029—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using an intermediate layer of polymer
Abstract
ABSTRACT OF THE DISCLOSURE
A vascular prosthesis and a process for preparing the same are disclosed, which vascular prosthesis has a composite structure of a porous tubing of polytetrafluoroethylene with polyethyleneimine in the pores of the tubing, the polyethylene-imine being water-solubilzed with the amino groups quaternized and having heparin ionically bound thereto. According to this invention, a microstructure composed of fibers and nodes which is obtained by stretching a tubing of polytetrafluoroethylene in at least one axial direction and heating the stretched tubing to at least 327°C is used as one starting material. Then, the pores of the microstructure are filled, with a solution of polyethyleneimine and the polyethyleneimine is subjected to a water-insolubilization treatment and a quaternization treatment.
Then, heparin is ionically bound to the polyethyleneimine to form a composite structure. Thus, the invention provides a vascular prosthesis having a high rate of patency which permits a thin neointima to form on the inner surface of the prosthesis after implantation with sufficient nutrition being provided the neointima thereby to retain a neointima without degenerative change and without occulsion of the interior cavity of the prosthesis.
A vascular prosthesis and a process for preparing the same are disclosed, which vascular prosthesis has a composite structure of a porous tubing of polytetrafluoroethylene with polyethyleneimine in the pores of the tubing, the polyethylene-imine being water-solubilzed with the amino groups quaternized and having heparin ionically bound thereto. According to this invention, a microstructure composed of fibers and nodes which is obtained by stretching a tubing of polytetrafluoroethylene in at least one axial direction and heating the stretched tubing to at least 327°C is used as one starting material. Then, the pores of the microstructure are filled, with a solution of polyethyleneimine and the polyethyleneimine is subjected to a water-insolubilization treatment and a quaternization treatment.
Then, heparin is ionically bound to the polyethyleneimine to form a composite structure. Thus, the invention provides a vascular prosthesis having a high rate of patency which permits a thin neointima to form on the inner surface of the prosthesis after implantation with sufficient nutrition being provided the neointima thereby to retain a neointima without degenerative change and without occulsion of the interior cavity of the prosthesis.
Description
1 Field of the Invention This invention relates to an antithrombic vascular prosthesis composed of polytetrafluoroethylene and quaternized polyethyleneimine having heparin bound theret:o.
2. Description of the Prior Art .
Fabric prostheses composed of a knitted or woven fabric of Dacron*orpolytetrafluoroethylene in the form of a tube having inner diameters that are relatively large are now being utilized with relatively good results. In particular, yood results are generally obtained with vascular prostheses for arteries which have an inner diamcker o at leas-t about 7mm. Despite this, Eew small inner-diametcr arterics are clinicalLy acccptable.
~n vcnous applications~ small inncr-cliameter pros~heses exhibi~
a lower patency rate than in arterial applications. The ra-te of blood flow in veins is smaller than in arteries, and to prevent -thrombosis, it is important to inhibit platelet adhesion to the inner surface of the artificial veins. This requirement is not fully met by presently available ar-tificial veins.
Some tubings made of stretched or expanded po~lytetra-Eluoroethylcne have been demonstrated -to be clinicalLy usefuL
as vascular pros-theses for arteries and veins. 'l'his is descr:ibed, for example, in Soyer et al., "A New Venous Prosthesis", Surgery, Vol. 72, page 86~ ~1972), Volder et al., "A-V Shunts Created in New Ways", Trans, Amer, Soc. Artif. Int. Organs, Vol. 19, p. 38 (1973), Matsumoto et al., "A New Vascular Prosthesis for a Small Caliber Artery", Surgery, Vol.7~, p. 519 (1973), "Application of Expanded Polytetrafluoroethylene to Artificial Vessels", Artificial Organs, Vol. 1, p. ~ (1972), ibicl./ Vol. 2, p. 262 (1973), and ibid., Vol. 3, p. 337 (197~), Fujiwara e-t al., "Use of Goretex Grafts for Replacement of the Superior and * Trade mark -1- ~a 1 Inferior Venae Canal", The Journal of ThoraciC and Cardiovascular Surgery, Vol. 67, p. 774 (1974~, and Belgian Patent No. 517,~15.
The results of these clinical experiments are summarized below.
When a suitable porous prosthesis is implanted as a conduit within the arterial system, the fine pores are clogged ~y clotted blood, and the inside of the prosthesis is covered with a clotted blood layer. The clotted blood layer is made up of fibrin, and the thickness of the fibrin varies, for example, according to the material of and the surface s-tructure of the prosthesis. Since the thickness of -the fibrin approaches 0.5 to 1 mm when a knitted or woven fabric of Dacron*
or po:lytetraEluoroethylene :is used as the prosthes:is, success :Ls achiev~d only with those blood vessels which are not occluded due to this increase in wall thickness by the fibrin layer (that is, arteries having an inside diameter of 5 or 6 mm or more). Generally, knitted or woven prostheses having smaller inner diameters have not been successful.
A polytetrafluoroethylene tubing which has been stretched has a microstructure composed of very fine fibers and nodes connected together by the ibers. The diameter of the Eibers vary depending on various stretching conditions, and can be made much smaller than fibers of the knitted and woven fabrics mentioned above.
I-t has been confirmed clinically that when a structure composed of fibers and nodes is expressed in terms of pore sizes and porosities, or fiber lengths and nodular s:izes, a polytetrafluoroethylene tubing having a pore size of from about 2 microns to abou-t 30 microns (pore sizes below about 2 microns are undesirable), a porosity of about 78% -to about 92%, * Trade mark ,. ,, ~ ,. .
2 ~:
1 a fiber length of not more than about 34 microns (fiber len~ths of about 40 microns to about 110 microns are undesirable), a nodular size of not more than about 20 microns,and a wall thickness of about 0.3 mm to about 1 mm exhibits a high patency rate without substantial occlusion by fibrin deposition.
It has been reported, however, that venous prostheses exhibit a much lower patency rate than arterial prostheses, and do not prove to be entirely satisfactory for prosthetic purposes. It has also been reported that when a vascular prosthesis has too high a porosity, a tearing of the prosthesis by the suture used in joining the prosthesis with the vessel of the patient tends to occur.
In the healing process aEter implatation, connective tissue Eirst develops on the outer periphery oE the polytetra~
fluoroethylene tubin~ and the tissue or~anizes, and aEterwards the fibrin layer on the inner surface of the tubing organizes.
At this time, a continuity of the intimas of the host's vessels with the neointima of the inner surface of the vascular prosthesis is established and simultaneously, the fibrin layer ~O is replaced by the fibrous tissue which has entered the pros-thesis through the eine pores from -the periphery of the prosthesis. Furthermore, after a certain period of -time, the neointimas a-t the inner surface are connected firmly to the connective tissue lining the outer wall of the prosthesis, thereby completing the formation of an artery. It is known that this artery formation requires a period of usually about 4 to 6 months. It is known on the other hand that with vascular prosthesis implanted in veins, the rate of entry of the connective tissue from the periphery thereof is slower than for arterial implantation.
.; . .....
l~Q~2 1 However, despite these reported clinical results, reproducible good results have not been obtained.
A porous tubing of polytetrafluor~ethylene permits the adsorption of plasma protein. Pla-telets adhere to the absorbed plasma protein to form fibrin fibers which capture blood corpuscles and become a fibrin deposited layer. This deposited layer is expected to subsequently form a pseudointima of the prosthesis. However, the fibrin deposited layer is frequently too thick, and insufficient nutrition of the pseudointima or neointima occurs. This will result in disconnection by necrosis or in thrombic occlusion of the inner surface of the prosthesis.
SUMMARY OF THE INVENTION
An object o this invention is to prov.ide a vascular prosthesis h~ving a composite structure composed of ~I porous tubing of polytetrafluoroethylene and water-insolubili~ed and quaternized polye-thyleneimine having heparin ionically bound thereto, with the polyethyleneimine being provided in the pores of the porous tubing. Functionally, the surface of the prosthesis is rendered hydrophobic and is simultaneously charged ~O negatively by the polytetrafluoroethylene having a low surface energy whereby antithrombic character is achieved. Polyethylene-imine which is water-insolubilized and qua~ernized and has heparin ionically bound thereto is provided in the pores of the porous tubing of polytetrafluoroethylene, and consequently, a film of water molecules strongly bound thereto is formed.
This prevents the adsorption of plasma protein which becomes a trigger for fibrin deposition. Furthermore, in conjunction with the anticoagulating action of the heparin, antithrombic characteristics is achieved.
1 Another object of this invention is to provide a vascular prosthesis of a stretch polytetrafluoroethylene tubing in which the pore size of the outer surface is larger than that of the inner surface thereby to increase the rate of entry of the connective tissue from the outer periphery of the prosthesis. The smaller size of the pores of the inner surface is believed to reduce the surface stasis of blood flow. Platelet adhesion is reduced by providing water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in the pores of the polytetrafluoroethylene tubing.
As a result, the amount of thrombus formation at the inner sur-eace decreases, and the fibrin layer becomes extremely thin.
Thu~, the neointima on the inner sur~ace is thinner than in similarly dimen~ioned prior a~t vascular prosthesis.
Still another object oE this invention is to provide a vascular prosthesis of a stretched polytetrafluoroethylene tubing in which the pore size of the outer surface is larger than that of the inner surface, thereby allowing the connective tissue from the outer periphery of the prosthesis to grow and 2b develop fully, and consecluently supplying sufficient nutrient to the neointima formed at -the inner surface to prevent calci-Eica-tion in the prosthesis wall that may otherwise occur due to degenerative change with the lapse of time, thus increasing the patency rate of the prosthesis after implantation.
According to this invention, a microstructure composed of fibers and nodes which is obtained by stretching a tubing of polytetrafluoroethylene in at least one axial direction and heating the stretched tubing to at least 327C is usecl as one starting material. Then, the pores of the microstructure are filled with, a solution of polyethyleneimine and the po:Lyethylene--5- ~.
1 imine is subjected to a water-insolubilization treatment and a quaternization treatment. Then, heparin is ionica~ly bound to the polyethyleneimine to form a composite structure. Thus, the invention provides a vascular prosthesis having a high rate of patency which permits a thin neointima to form on the inner surface of the prosthesis after implantation with sufficient nutrition being provided the neointima thereby to retain a neointima without degenerative change and without occlusion of the interior cavity of the prosthesis.
1~ DETAILED DESCRIPTION OF THE INVENTION
In order to stretch and sinter tubings of polytetra-fluoroethylene, the methods described in Japanese Patent Publications Nos. 13560/67 and U.S. Patent Nos. 3,953,566 and
Fabric prostheses composed of a knitted or woven fabric of Dacron*orpolytetrafluoroethylene in the form of a tube having inner diameters that are relatively large are now being utilized with relatively good results. In particular, yood results are generally obtained with vascular prostheses for arteries which have an inner diamcker o at leas-t about 7mm. Despite this, Eew small inner-diametcr arterics are clinicalLy acccptable.
~n vcnous applications~ small inncr-cliameter pros~heses exhibi~
a lower patency rate than in arterial applications. The ra-te of blood flow in veins is smaller than in arteries, and to prevent -thrombosis, it is important to inhibit platelet adhesion to the inner surface of the artificial veins. This requirement is not fully met by presently available ar-tificial veins.
Some tubings made of stretched or expanded po~lytetra-Eluoroethylcne have been demonstrated -to be clinicalLy usefuL
as vascular pros-theses for arteries and veins. 'l'his is descr:ibed, for example, in Soyer et al., "A New Venous Prosthesis", Surgery, Vol. 72, page 86~ ~1972), Volder et al., "A-V Shunts Created in New Ways", Trans, Amer, Soc. Artif. Int. Organs, Vol. 19, p. 38 (1973), Matsumoto et al., "A New Vascular Prosthesis for a Small Caliber Artery", Surgery, Vol.7~, p. 519 (1973), "Application of Expanded Polytetrafluoroethylene to Artificial Vessels", Artificial Organs, Vol. 1, p. ~ (1972), ibicl./ Vol. 2, p. 262 (1973), and ibid., Vol. 3, p. 337 (197~), Fujiwara e-t al., "Use of Goretex Grafts for Replacement of the Superior and * Trade mark -1- ~a 1 Inferior Venae Canal", The Journal of ThoraciC and Cardiovascular Surgery, Vol. 67, p. 774 (1974~, and Belgian Patent No. 517,~15.
The results of these clinical experiments are summarized below.
When a suitable porous prosthesis is implanted as a conduit within the arterial system, the fine pores are clogged ~y clotted blood, and the inside of the prosthesis is covered with a clotted blood layer. The clotted blood layer is made up of fibrin, and the thickness of the fibrin varies, for example, according to the material of and the surface s-tructure of the prosthesis. Since the thickness of -the fibrin approaches 0.5 to 1 mm when a knitted or woven fabric of Dacron*
or po:lytetraEluoroethylene :is used as the prosthes:is, success :Ls achiev~d only with those blood vessels which are not occluded due to this increase in wall thickness by the fibrin layer (that is, arteries having an inside diameter of 5 or 6 mm or more). Generally, knitted or woven prostheses having smaller inner diameters have not been successful.
A polytetrafluoroethylene tubing which has been stretched has a microstructure composed of very fine fibers and nodes connected together by the ibers. The diameter of the Eibers vary depending on various stretching conditions, and can be made much smaller than fibers of the knitted and woven fabrics mentioned above.
I-t has been confirmed clinically that when a structure composed of fibers and nodes is expressed in terms of pore sizes and porosities, or fiber lengths and nodular s:izes, a polytetrafluoroethylene tubing having a pore size of from about 2 microns to abou-t 30 microns (pore sizes below about 2 microns are undesirable), a porosity of about 78% -to about 92%, * Trade mark ,. ,, ~ ,. .
2 ~:
1 a fiber length of not more than about 34 microns (fiber len~ths of about 40 microns to about 110 microns are undesirable), a nodular size of not more than about 20 microns,and a wall thickness of about 0.3 mm to about 1 mm exhibits a high patency rate without substantial occlusion by fibrin deposition.
It has been reported, however, that venous prostheses exhibit a much lower patency rate than arterial prostheses, and do not prove to be entirely satisfactory for prosthetic purposes. It has also been reported that when a vascular prosthesis has too high a porosity, a tearing of the prosthesis by the suture used in joining the prosthesis with the vessel of the patient tends to occur.
In the healing process aEter implatation, connective tissue Eirst develops on the outer periphery oE the polytetra~
fluoroethylene tubin~ and the tissue or~anizes, and aEterwards the fibrin layer on the inner surface of the tubing organizes.
At this time, a continuity of the intimas of the host's vessels with the neointima of the inner surface of the vascular prosthesis is established and simultaneously, the fibrin layer ~O is replaced by the fibrous tissue which has entered the pros-thesis through the eine pores from -the periphery of the prosthesis. Furthermore, after a certain period of -time, the neointimas a-t the inner surface are connected firmly to the connective tissue lining the outer wall of the prosthesis, thereby completing the formation of an artery. It is known that this artery formation requires a period of usually about 4 to 6 months. It is known on the other hand that with vascular prosthesis implanted in veins, the rate of entry of the connective tissue from the periphery thereof is slower than for arterial implantation.
.; . .....
l~Q~2 1 However, despite these reported clinical results, reproducible good results have not been obtained.
A porous tubing of polytetrafluor~ethylene permits the adsorption of plasma protein. Pla-telets adhere to the absorbed plasma protein to form fibrin fibers which capture blood corpuscles and become a fibrin deposited layer. This deposited layer is expected to subsequently form a pseudointima of the prosthesis. However, the fibrin deposited layer is frequently too thick, and insufficient nutrition of the pseudointima or neointima occurs. This will result in disconnection by necrosis or in thrombic occlusion of the inner surface of the prosthesis.
SUMMARY OF THE INVENTION
An object o this invention is to prov.ide a vascular prosthesis h~ving a composite structure composed of ~I porous tubing of polytetrafluoroethylene and water-insolubili~ed and quaternized polye-thyleneimine having heparin ionically bound thereto, with the polyethyleneimine being provided in the pores of the porous tubing. Functionally, the surface of the prosthesis is rendered hydrophobic and is simultaneously charged ~O negatively by the polytetrafluoroethylene having a low surface energy whereby antithrombic character is achieved. Polyethylene-imine which is water-insolubilized and qua~ernized and has heparin ionically bound thereto is provided in the pores of the porous tubing of polytetrafluoroethylene, and consequently, a film of water molecules strongly bound thereto is formed.
This prevents the adsorption of plasma protein which becomes a trigger for fibrin deposition. Furthermore, in conjunction with the anticoagulating action of the heparin, antithrombic characteristics is achieved.
1 Another object of this invention is to provide a vascular prosthesis of a stretch polytetrafluoroethylene tubing in which the pore size of the outer surface is larger than that of the inner surface thereby to increase the rate of entry of the connective tissue from the outer periphery of the prosthesis. The smaller size of the pores of the inner surface is believed to reduce the surface stasis of blood flow. Platelet adhesion is reduced by providing water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in the pores of the polytetrafluoroethylene tubing.
As a result, the amount of thrombus formation at the inner sur-eace decreases, and the fibrin layer becomes extremely thin.
Thu~, the neointima on the inner sur~ace is thinner than in similarly dimen~ioned prior a~t vascular prosthesis.
Still another object oE this invention is to provide a vascular prosthesis of a stretched polytetrafluoroethylene tubing in which the pore size of the outer surface is larger than that of the inner surface, thereby allowing the connective tissue from the outer periphery of the prosthesis to grow and 2b develop fully, and consecluently supplying sufficient nutrient to the neointima formed at -the inner surface to prevent calci-Eica-tion in the prosthesis wall that may otherwise occur due to degenerative change with the lapse of time, thus increasing the patency rate of the prosthesis after implantation.
According to this invention, a microstructure composed of fibers and nodes which is obtained by stretching a tubing of polytetrafluoroethylene in at least one axial direction and heating the stretched tubing to at least 327C is usecl as one starting material. Then, the pores of the microstructure are filled with, a solution of polyethyleneimine and the po:Lyethylene--5- ~.
1 imine is subjected to a water-insolubilization treatment and a quaternization treatment. Then, heparin is ionica~ly bound to the polyethyleneimine to form a composite structure. Thus, the invention provides a vascular prosthesis having a high rate of patency which permits a thin neointima to form on the inner surface of the prosthesis after implantation with sufficient nutrition being provided the neointima thereby to retain a neointima without degenerative change and without occlusion of the interior cavity of the prosthesis.
1~ DETAILED DESCRIPTION OF THE INVENTION
In order to stretch and sinter tubings of polytetra-fluoroethylene, the methods described in Japanese Patent Publications Nos. 13560/67 and U.S. Patent Nos. 3,953,566 and
3,962,153 can basically be utilized. First, a liquid ~.ubr:icant is mi~ed with a sintered powder of polytetrafluoroethylene, and the mixture is extruded into a tubular form by a ram-type extruder. The tubing is stretched at least monoaxially while the tubing is heated at a temperature of less than about 327C, the polytetrafluoroethylene sintering temperature. Then while the tubing is fixed so that it does not shrink, the tubing is heated to a temperature of at least 327C to set the stretched and expanded structure and to form a tubing having increased strength. Any polytetrafluoroethylenes, e.g., homopolymers, which are commercially available can be used in this invention with those having a molecular weight ranging from about 1,000,000 to about 90,000,000 being preferred.
Polyethyleneimine, anGther starting material, is used to bind heparin to the polytetrafluoroethylene tubing to render the tubing antithrombic and form a hydrophilic film. A suitable molecular weight range for the polyethyleneimine which can be used in this invention is about 10,000 to 900,000. Any commercial
Polyethyleneimine, anGther starting material, is used to bind heparin to the polytetrafluoroethylene tubing to render the tubing antithrombic and form a hydrophilic film. A suitable molecular weight range for the polyethyleneimine which can be used in this invention is about 10,000 to 900,000. Any commercial
4 ~
1 grades of polyethyleneimine can be used for this purpose. Commer-cially available polyethyleneimines are obtained by the polyermiza-tion of ethyleneimine. Usually, they are not linear high-molecular weight polymers, but have a branched structure containing primary, secondary or tertiary amine groups. PGlyethyleneimine of such a structure suffices for the purposes of the present invention, and the polyethyleneimine may also contain a substituent. In short, polyethyleneimines of any structure can be utilized in the present invention. Since, commercially available grades can be used, their quality is constant for example in regard to the degree of polymerization. In actually impregnating or coating a solution o~
polyethyleneimine in and on a porous tubing oE polytetrafluoro-~thylene, the concentration of the polyethyleneimine and the mcthod o:E in~olubi:Lization are selected depelldlny on the porosity, pore size, of the porous tubiny. In general, the polyethylene-imine can be employed in a concentration of about 0.1 to about 30 percent by weight.
Water is suitable as a solvent for the polyethylene-imine. When the pore size of the polytetrafluoroethylene tubing is small, the pores of the polytetrafluoroethylene tubiny cannot be di~ectly illed wi-th an aqueous solution of polyethyleneimine.
Fo~ thi5 reason, the tubiny is first immersed in a liquid which is soluble in water and having a low surEace tension, such as methanol, ethanol, acetone and an aqueous solution of a surface active agent, and then in water to replace the liquid in the pores of the tubing with water. The tubing is then immersed in an aqueous solution of polyethyleneimine, preEerably at a polyethyleneimine concentration of about 0.1 to about 20 percent by weiqht. Since polyethyleneimine is also soluhle in a lower alcohol such as methanol, ethanol, or ethylene glycol, the polyethyleneimine may be dissolved in such a solvent and the porous tubing can be impregnated directly with such a solution.
4~
1 In order to uniformly impregnate the pores of the porous tubing with the aqueous solution of polyethyleneimine, a sufficient period of time for the diffusion of the poly-ethyleneimine to occur is allowed to elapse after the immersion, before the subsequent insolubilization reaction step is performed. In general, a sufficient period of time for the diffusion has been found to be about 0.1 to about 20 hours.
Another method ~or distributing the polyethyleneimine uniformly in the pores of the tubing is to repeat the steps of immersion of the porous tubing in the dilute polyethyleneimine solution and drying the tubing. It has been ascertained that by again con-tacting the porous tubing, which has been impregnated with the polyethyleneimine solution and then dricd, (c.CJ./ At room temp~r~tur~ 10-25~C to ~bout 100C, preferably up to 80C) with the poIyethylenelmine solution, the solution r~ad:ily penetrates into the~interior of the pores, and the polyethyleneimine con-centration in the intèrior spaces of the pores roughly doubles.
For repeat impregnation, dryiny between impregnations is desirable but not essential. Vacuum impregnation, or pressure 20~ impregnation may be utilized, if desired. In particular, the pore~ can be e~fectively impregnated with the polyethyleneimine solution Erom the inner cavity oE the porous tubincJ hy app1ying pressure to the solution.
After the impregnation of the polytetrafluoroethylene by the polyethyleneimine, a chemical reaction to render the polyethyleneimine water-insoluble is carried out. This chemical reaction is not particularly critical so long as the polyethylene-imine is rendered water-insoluble. The type of the reaction can be chosen freely also in view of the fact that the material constituting the porous tubing is polytetrafluoroethy]ene which has very good chemical resistance and thermal stability.
., I
I j l -8-1 Polyethyleneimine is a very readily water-soluble polymer. Water-insolubilization can be achieved by cross-linking the polyethyleneimine into a network structure. Reaction of the polyethyleneimine with an aldehyde such as formaldehyde or glyo~al is a typical example of the cross-linking process. If the reaction takes place in a single molecu]e of polyethyleneimine, the linear molecule changes to a cyclic molecule. If the reaction takes place between two molecules of polyethyleneimine, the molecules change to star-like molecules or macrocyclic molecules.
When the cross-linking reaction further proceeds and involves many molecules, a three-dimensional cross-linked network structure will result. As the degree of polymerication of polyethyleneimine increases, the water-insolubilization of the polyethyleneimine can b~ advantageously achieved with fewer cross-linking reactions.
Furthermore, the swellability oE polyethyleneimine with watèr becomes greater. Examples of compounds which react with poly-ethyleneimine and act as cross-linking agents include ketones, carboxylic acids, acid anhydrides, acyl halides, isocyanic acid ` esters, isothiocyanic acid esters, and epoxides in addition to the aldehydes. Reactions with these compounds, with carbonyl group containing compounds being preferred, can be utilized for watex-insolubilization.
The water-swellability, or the water content, of the polyethyleneimine after water insolubilization varies greatly according to the reaction procedure for water insolubilization and the reaction conditions used. Hence, these factors may be selected depending on the intended end-use purpose. When a suitable reaction procedure and suitable reaction conditions are selected, a porous composite structure can also be obtained 3~ which consists of a tubing of polytetrafluoroethylene and a micro-porous swollen gel-like product of polyethyleneimine impregnated _ g _ z 1 in the pores of the tubing. It is surprising to note that by varying the factors described above, the pore size of the microporous swollen gel changes from 10 rnicrons to 0.01 mircon or even to 0.001 micron. Thus, the adsorption of plasma protein can be reduced, and the surface of the interior cavity of the tubing can be made smooth to an extent that the stream of the blood flow is not disturbed.
Following the water-insolubilization reaction, a quaternization reaction is carried out. The water-insolubilized polyethyleneimine is converted by quaternization into a compound having a quaternary ammonium salt type cation as a fixed ion.
A typical example of a reaction Eor this purpose is the reaction of the water-insolubili~ed polyethyleneimine with an alkyl halide. Use of an excess amount oE the alkyl halide is preferred in order to assure complete quaternization. Examples of suitable alkyl halides which can be used are ethyl chloride, butyl chloride, allyl chloride, benzyl chloride, ethyl bromide, propyl bromide, butyl bromide, methyl iodide,and ethyl iodideO
A similar reaction can be carried out by using alkyl sulEates or alkyl sulfonates corresponding to these halides described above.
The product is then subjected to a treatment to ionically bind heparin to the Eixed cation generated as a result~
of the quaternization. ~eparin is known -to be an anticoagulant for blood. According to this inven-tion, a vascular prosthesis having antithrombic properties can be obtained by ionically binding heparin to the fixed cation. To achieve -this, the produc-t is immersed in an aqueous solu-tion of heparin at room temperature (e.g. 10-25C) to a temperature of not more than about 100C for 1 hour to several days. A suitable concen-tration of heparin which can be employed in this invention is about 100 4~2 1 to about 10,000 units/ml. The heparin solution may also be an aqueous solution of a suitable concentration of commercially available sodium heparin.
Coating or mixing of heparin on or with a material to be used for medical treatments is also practiced to achieve antithrombic characteristics. However, this method has the defect that heparin easily comes off from the material. A
method involving covalently bonding heparin to the material is also prackiced, but has not given good antithrombic properties.
1~ In view of this, ionic bonding of heparin in accordance with this invention is believed to be most effective for imparting anti~
thrombic properties.
Polyethyleneimine water~insolubilized and quaternized and havlng heparin lonically bound thereko ma~ be provided only partially in the pores oE the porous polytetrafluoroethylene tubing. Particularly, in a preferred emboidment, a vascular prosthesis of a porous polytetrafluoroethylene tubing in which heparin-bound polyethyleneimine is provided only on those pores which are on the inner surface of the tubing reduces blood leak-age after implantation,and the interior cavity of the prosthesisis not occluded because of the antithrombic property o the inner surface of the tubing. Such a prosthesis exhibits a high patency rate even in application to small-caliber vessels in which the patency rate has in the past been regarded as extremely low. In order to provide water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in those pores which are on the inner surface side of the porous tubing, the polyethyleneimine solution can be impregnated only from the inner surface of the porous tubing, and the subsequent water-3~ insolubilization reaction should be started only at the inner z 1 surface. Thereaction should be terminated by washing the productwith water after an appropriate period of tirne before the reaction reaches the outer surface of the tubing.
In another preferred embodiment of the invention, a polytetrafluoroethylene tubing whose outer surface and inner surfaces have different micro-fibrous structures is used as a starting material. The micro-fibrous structure comprises fibers and nodes connected to one another by the fibers. Such a starting material desirably has a micro-fibrous structure in which the average fiber diameter of the outer surface is at least two times the average fiber diameter of the inner surface.
~ nother preferrecl micro-fibrous s-tructure is one ln which the fiber direction o~ the inner sur~ace is more raclially ~i~trLbuted than the fiber direction of the outer sur~ace, or the long axes of the nodes at the outer surfaceare at least two times longer than those of the nodes at the inner surace.
In these micro-fibrous structures, the inner sur-face is finer and smoother than the outer surface. Consequently, the rate of entry of the connective tissues from the outer periphery after implantation increases and -the surface s-tatis of the blood flow on the inner surface is recluced. Furthermore, platele-t aclh~sion can be reduced by providing ~ater-insolubilizea and quaternized polyethyleneimine having heparin ionically bound thereto in -the pores of the micro-fibrous struc-ture.
A structure of these types can be obtained by sintering the stretched tubing at a temperature of at least about 327C
while forcibly cooling the inner surface of the tubing and starting -the heating at the outer periphery of the tubing.
The -temperature is so adjusted that the res:in portion of the inner surface oE the tubing is at a temperature of at . ., . ~ . .
least about 327C, the sintering temperature, while continuously exposing ~he inner surface of the tubing to a cooling medium such as air by continuously introducing the cooling medium into the interior cavity of the tubing, or continuously reduciny the pressure of the interior cavity of the tubing.
~ s a result, the resin fibers at the outside surface of the tubing are exposed for a long time to a temperature of at least about 327C, and two or more fibers at the outer surEace originally having the same fibrous structure (especlally tO the same size) as the inner surface coalesce and gradually become thicker. For example, when the fiber diameter doubles four fibers are Eused and coal~sc~d.
rrh~ th.ickn~ss oE th~ :i.nner surEace structural portion o~ ~h~ t~blng ~nd the~ th:i~lcn~s.s oE th~ out~r surE~ce structural portion of the tubing are varied by changing the amount of the cooling medium passed through the interior cavity of the tubing and the amount oE heat supplied externally. When the amount of the cooling medium is decreased, and the amount of heat supplied externally is increased, the thickness of the outer surface structural portion increase~. Increasing the amount o:E the coo:ling medium results in an increase in the -thickness of the inside surface structural portion. S:ince :in -this case also, the size of the nodular portion does not change, the nodular dimension of the outer surface is approximately equal to that of the inner surEace.
When the tubing is stretched lengthwise and then expanded in the radial direction, the micro-fibrous struc-ture oE fibers and nodes changes abruptly. The nodes of a tubing which has been stretched only in the longitudinal direction have a shape approximating an ellipsoid and have a relatively uniform ~ -13-1 size. However, with a tubing which has been stretched in the longitudinal direction and then expanded in the radial direction, the nodes generated in the longitudinal direction divide into smaller portions depending on the extent of expansion, and fibers form again among the nodes. The shape of the nodes or the length, direction and size of the fibers will vary depending .:
on the stretch ratios in the longitudinal direction and the radical direction. At any rate, it is to be noted that the shape of the nodes, the length, the diameter, of the fibe:rs change depending on the extend of expansion in the radial direction Erom the shape, lencJth, diameter, at-tained by stretching the tub:ing onl.y in thc l.ong:itucl:i.na:l. d:i.recl;.i.on.
Th~ most pr~ferr~d ~mbod:iment comprises st~e-tch:ing the ~ub~.nc3 ~irst in the longl~ud.inal dir~ction and then ~xpand:in~J
the tubing in the radial direction. By heating the outer surEace of the tubing to at least about 327C, the crystalline melti.ng point of polytetrafluoroethylene, but maintaining the inner sur-face o the tubing at below about 327~C prior -to expansion in the .
radial direction, a composite structure can be produced in which the outer surface of the tubing has a micro-fibrous structure ormed by stre~ch.incJ only in -the longitudinal direct:Lon and -the inner surface of the -tubing has a biax:ial:ly stretch~-~d micro-fibrous structure formed by stretching also in the radial direction. Needless to say, it is possible to change the micro-fibrous structures of the outer and inner surfaces of the tubing by first expanding the tubing in the radial direction and then stretching the tubing in the longitudinal direction. A more detailed description of the polytetrafluoroethylene -tu:bing and their characteristics which can be used in this invention are set out in the applicant's co-pending Canadi.an applications serial no. 269,339 filed 7-1-77 and serial no. 2~5,033 filed 19-8-77.
. ~',, -1~-1 Water-insolubilized and quaternized polyethyleneimine having heparin bound thereto can be provided in the pores of such a polytetrafluoroethylene tubing by the procedure described hereinabove.
The fibrous structure at the outer surface of the tubing is less dense than that at the inner surface, and this produces various effects as described below.
Firstly, this serves to increase the mechanical strength of vascular prostheses made of such a tubing preventing the prosthesis from being torn in the longitudinal direction by the suture during implantation. It is possible for only the inner surface fibrous structure of the tub.ing to act as a bag-l.ike reccptacle for transportin~ bloocl. For applicati.on to artcrl~s, how~v~r, the tub:in~ m~lst withstand a blood p~e~sure of about 120 mm~lg, and should not be compressed by elastic fibroblasts that develop on the outer periphery thereof. In addit.ion, the tubing must withstand suturing at the time of surgery. The force required to cut the fibers can be increased by increasing the diameters of the fibers at -the outer surface of ~O the -tubing, and increasing the number of fibers -that are aligned at right angles -to the direction of possible tearing. I~
particular, a tubing -that has been stretched and then expanded to increase the fiber diameter has improved tear streng-th.
Secondly, as a result of decreasing the dimensions of -the fibrous structure at the inner surface of the vascular prosthesis made of the polytetrafluoroethylene tubing, the surface resistance of the tubing to blood flow is reduced, and conse~uently, platelet adhesion is reduced. Platele-ts which have contacted the surface of the prosthesis and adhered thereto aggregate with each other reversibly in the presence oE adenosi.ne .. ., ~
.. . .
l~ Z
1 diphosphate and calcium ion, after which they adhere irreversibly and form a thrombus together with fibrin. The thrombus layer becomes thinner as the amount of platelets that have adhered decreases. The thickness of the initial thrombus layer increases as the fibrin deposits onto it, and this finally causes occlusion.
Therefore, in order to obtain vascular prostheses free from occlusion, it is essential to decrease the thickness of the initial thrombus layer. This necessity is more pronounced in veins than in arteries. In other words, a reduction in the thickness of neointimas on the inner surface of the prostheses can be expected.
As a third effect, fibroblasts rapidly enter the prosthQsis from the outer p~riph~ry oE thc pro~the~sis and ~row Eully ~s a result of an lncrease ln the s:ixe of the op~ni.ncJs in the outer surface ibrous structure of the prosthesis. ~t is already known that fibroblasts readily enter a vascular prosthesis made of a knitted or woven fabric of Dacron*,or polytetrafluoroethylene, because such a prosthesis has a tubular wall of a loose structure. However, bleeding occurs ~0 through the wall immediately after implantation, and results in an increase in the thickness of the fibrin layer on -the inner surEace of the prosthesis. Further increase l~ads to calciEi-cation and occlusion. In a prosthesis made of polyte-trafluoro-ethylene havin~ the same fibrous structures both at the outer and inner surfaces, it is essential to decrease the thickness of the fibrin layer that results from platelet adhesion by making the pore size sufficiently small to prevent bleeding, and therefore, the ease of entry of fibroblasts from the outer periphery of the prosthesis must be sacrificed to some extent.
* Trade mark r,~ , 1 When the fiber diameter of the outer surface of the prosthesis of this invention is at least two times larger than the fiber diameter of the inner surface, it is possible to reduce the thickness of the fibrin layer at the inner surface of the prosthesis and facilitate entry of fibroblasts from the periphery. Furthermore, nutrient supply to the neointimas formed at the inner surface of the prosthesis can be effected suffici-ently through capillaries which densely develop on fully grown fibroblasts. It is possible therefore to greatly reduce ;~
calcification of the neointimas that may result from nutritional deficiency.
In arterial prostheses, nutrition can be effected not only through capillaries at the fibroblasts, but also from the b~ood within the cavity of the prostheses. However, in venous prostheses, nutrition from the blood can hardly be expecte~, and must rely exclusively upon the capillaries present on the fibroblasts that have come through the outer periphery. Accord-ingly, the entry of fibroblasts from the outer periphery of vascular prostheses is important not only for the formation of neointimas, but also for preventing calcification of the neo-intimas which may occur due to nutritional deficiency after implantation and thereby for increasing the patency rate of the prosthesis after operation. This is more important in venous prostheses.
Vascular prostheses must have pore sizes which are small enough to keep the blood during circulation from leaking through the tubular wall, and which are large enough to permit entry of fibroblasts from the outer periphery without obstruction.
With the prosthesis of this invention, this requirement can be met only by the porosity (e.g., of about 78 percent to about 92 41~Z
1 percent), fiber length (e.g., of not more than about 34 microns) and pore size (e.g., of about 2 microns to about 30 microns) of the polytetrafluoroethylene tubing in conjunction with water-insolubilized and quaternized polyethyleneirnines having heparin ionically bound thereto, being provided in the pores of the tubing.
A polytetrafluoroethylene tubing used as a conventional prosthesis from which leakage of the circulating blood through the wall of the prosthesis occurs because of high porosity, can also have blood leakage prevented by completely ~ ing a microporous swollen gel of water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in the pores of the tubing. Fibroblasts Erom th~ outer periphery of the p~osthesis can succ~ssively enter the Eilled poLyethyl~n~
and thus grow.
The effect of providing the water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in a polytetrafluoroethylene tubing having porosity characteristics within the ranges feasible heretofore as vascular prostheses is that at the time of contact with the blood, the water of adsorption of the polyethyleneimine inhibits the adsorption of plasma protein, and thus it is difEicu:Lt for a Eibrin layer to form. In conjunction with the anti-clo-tting action of heparin, this effect provides the vascular prosthesis with antithrombic properties.
The composite vascular prosthesis of the invention composed of a porous tubing of polytetrafluoroethylene and water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto provided in the pores, especially in those pores which are on the inner surface side, ~. ~
... .
4~ i 1 results in little vascular occlusion by the increased thickness of the fibrin layer after surgical operation, which expedites the healing of the patients, and prevents the degenerative change of the neointimas formecl. Accordingly, the prostheses in accordance with this invention contribute greatly not only to surgery but also to industry.
The following Examples, are given to illustrate the present invention more specifically. It should be unders-tood however that the present invention is not to be construed as being limited by these examples.
In these examples, the bubble point is the pressure at which the first air bubble passes through the porous tublng when a pneumatic pressure is applied to the inner surEace o~ the tubin~ immersed in ieopropyl alcohol. Unless otherwise Lnclicated herein percents are represented by weight.
A commercially available 30% aqueous solution of poly-ethyleneimine (M.W.: about 40,000) was diluted with isopropyl alcohol to prepare a 2% solution. The solution was forced into a porous polytetrafluoroethylene tubing from the inner surface of the tubing. The porous tubing had been prepared Erom polytetra~luoroethylene by stretching and sintering and had an inside diameter of 4.3 mm, a thickness of 0.40 mm, a bubhle point of 0.25 kg/cm2 and a porosity of 80%. The porous tubing was air dried at 20C for 2 minutes, and then immersed for 2 minutes in a 4% aqueous solution of glyoxal to render the polyethyleneimine water-insoluble. The tubing was washed with water, dried, and then immersed in a 50% e-thanol solution of methyl iodide at 20C for 3 hours to quaternize the polyethylene-imine. The tubing was washed with water, and heated at 90C
1 for 30 minutes in distilled water to remove unreacted material.Furthermore, the tubing was washed with a 1% aqueous solution of sodium chloride, dried, and impregnated with an aqueous solution of heparin sodium in a concentration of 1000 units/ml to bind the heparin. Two hours later, a part Gf the tubing was taken as a sample. The sample was washed with water, and then contacted with a solution of toluidine blue indicator, whereupon it assumed a reddish violet color. Thus, the bonding of heparin was confirmed. The resulting tubing had a bubble point of 0.29 kg/cm2, A commercially available 30~ aqueous solution of poly-ethyleneimine (~.W.: about 50,000) was diluted with isopropyl alcohol ~o prepare a 7~ solution. The solut.ion was forced into the same type of porous polytekra~luoroethylene tubing as describ-ed in Example 1 from the inner surface o the tubing, dried in air at 20C for 2 minutes, and immersed for 2 minutes in a 5%
aqueous solution of glyoxal to render the polyethyleneimine water-insoluble. In the same manner as in Example 1, the tubing was subjected to a quaternization reaction and a heparin-binding treatment. The bonding of heparin was confirmed in the same manner as in Example 1. The resulti.ng tubing had a bubble point of 0.44 kg/cm2.
While the present invention has been described in detail with reference to specific emboidments thereof, it is apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and the scope of the present invention.
1 grades of polyethyleneimine can be used for this purpose. Commer-cially available polyethyleneimines are obtained by the polyermiza-tion of ethyleneimine. Usually, they are not linear high-molecular weight polymers, but have a branched structure containing primary, secondary or tertiary amine groups. PGlyethyleneimine of such a structure suffices for the purposes of the present invention, and the polyethyleneimine may also contain a substituent. In short, polyethyleneimines of any structure can be utilized in the present invention. Since, commercially available grades can be used, their quality is constant for example in regard to the degree of polymerization. In actually impregnating or coating a solution o~
polyethyleneimine in and on a porous tubing oE polytetrafluoro-~thylene, the concentration of the polyethyleneimine and the mcthod o:E in~olubi:Lization are selected depelldlny on the porosity, pore size, of the porous tubiny. In general, the polyethylene-imine can be employed in a concentration of about 0.1 to about 30 percent by weight.
Water is suitable as a solvent for the polyethylene-imine. When the pore size of the polytetrafluoroethylene tubing is small, the pores of the polytetrafluoroethylene tubiny cannot be di~ectly illed wi-th an aqueous solution of polyethyleneimine.
Fo~ thi5 reason, the tubiny is first immersed in a liquid which is soluble in water and having a low surEace tension, such as methanol, ethanol, acetone and an aqueous solution of a surface active agent, and then in water to replace the liquid in the pores of the tubing with water. The tubing is then immersed in an aqueous solution of polyethyleneimine, preEerably at a polyethyleneimine concentration of about 0.1 to about 20 percent by weiqht. Since polyethyleneimine is also soluhle in a lower alcohol such as methanol, ethanol, or ethylene glycol, the polyethyleneimine may be dissolved in such a solvent and the porous tubing can be impregnated directly with such a solution.
4~
1 In order to uniformly impregnate the pores of the porous tubing with the aqueous solution of polyethyleneimine, a sufficient period of time for the diffusion of the poly-ethyleneimine to occur is allowed to elapse after the immersion, before the subsequent insolubilization reaction step is performed. In general, a sufficient period of time for the diffusion has been found to be about 0.1 to about 20 hours.
Another method ~or distributing the polyethyleneimine uniformly in the pores of the tubing is to repeat the steps of immersion of the porous tubing in the dilute polyethyleneimine solution and drying the tubing. It has been ascertained that by again con-tacting the porous tubing, which has been impregnated with the polyethyleneimine solution and then dricd, (c.CJ./ At room temp~r~tur~ 10-25~C to ~bout 100C, preferably up to 80C) with the poIyethylenelmine solution, the solution r~ad:ily penetrates into the~interior of the pores, and the polyethyleneimine con-centration in the intèrior spaces of the pores roughly doubles.
For repeat impregnation, dryiny between impregnations is desirable but not essential. Vacuum impregnation, or pressure 20~ impregnation may be utilized, if desired. In particular, the pore~ can be e~fectively impregnated with the polyethyleneimine solution Erom the inner cavity oE the porous tubincJ hy app1ying pressure to the solution.
After the impregnation of the polytetrafluoroethylene by the polyethyleneimine, a chemical reaction to render the polyethyleneimine water-insoluble is carried out. This chemical reaction is not particularly critical so long as the polyethylene-imine is rendered water-insoluble. The type of the reaction can be chosen freely also in view of the fact that the material constituting the porous tubing is polytetrafluoroethy]ene which has very good chemical resistance and thermal stability.
., I
I j l -8-1 Polyethyleneimine is a very readily water-soluble polymer. Water-insolubilization can be achieved by cross-linking the polyethyleneimine into a network structure. Reaction of the polyethyleneimine with an aldehyde such as formaldehyde or glyo~al is a typical example of the cross-linking process. If the reaction takes place in a single molecu]e of polyethyleneimine, the linear molecule changes to a cyclic molecule. If the reaction takes place between two molecules of polyethyleneimine, the molecules change to star-like molecules or macrocyclic molecules.
When the cross-linking reaction further proceeds and involves many molecules, a three-dimensional cross-linked network structure will result. As the degree of polymerication of polyethyleneimine increases, the water-insolubilization of the polyethyleneimine can b~ advantageously achieved with fewer cross-linking reactions.
Furthermore, the swellability oE polyethyleneimine with watèr becomes greater. Examples of compounds which react with poly-ethyleneimine and act as cross-linking agents include ketones, carboxylic acids, acid anhydrides, acyl halides, isocyanic acid ` esters, isothiocyanic acid esters, and epoxides in addition to the aldehydes. Reactions with these compounds, with carbonyl group containing compounds being preferred, can be utilized for watex-insolubilization.
The water-swellability, or the water content, of the polyethyleneimine after water insolubilization varies greatly according to the reaction procedure for water insolubilization and the reaction conditions used. Hence, these factors may be selected depending on the intended end-use purpose. When a suitable reaction procedure and suitable reaction conditions are selected, a porous composite structure can also be obtained 3~ which consists of a tubing of polytetrafluoroethylene and a micro-porous swollen gel-like product of polyethyleneimine impregnated _ g _ z 1 in the pores of the tubing. It is surprising to note that by varying the factors described above, the pore size of the microporous swollen gel changes from 10 rnicrons to 0.01 mircon or even to 0.001 micron. Thus, the adsorption of plasma protein can be reduced, and the surface of the interior cavity of the tubing can be made smooth to an extent that the stream of the blood flow is not disturbed.
Following the water-insolubilization reaction, a quaternization reaction is carried out. The water-insolubilized polyethyleneimine is converted by quaternization into a compound having a quaternary ammonium salt type cation as a fixed ion.
A typical example of a reaction Eor this purpose is the reaction of the water-insolubili~ed polyethyleneimine with an alkyl halide. Use of an excess amount oE the alkyl halide is preferred in order to assure complete quaternization. Examples of suitable alkyl halides which can be used are ethyl chloride, butyl chloride, allyl chloride, benzyl chloride, ethyl bromide, propyl bromide, butyl bromide, methyl iodide,and ethyl iodideO
A similar reaction can be carried out by using alkyl sulEates or alkyl sulfonates corresponding to these halides described above.
The product is then subjected to a treatment to ionically bind heparin to the Eixed cation generated as a result~
of the quaternization. ~eparin is known -to be an anticoagulant for blood. According to this inven-tion, a vascular prosthesis having antithrombic properties can be obtained by ionically binding heparin to the fixed cation. To achieve -this, the produc-t is immersed in an aqueous solu-tion of heparin at room temperature (e.g. 10-25C) to a temperature of not more than about 100C for 1 hour to several days. A suitable concen-tration of heparin which can be employed in this invention is about 100 4~2 1 to about 10,000 units/ml. The heparin solution may also be an aqueous solution of a suitable concentration of commercially available sodium heparin.
Coating or mixing of heparin on or with a material to be used for medical treatments is also practiced to achieve antithrombic characteristics. However, this method has the defect that heparin easily comes off from the material. A
method involving covalently bonding heparin to the material is also prackiced, but has not given good antithrombic properties.
1~ In view of this, ionic bonding of heparin in accordance with this invention is believed to be most effective for imparting anti~
thrombic properties.
Polyethyleneimine water~insolubilized and quaternized and havlng heparin lonically bound thereko ma~ be provided only partially in the pores oE the porous polytetrafluoroethylene tubing. Particularly, in a preferred emboidment, a vascular prosthesis of a porous polytetrafluoroethylene tubing in which heparin-bound polyethyleneimine is provided only on those pores which are on the inner surface of the tubing reduces blood leak-age after implantation,and the interior cavity of the prosthesisis not occluded because of the antithrombic property o the inner surface of the tubing. Such a prosthesis exhibits a high patency rate even in application to small-caliber vessels in which the patency rate has in the past been regarded as extremely low. In order to provide water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in those pores which are on the inner surface side of the porous tubing, the polyethyleneimine solution can be impregnated only from the inner surface of the porous tubing, and the subsequent water-3~ insolubilization reaction should be started only at the inner z 1 surface. Thereaction should be terminated by washing the productwith water after an appropriate period of tirne before the reaction reaches the outer surface of the tubing.
In another preferred embodiment of the invention, a polytetrafluoroethylene tubing whose outer surface and inner surfaces have different micro-fibrous structures is used as a starting material. The micro-fibrous structure comprises fibers and nodes connected to one another by the fibers. Such a starting material desirably has a micro-fibrous structure in which the average fiber diameter of the outer surface is at least two times the average fiber diameter of the inner surface.
~ nother preferrecl micro-fibrous s-tructure is one ln which the fiber direction o~ the inner sur~ace is more raclially ~i~trLbuted than the fiber direction of the outer sur~ace, or the long axes of the nodes at the outer surfaceare at least two times longer than those of the nodes at the inner surace.
In these micro-fibrous structures, the inner sur-face is finer and smoother than the outer surface. Consequently, the rate of entry of the connective tissues from the outer periphery after implantation increases and -the surface s-tatis of the blood flow on the inner surface is recluced. Furthermore, platele-t aclh~sion can be reduced by providing ~ater-insolubilizea and quaternized polyethyleneimine having heparin ionically bound thereto in -the pores of the micro-fibrous struc-ture.
A structure of these types can be obtained by sintering the stretched tubing at a temperature of at least about 327C
while forcibly cooling the inner surface of the tubing and starting -the heating at the outer periphery of the tubing.
The -temperature is so adjusted that the res:in portion of the inner surface oE the tubing is at a temperature of at . ., . ~ . .
least about 327C, the sintering temperature, while continuously exposing ~he inner surface of the tubing to a cooling medium such as air by continuously introducing the cooling medium into the interior cavity of the tubing, or continuously reduciny the pressure of the interior cavity of the tubing.
~ s a result, the resin fibers at the outside surface of the tubing are exposed for a long time to a temperature of at least about 327C, and two or more fibers at the outer surEace originally having the same fibrous structure (especlally tO the same size) as the inner surface coalesce and gradually become thicker. For example, when the fiber diameter doubles four fibers are Eused and coal~sc~d.
rrh~ th.ickn~ss oE th~ :i.nner surEace structural portion o~ ~h~ t~blng ~nd the~ th:i~lcn~s.s oE th~ out~r surE~ce structural portion of the tubing are varied by changing the amount of the cooling medium passed through the interior cavity of the tubing and the amount oE heat supplied externally. When the amount of the cooling medium is decreased, and the amount of heat supplied externally is increased, the thickness of the outer surface structural portion increase~. Increasing the amount o:E the coo:ling medium results in an increase in the -thickness of the inside surface structural portion. S:ince :in -this case also, the size of the nodular portion does not change, the nodular dimension of the outer surface is approximately equal to that of the inner surEace.
When the tubing is stretched lengthwise and then expanded in the radial direction, the micro-fibrous struc-ture oE fibers and nodes changes abruptly. The nodes of a tubing which has been stretched only in the longitudinal direction have a shape approximating an ellipsoid and have a relatively uniform ~ -13-1 size. However, with a tubing which has been stretched in the longitudinal direction and then expanded in the radial direction, the nodes generated in the longitudinal direction divide into smaller portions depending on the extent of expansion, and fibers form again among the nodes. The shape of the nodes or the length, direction and size of the fibers will vary depending .:
on the stretch ratios in the longitudinal direction and the radical direction. At any rate, it is to be noted that the shape of the nodes, the length, the diameter, of the fibe:rs change depending on the extend of expansion in the radial direction Erom the shape, lencJth, diameter, at-tained by stretching the tub:ing onl.y in thc l.ong:itucl:i.na:l. d:i.recl;.i.on.
Th~ most pr~ferr~d ~mbod:iment comprises st~e-tch:ing the ~ub~.nc3 ~irst in the longl~ud.inal dir~ction and then ~xpand:in~J
the tubing in the radial direction. By heating the outer surEace of the tubing to at least about 327C, the crystalline melti.ng point of polytetrafluoroethylene, but maintaining the inner sur-face o the tubing at below about 327~C prior -to expansion in the .
radial direction, a composite structure can be produced in which the outer surface of the tubing has a micro-fibrous structure ormed by stre~ch.incJ only in -the longitudinal direct:Lon and -the inner surface of the -tubing has a biax:ial:ly stretch~-~d micro-fibrous structure formed by stretching also in the radial direction. Needless to say, it is possible to change the micro-fibrous structures of the outer and inner surfaces of the tubing by first expanding the tubing in the radial direction and then stretching the tubing in the longitudinal direction. A more detailed description of the polytetrafluoroethylene -tu:bing and their characteristics which can be used in this invention are set out in the applicant's co-pending Canadi.an applications serial no. 269,339 filed 7-1-77 and serial no. 2~5,033 filed 19-8-77.
. ~',, -1~-1 Water-insolubilized and quaternized polyethyleneimine having heparin bound thereto can be provided in the pores of such a polytetrafluoroethylene tubing by the procedure described hereinabove.
The fibrous structure at the outer surface of the tubing is less dense than that at the inner surface, and this produces various effects as described below.
Firstly, this serves to increase the mechanical strength of vascular prostheses made of such a tubing preventing the prosthesis from being torn in the longitudinal direction by the suture during implantation. It is possible for only the inner surface fibrous structure of the tub.ing to act as a bag-l.ike reccptacle for transportin~ bloocl. For applicati.on to artcrl~s, how~v~r, the tub:in~ m~lst withstand a blood p~e~sure of about 120 mm~lg, and should not be compressed by elastic fibroblasts that develop on the outer periphery thereof. In addit.ion, the tubing must withstand suturing at the time of surgery. The force required to cut the fibers can be increased by increasing the diameters of the fibers at -the outer surface of ~O the -tubing, and increasing the number of fibers -that are aligned at right angles -to the direction of possible tearing. I~
particular, a tubing -that has been stretched and then expanded to increase the fiber diameter has improved tear streng-th.
Secondly, as a result of decreasing the dimensions of -the fibrous structure at the inner surface of the vascular prosthesis made of the polytetrafluoroethylene tubing, the surface resistance of the tubing to blood flow is reduced, and conse~uently, platelet adhesion is reduced. Platele-ts which have contacted the surface of the prosthesis and adhered thereto aggregate with each other reversibly in the presence oE adenosi.ne .. ., ~
.. . .
l~ Z
1 diphosphate and calcium ion, after which they adhere irreversibly and form a thrombus together with fibrin. The thrombus layer becomes thinner as the amount of platelets that have adhered decreases. The thickness of the initial thrombus layer increases as the fibrin deposits onto it, and this finally causes occlusion.
Therefore, in order to obtain vascular prostheses free from occlusion, it is essential to decrease the thickness of the initial thrombus layer. This necessity is more pronounced in veins than in arteries. In other words, a reduction in the thickness of neointimas on the inner surface of the prostheses can be expected.
As a third effect, fibroblasts rapidly enter the prosthQsis from the outer p~riph~ry oE thc pro~the~sis and ~row Eully ~s a result of an lncrease ln the s:ixe of the op~ni.ncJs in the outer surface ibrous structure of the prosthesis. ~t is already known that fibroblasts readily enter a vascular prosthesis made of a knitted or woven fabric of Dacron*,or polytetrafluoroethylene, because such a prosthesis has a tubular wall of a loose structure. However, bleeding occurs ~0 through the wall immediately after implantation, and results in an increase in the thickness of the fibrin layer on -the inner surEace of the prosthesis. Further increase l~ads to calciEi-cation and occlusion. In a prosthesis made of polyte-trafluoro-ethylene havin~ the same fibrous structures both at the outer and inner surfaces, it is essential to decrease the thickness of the fibrin layer that results from platelet adhesion by making the pore size sufficiently small to prevent bleeding, and therefore, the ease of entry of fibroblasts from the outer periphery of the prosthesis must be sacrificed to some extent.
* Trade mark r,~ , 1 When the fiber diameter of the outer surface of the prosthesis of this invention is at least two times larger than the fiber diameter of the inner surface, it is possible to reduce the thickness of the fibrin layer at the inner surface of the prosthesis and facilitate entry of fibroblasts from the periphery. Furthermore, nutrient supply to the neointimas formed at the inner surface of the prosthesis can be effected suffici-ently through capillaries which densely develop on fully grown fibroblasts. It is possible therefore to greatly reduce ;~
calcification of the neointimas that may result from nutritional deficiency.
In arterial prostheses, nutrition can be effected not only through capillaries at the fibroblasts, but also from the b~ood within the cavity of the prostheses. However, in venous prostheses, nutrition from the blood can hardly be expecte~, and must rely exclusively upon the capillaries present on the fibroblasts that have come through the outer periphery. Accord-ingly, the entry of fibroblasts from the outer periphery of vascular prostheses is important not only for the formation of neointimas, but also for preventing calcification of the neo-intimas which may occur due to nutritional deficiency after implantation and thereby for increasing the patency rate of the prosthesis after operation. This is more important in venous prostheses.
Vascular prostheses must have pore sizes which are small enough to keep the blood during circulation from leaking through the tubular wall, and which are large enough to permit entry of fibroblasts from the outer periphery without obstruction.
With the prosthesis of this invention, this requirement can be met only by the porosity (e.g., of about 78 percent to about 92 41~Z
1 percent), fiber length (e.g., of not more than about 34 microns) and pore size (e.g., of about 2 microns to about 30 microns) of the polytetrafluoroethylene tubing in conjunction with water-insolubilized and quaternized polyethyleneirnines having heparin ionically bound thereto, being provided in the pores of the tubing.
A polytetrafluoroethylene tubing used as a conventional prosthesis from which leakage of the circulating blood through the wall of the prosthesis occurs because of high porosity, can also have blood leakage prevented by completely ~ ing a microporous swollen gel of water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in the pores of the tubing. Fibroblasts Erom th~ outer periphery of the p~osthesis can succ~ssively enter the Eilled poLyethyl~n~
and thus grow.
The effect of providing the water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto in a polytetrafluoroethylene tubing having porosity characteristics within the ranges feasible heretofore as vascular prostheses is that at the time of contact with the blood, the water of adsorption of the polyethyleneimine inhibits the adsorption of plasma protein, and thus it is difEicu:Lt for a Eibrin layer to form. In conjunction with the anti-clo-tting action of heparin, this effect provides the vascular prosthesis with antithrombic properties.
The composite vascular prosthesis of the invention composed of a porous tubing of polytetrafluoroethylene and water-insolubilized and quaternized polyethyleneimine having heparin ionically bound thereto provided in the pores, especially in those pores which are on the inner surface side, ~. ~
... .
4~ i 1 results in little vascular occlusion by the increased thickness of the fibrin layer after surgical operation, which expedites the healing of the patients, and prevents the degenerative change of the neointimas formecl. Accordingly, the prostheses in accordance with this invention contribute greatly not only to surgery but also to industry.
The following Examples, are given to illustrate the present invention more specifically. It should be unders-tood however that the present invention is not to be construed as being limited by these examples.
In these examples, the bubble point is the pressure at which the first air bubble passes through the porous tublng when a pneumatic pressure is applied to the inner surEace o~ the tubin~ immersed in ieopropyl alcohol. Unless otherwise Lnclicated herein percents are represented by weight.
A commercially available 30% aqueous solution of poly-ethyleneimine (M.W.: about 40,000) was diluted with isopropyl alcohol to prepare a 2% solution. The solution was forced into a porous polytetrafluoroethylene tubing from the inner surface of the tubing. The porous tubing had been prepared Erom polytetra~luoroethylene by stretching and sintering and had an inside diameter of 4.3 mm, a thickness of 0.40 mm, a bubhle point of 0.25 kg/cm2 and a porosity of 80%. The porous tubing was air dried at 20C for 2 minutes, and then immersed for 2 minutes in a 4% aqueous solution of glyoxal to render the polyethyleneimine water-insoluble. The tubing was washed with water, dried, and then immersed in a 50% e-thanol solution of methyl iodide at 20C for 3 hours to quaternize the polyethylene-imine. The tubing was washed with water, and heated at 90C
1 for 30 minutes in distilled water to remove unreacted material.Furthermore, the tubing was washed with a 1% aqueous solution of sodium chloride, dried, and impregnated with an aqueous solution of heparin sodium in a concentration of 1000 units/ml to bind the heparin. Two hours later, a part Gf the tubing was taken as a sample. The sample was washed with water, and then contacted with a solution of toluidine blue indicator, whereupon it assumed a reddish violet color. Thus, the bonding of heparin was confirmed. The resulting tubing had a bubble point of 0.29 kg/cm2, A commercially available 30~ aqueous solution of poly-ethyleneimine (~.W.: about 50,000) was diluted with isopropyl alcohol ~o prepare a 7~ solution. The solut.ion was forced into the same type of porous polytekra~luoroethylene tubing as describ-ed in Example 1 from the inner surface o the tubing, dried in air at 20C for 2 minutes, and immersed for 2 minutes in a 5%
aqueous solution of glyoxal to render the polyethyleneimine water-insoluble. In the same manner as in Example 1, the tubing was subjected to a quaternization reaction and a heparin-binding treatment. The bonding of heparin was confirmed in the same manner as in Example 1. The resulti.ng tubing had a bubble point of 0.44 kg/cm2.
While the present invention has been described in detail with reference to specific emboidments thereof, it is apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and the scope of the present invention.
Claims (11)
1. A vascular prosthesis having a composite structure of a porous tubing of polytetrafluoroethylene with polyethyleneimine in the pores of the tubing, said polyethyleneimine being water-insolubilized with the amino groups quaternized and having heparin ionically bound thereto.
2. The vascular prosthesis of Claim 1, wherein the polyethyleneimine is microporous, water-insolublized, has the amino groups quaternized and has heparin ionically bound thereto.
3. The vascular prosthesis of Claim 1, wherein the polytetrafluoroethylene has a microstructure composed of fibers and nodes connected to one another by the fibers, and the microstructure of the outer surface of the tubing differs from the microstructure of the inner surface of the tubing.
4. The vascular prosthesis of Claim 3, wherein the outer surface of the porous tubing has an average fiber diameter at least two times larger than the average fiber diameter of the inner surface of the porous tubing.
5. The vascular prosthesis of Claim 3, wherein the direction of the fiber alignment of the inner surface of the porous tubing is more radially distributed than the direction of the fiber alignment of the outer surface of the porous tubing.
6. The vascular prosthesis of Claim 3, wherein the long axes of the nodes at the outside surface of the porous tubing are at least two times longer than the long axes of the nodes at the inner surface of the porous tubing.
7. The vascular prosthesis of Claim 3, wherein the pore diameter of the outside surface of the porous tubing is larger than the pore diameter of the inner surface of the porous tubing.
8. The vascular prosthesis of Claim 1, wherein said polyethyleneimine is present only in those pores of the porous tubing which are on the inner surface side of the porous tubing.
9. A process for producing a vascular prosthesis having a composite structure of a porous tubing of polytetrafluoro-ethylene with polyethyleneimine in the pores of the tubing, said polyethyleneimine being water-insolublized with the amino groups quaternized and having heparin ionically bound thereto, which comprises impregnating the pores of a porous tubing of polytetrafluoroethylenen with a solution of polyethyleneimine, water-insolubilizing the polyethyleneimine in the porous tubing, chemically quaternizing the amino groups of the water-insolubi-lized polyethyleneimine in the porous tubing, and then contacting the quaternized polyethyleneimine with a solution of heparin to bind the heparin ionically to the quaternized polyethylene-imine.
10. The process of Claim 9, wherein water-insolubilizing the polyethyleneimine comprises reacting the polyethyleneimine with a compound containing a carbonyl group.
11. The process of Claim 9, wherein chemically quaternizing the amino groups of the water-insolubilized polyethyleneimine comprises reacting the water-insolubilized polyethyleneimine with an alkyl halide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP79385/77 | 1977-07-01 | ||
| JP7938577A JPS5413694A (en) | 1977-07-01 | 1977-07-01 | Composite blood vessel prosthesis and method of producing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1110402A true CA1110402A (en) | 1981-10-13 |
Family
ID=13688390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA306,564A Expired CA1110402A (en) | 1977-07-01 | 1978-06-29 | Vascular prosthesis having a composite structure and a process for producing same |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4229838A (en) |
| JP (1) | JPS5413694A (en) |
| AU (1) | AU519350B2 (en) |
| BE (1) | BE868624A (en) |
| BR (1) | BR7804126A (en) |
| CA (1) | CA1110402A (en) |
| DE (1) | DE2828369B2 (en) |
| FR (1) | FR2395740A1 (en) |
| GB (1) | GB2000978B (en) |
| IT (1) | IT1105224B (en) |
| NL (1) | NL177656C (en) |
| SE (1) | SE423863B (en) |
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-
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- 1977-07-01 JP JP7938577A patent/JPS5413694A/en active Granted
-
1978
- 1978-06-28 DE DE2828369A patent/DE2828369B2/en active Granted
- 1978-06-29 NL NLAANVRAGE7807024,A patent/NL177656C/en not_active IP Right Cessation
- 1978-06-29 BR BR7804126A patent/BR7804126A/en unknown
- 1978-06-29 CA CA306,564A patent/CA1110402A/en not_active Expired
- 1978-06-30 BE BE188974A patent/BE868624A/en not_active IP Right Cessation
- 1978-06-30 FR FR7819631A patent/FR2395740A1/en active Granted
- 1978-06-30 AU AU37661/78A patent/AU519350B2/en not_active Expired
- 1978-06-30 SE SE7807436A patent/SE423863B/en not_active IP Right Cessation
- 1978-06-30 IT IT50119/78A patent/IT1105224B/en active
- 1978-07-03 GB GB7828665A patent/GB2000978B/en not_active Expired
- 1978-07-03 US US05/921,680 patent/US4229838A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IT1105224B (en) | 1985-10-28 |
| AU519350B2 (en) | 1981-11-26 |
| IT7850119A0 (en) | 1978-06-30 |
| SE423863B (en) | 1982-06-14 |
| AU3766178A (en) | 1980-01-03 |
| DE2828369C3 (en) | 1988-07-28 |
| NL177656C (en) | 1985-11-01 |
| BR7804126A (en) | 1979-04-10 |
| GB2000978B (en) | 1982-01-13 |
| JPS5413694A (en) | 1979-02-01 |
| SE7807436L (en) | 1979-03-01 |
| DE2828369B2 (en) | 1980-09-04 |
| GB2000978A (en) | 1979-01-24 |
| FR2395740A1 (en) | 1979-01-26 |
| US4229838A (en) | 1980-10-28 |
| BE868624A (en) | 1978-10-16 |
| FR2395740B1 (en) | 1982-03-05 |
| JPS5650581B2 (en) | 1981-11-30 |
| NL7807024A (en) | 1979-01-03 |
| NL177656B (en) | 1985-06-03 |
| DE2828369A1 (en) | 1979-01-11 |
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