WO1989011836A1

WO1989011836A1 - Implantable artifact and method of making

Info

Publication number: WO1989011836A1
Application number: PCT/US1989/002380
Authority: WO
Inventors: Hirotsugu Koge Yasuda
Original assignee: Biogold Inc.
Priority date: 1988-06-07
Filing date: 1989-06-06
Publication date: 1989-12-14
Also published as: JPH04501965A

Abstract

An artifact for implantation into a living animal body, said artifact or part thereof having a thin surface coating which is biocompatible where implanted, characterized in that said coating is comprised of a carbonaceous material which is amorphous and mainly consists of a three-dimensional network of carbon atoms covalently bound to each other and, covalently bound to said carbon atoms, other atoms selected from hydrogen and fluorine atoms, wherein the atomic ratio of (H+F) to C is less than about 1.5; and a method for the manufacture of such artifact.

Description

An lmplantable artifact and a method of making same.

The present invention relates to artifacts for permanent or temporary insertion or implantation into a living animal (including human) body, such artifacts or part thereof having a thin surface coating which is biocompatible at the site where the artifact is implanted. The invention also relates to a method of making such an implantable artifact.

BACKGROUND OF THE INVENTION

Artifacts or devices which are intended for use in a living animal body usually are made of materials having limited biocompatibility, such as non-thrombogenicity and compatibility vis-a-vis living tissue. Such artifacts are therefore generally coated with surface coatings for improving the biocompatibility, such coating being made without affecting other important properties of the artifact. In recent years such coating of implantable artifacts has been provided by so called plasma polymerization. Such technique has been used mainly when coating artifacts made of polymeric materials.

Plasma polymerization generally is based on introducing a gas comprising one or more polymerizable organic monomers into a vacuum zone, wherein the material to be coated is placed. The polymerizable monomers are then subjected to an electric discharge for initiating polymerization reactions by the generation of ions of free radicals reacting with each other and also with the substrate when made of an organic material to form a deposit on the substrate. The polymerizable monomers are often constituted by fluorinated hydrocarbons, such as tetrafluoro ethylene.

Although plasma polymerization for modifying biomaterials has been used as early as in the late 1960:ies relatively little work has been done until recent years, but presently the number of publications and patents is rapidly increasing and plasma polymerization has become increasingly interesting for improving the surface properties of implantable devices or artifacts.

As examples of close prior art there may be mentioned US patents 4,656,083 and 4,718,907, each relating to techniques for improving the biocompatibility of implantable devices or prostheses. Both patents relate to the use of fluorine-containing compounds as plasma polymerizable monomers, but both techniques suffer from shortcomings in regard to rendering the substrate sufficiently in non-thrombogenic or tissue-compatible. US patent 4,718,907 aims at providing improvement of the surface of the substrate by controlling the fluorine to carbon atomic ratio so that the coating on the interior surface of the tube has a higher ratio than the exterior surface. Moreover, this technique aims at providing for a fluorine to carbon ratio greater than 1,5. One could say that the basic concept of this prior art is to mimic or approach the properties of polytetrafluoroethylen (PTFE).

The object of the present invention is to provide new techniques for treating substrate materials for the purpose of improving their biocompatibility by subjecting the substrate material to plasma gas discharge in the presence of a monomeric gas capable of plasma polymerization under deposition of a biocompatible surface coating on the substrate.

Another object of the invention is to deposit by plasma polymerization onto the substrate a carbonaceous coating which is amorphous and mainly consists of a three-dimensional network of carbon atoms covalently bound to each other, other atoms being covalently bound to said carbon atoms which other atoms are selected from hydrogen and fluorine. Yet another object is to provide such carbonaceous coating, wherein the atomic ratio of hydrogen plus fluorine to carbon is less than about 1.3.

A further object of the invention is to provide a method for making an implantable device or artifact provided with a thin surface coating which is biocompatible at the site of implantation. Still another object is to provide such method wherein the exposed surface of the substrate is subjected to a plasma gas discharge in the presence of a monomeric gas containing selected monomers making the plasma polymerization capable of depositing onto the substrate a thin amorphous carbonaceous layer of improved biocompatibility.

SUMMARY OF THE INVENTION

Generally, it has been discovered that implantable artifacts can be provided with a very thin and uniform surface coating by the use of plasma polymerization. The coating obtained in accordance with the present invention is of a non- -crystalline i.e. amorphous nature, and is constituted by a three-dimensional carbon to carbon covalently bound network, in which the majority of the bonds are of the sp₃ type. To said carbon atoms there are covalently bound other atoms selected from hydrogen and fluorine atoms, and the atomic ratio of (H+F) to C shall be less than about 1.3.

The invention is largely based on the surprising discovery that biocompatibility through a plasma-deposited coating is substantially improved if the coating is comprised of a carbonaceous material which is amorphous and which has a structure which contrary to US patent 4,718,907 approaches that of diamond. As is generally known, diamond is a crystalline three-dimensional network of carbons solely joined by sp₃ carbon-carbon bonds. On the other hand, graphite is a two-dimensional planar network of carbons built up from both sp₃ and sp₂ bonds. The refractive index of diamond is about 2.3 and in the coating conceived by the present invention it is preferred that the refractive index is greater than about 1.6.

With regard to the carbon-to-carbon bonds these are thus predominantly of the sp₃ type, and it is particularly preferred that not more than about 25X of said carbon-to-carbon bonds are of the sp₂ type.

The techniques of the present invention make it possib le to deposit an extremely thin coating of a thickness generally less than about 1000 nm, preferably not more than about 100 nm. The coating is sufficiently flexible and can accordingly be deposited on any type of substrate useful for the present purpose, such as substrates made of organic or inorganic polymeric materials or non-polymeric inorganic materials, such as metallic, ceramic, glass or composite materials. The excellent adherence to the substrate and the flexibility of the coating makes it particularly suited for use in covering expandible stents, such as self-expanding stents of the type disclosed in US patent No. 4,655,771. The invention is also of particular interest in relation to further developments of such prostheses as disclosed in published UK patent application 2 189 150. (The disclosures of these specifications are incorporated herein by reference thereto). It was quite unexpected that one could obtain by plasma polymerization a coating of sufficient strength and adherence to endure the stress and strain associated with the use of such expandable stents. On organic polymeric substrates the adherence is also excellent, partly due to the fact that in the plasma polymerization deposition covalent bonds are formed between the carbon atoms of the coating and elements of the organic material. The present invention also provides for a method of making implantable artifacts comprising a substrate and a thin surface coating which is biocompatible in its environment. The method of the invention involves subjecting the exposed surface of the substrate to a plasma gas discharge in the presence of a monomeric gas containing monomers selected from hydrocarbons and halogenated hydrocarbons, optionally together with hydrogen, whereby there is deposited onto the substrate a thin amorphous carbonaceous layer having the desired biocompatibility, such as blood and tissue compatibility. These desired properties of the deposited coating are obtained by selecting the composition of said monomeric gas such as to form a surface coating wherein the atomic ratio (H+F) to C is less than about 1.3.

It is preferred to use in the method monomers selected from fluoπnated hydrocarbons and hydrocarbons having 1 to 6 carbon atoms. It is particularly preferred to use fluorinated hydrocarbons and hydrocarbons having 1, 2 or 3 carbon atoms. As examples of such monomers there may be mentioned tetrafluoroethylene, hexafluoroethane, perfluoropropylene, methane, ethane and such monomers can be used in different combmations with or without hydrogen to obtain varying atomic ratios (H+F) to C at levels less than about 1.5, preferably less than about 1.5.

Mixtures of tetrafluoroethylene and methane can be used in roughly equal proportions, and such mixtures may be diluted using hydrogen. Alternatively, solely a pure hydrocarbon may be used as a monomeric gas. It is also possible to use mixtures of methane and hydrogen. When using a halogenated hydrocarbon in combination with hydrogen the plasma discharge will result in reactions whereby a corresponding hydrogen halogenide, such as hydrofluoric acid, escapes in gaseous form. In the plasma polymerization process it is generally preferred that the monomeric gas is free from oxygen-containing constituents. Due to the presence of unpaired electrones, i.e. free-radicals, in the deposited coating some oxygen from the environment may be found on the surface of the coating but will not constitute any problem with regard to biocompatibility of the coating.

In this disclosure the term "biocompatible" has the meaning biologically non-interfering rather than any meaning in the direction of providing any specific bioactivity. Thus, the principal object of providing a surface coating in accord with this invention is to create a biologically inert surface of a non-interfering character.

Articles, devices or artifacts provided by the present invention have a surface coating with outstanding properties, such as hardness, chemical inertness, surface dynamic stabi lity, excellent bonding to the substrate, and the coating is furthermore a very good barrier to the underlying substrate. These properties provide for excellent biocompatibility, corrosion resistance and general protection of the substrate. Another advantage is the fact that the coating has good resistance to sterilization by irradiation at the energy level required, such as several Mrads, using γ- or β-radiation. The conditions for the plasma polymerization to deposit the coating on a substrate are not of a critical nature but it is preferred to use high plasma energy density expressed as Joules per kilogram monomers and hydrogen, such value preferably being above 1 GJ/kg. The minimum value varies with the type of monomeric gas used, and as examples there may be mentioned that when using methane as a monomer the value is about 8 GJ/kg, whereas when using fluorinated hydrocarbons together with hydrogen the lower value of about 1 can be used.

The reactor used for the plasma polymerization is quite generally of a conventional character but shall be designed to allow for sufficient residence time of reactor species in the plasma state, i.e. provision of sufficient kinetic path length before deposition occurs, and this can be achieved by combinations of plasma volume, system pressure and plasma energy density. The present disclosure will enable the skilled artisan to provide implantable artifacts, such as heart valves, vascular prostheses, stents, catheters and various other devices intended for implantation for a longer period of time. Among vascular prostheses there may be mentioned polymer-based ones, such as expanded PTFE (Goretex) grafts, knitted or woven polyester grafts, in particular small diameter grafts, such as 0 =10 mms or less. The biocompatible coating of such artifacts having a low (H+F) to C ratio will provide for excellent thromboresistance and tissue compatibility. The present techniques are useful also for coating filaments (mono- or polyfilaments or yarns) which are then braided, weaved or knitted to form the final product

The invention will now be further described below by non-limiting examples.

In the following examples the stents and grafts modified by plasma polymerization are exposed to flowing blood using a baboon arteriovenous shunt system described by Hanson et al., Arteriosclerosis 5:595, 1985. The medicinal implants were placed inside a 10 cm length of rigid-walled Teflon tubing (Small Parts Inc. Miami, Florida, USA). In all cases these Teflon tubings containing stents or grafts are placed between the arterial and venous silicone rubber tubing segments comprising a chronic femoral arteriovenous (A-V) shunt in baboons as described by Hanson et al. loc.cit. The thrombogenicity inregard to platelet adhesion of both untreated and plasma polymer modified artifacts or deplants is determined by dynamic scintillation camera imaging of the accumulation of autologous blood platelets labeled with Indιum-111-oxine following exposure to flowing blood in the baboon A-V shunt system. The results are expressed as the total number of platelets deposited over one hour according to the method described by Hanson et al., loc.cit.

EXAMPLES Example 1 A stent of the type described in UK patent application

2 189 150 having a diameter of 3.5 mm, a length of 30 mm ( 5 of filament = 0.08 mm, n = 16) is placed on a substrate holding device constituted by an aluminum disc having a diameter of 300 mm and a thickness of 1 mm and having equally spaced four openings of the dimension 40 mm x 155 mm. The stent is fastened in the opening of the sample holding disc by means of small clips located at both ends of the opening. The sample holding disc is placed at equidistance from two electrodes used in a Plasma Polymerization Apparatus of the type LCVD--12-400A, Shimadzu Corporation, Kyoto, Japan. The two electrodes are assisted by magnetic enhancement providing the maximum parallel component with respect to the electric field of a magnetic field of approximately 600 Gauss and the distance between the two electrodes is approximately 120 mm. The sample holding disc is rotated in such a manner that the stent will pass the center portion of plasma volume created by the two parallel electrodes at a rate of approximately 30 rpm. After evacuation of the reactor to approximately 1 mtorr methane gas is introduced into the reactor at a rate of 0.5 seem, and plasma polymerization is initiated by applying 150 watts. Plasma polymerization is sustained till a stationary thickness monitor, located near the edge of the rotating substrate holding disc indicates that the accumulated thickness of deposition onto the sensor reaches approximately 100 nm, corresponding to approximately 30 nm on the rotating stent. The coating prepared by the process has a refractive index of about 1.9 and an estimated value (F+H)/C of about 0.8.

In the biological testing five coated stents were used and compared to ten untreated control stents. At all time points over the 60 minute blood exposure period using the techniques described above platelet deposition onto the five treated stents is markedly reduced as compared to the number of platelets deposited onto the ten untreated control stents. For example, after 60 minutes exposure to flowing blood the untreated stents accumulated 3.8 + 0.8 x 10⁹ platelets (+ 1 SEM) while the treated stents accumulated only 1.3 + 0.7 x

10⁹ platelets, i.e. platelet deposition was reduced by 66% (p < 0.01, unpaired Student t-test).

The results of the platelet deposition experiments are illustrated in Fig. 1 of the drawing, wherein deposited platelets are plotted against blood exposure time in minutes.

Example 2

A vascular graft of the type Goretex (W.L.Gore & Associates Inc., 111., USA) of 4 mm i.d. and length 100 mm is snugly positioned within a glass tube which is connected to a vacuum pump and a gas inlet tube at the other end. Two elec trodes constituted by copper plates, width 5 mm, length 50 mm and thicknes 1 mm, are bent to surround a glass tube and are kept approximately 30 mm apart. These two electrodes are connected to 13.5MHz radio frequence power source in a floating mode. After the stent-containmg glass tube is evacuated to less than 1 mtorr a mixture of methane and hydrogen in a ratio of one to one is introduced into the reactor system at a flow rate of 1 seem, and rf power of 50 watts is applied to the electrodes. Plasma generated by the electrodes located at the upstream side of the graft penetrates into the inside of the graft tube, and a coating of amorphous carbonaceous film having a refractive index of 1.9 and a ratio (F+H)/C of about 1.0 is applied onto the inner surface of the substrate by sustaining the plasma for one minute. Four vascular grafts treated as described above are evaluated in four baboons by 60 minutes blood exposure. The four treated grafts show a marked reduction in platelet accumulation as compared to seven untreated control grafts. Thus, after one hour of blood exposure the treated grafts have accumulated only 1.4 + 0.5 x 10⁹ platelets (+ 1 SEM) as compared to the untreated grafts accumulating 10.6 + 1.6 x 10⁹ platelets per graft. This means that platelet deposition is reduced by 87. and this difference is statistically significant (p < 0.001, Student t-test). The results are illustrated in appended Fig. 2 wherein total deposited platelets are plotted against exposure time in minutes.

Example 3 Example 1 is repeated but using stainless steel stents having a diameter of 6 mm and a length of 150 mm. After evacuation of the reactor to approximately 1 mtorr a mixture of methane and hydrogen in the ratio of one to one is introduced into the reactor at a rate of 0.5 seem, and plasma polymerization is initiated by applying 150 watts. Plasma polymerization is sustained till a stationary thickness monitor indica tes an accumulated thickness of deposition of approximately 100 nm, corresponding to about 30 nm deposition on the rotating stent. The material prepared by this process has the refractive index 1.9, and estimated value (F+H)/C of approximately 0.8.

Five stents coated as described above are tested for a 60 minute blood exposure period in baboons, and the platelet deposition was compared to the deposition on untreated control stents. After 60 minutes of blood exposure the untreated stents accumulated 3.8 ± 0.8 x 10⁹ platelets (± 1 SEM), while the coated stents accumulated only 1.3 ± 0.6 x 10⁹ platelets, i.e. platelet deposition is reduced by 66% (p < 0.01, unpaired Student t-test).

The experimental results are shown in appended Fig. 3, wherein deposited platelets are plotted against blood exposure time in minutes.

Example 4

The same apparatus as used in Example 1 is used and stainless steel stents of the same type as in Example 3 are placed on the aluminum disc of the apparatus. However, the electrodes of the reactor are replaced by a hollow anode system designed as follows.

The hollow anode system consists of an aluminum cup, 100 mm x 100 mm and of 50 mm depth, the cup being connected to two aluminum plates, 100 mm x 50 mm, via dielectric materials (Macor, Corning Glass, Corning, NY, USA) in the plane of the opening side of the cup. One terminal of a radio frequence (rf) power supply is connected to the cup and another terminal is connected to the two plates. Monomeric gas is fed into the cup through an inlet, which is attached to the back side of the cup. The hollow anode system is placed parallel to the rotating disc maintaining a distance of approximately 30 mm. After the reactor is evacuated to approximately 1 mtorr, a mixture of methane and tetrafluoroethylen in a ratio of one to one is introduced at a flow rate of 0.5 seem, and plasma polymerization is initiated by applying 50 watts. The stent is coated uniformly after five minutes' operation. During this period the stent passes through plasma created in the space determined by the cup and the rotating plates, repeated passages being obtained at the rotating rate of approximately 30 rpm. A piece of silicons wafer is placed on the surface of the rotating disc to collect film sample for measurement of the refractive index by Elipsometry. The thin coating obtained has a refractive index of about 1.8 and a ratio (F+H)/C of about 0.7.

The biological properties of the coated stents are similar to those obtained with the stents treated according to Example 3.

Example 5

A stainless steel wire used for preparing the stainless steel stent treated according to Example 1 is coated in a continuous manner by using the plasma polymerization reactor described in Example 1. A feeding spool, on which approximately 100 meter of stainless steel wire is wound, and a take-up spool are placed in a vacuum vessel attached to the reactor through a vacuum joint located on the stainless steel skirt portion of the reactor. The wire is fed through the center portion of the inter electrode space five times and is rewound on the take-up spool at a linear speed of approximately one meter per minute. Identical conditions as to plasma polymerization as described in Example 1 are used for coating the wire. A uniform coating of homogeneous, amorphous carbonaceous film (F+H)/C approximately 0.8 is applied on the surface of the wire, and then the coated wire is used to braid the stent in accordance with the disclosure of UK patent application 2 189 150.

Claims

1. An artifact for implantation into a living animal body, said artifact or part thereof having a thin surface coating which is biocompatible where implanted, characterized in that said coating is comprised of a carbonaceous material which is amorphous and mainly consists of a three-dimensional network of carbon atoms covalently bound to each other and, covalently bound to said carbon atoms, other atoms selected from hydrogen and fluorine atoms, wherein the atomic ratio of (H+F) to C is less than about 1.5.

2 . An artifact according to claim 1, wherein the refractive index of said coating is greater than about 1.6.

3. An artifact according to claim 1 or 2, wherein said carbon-to-carbon bonds are predominantly of the sp₃ type.

4. An artifact according to claim 3, wherein not more than about 25% of said carbon-to-carbon bonds are of the sp2 type.

5. An artifact according to any preceding claim, wherein the said coating is substantially uniform and has a thickness of less than about 1000 nm, preferably < 100 nm.

6. An artifact according to any preceding claim, wherein its substrate is constituted by an organic or inorganic polymeric material.

7 . An artifact according to any preceding claim, wherein its substrate is constituted by an inorganic non-polymeric material.

8. An artifact according to claim 7, wherein its substrate is constituted by a metallic material.

9. An artifact according to claim 8, which is a self--expandable stent.

10. A method of making an artifact for implantation into a living animal body, said artifact comprising a substrate and a thin surface coating which is biocompatible where implanted, comprising: subjecting the exposed surface of said substrate to a plasma gas discharge in the presence of a monomeric gas con taming monomers selected from hydrocarbons and halogenated hydrocarbons, optionally together with hydrogen, to deposit onto the substrate a thin amorphous carbonaceous layer mainly consisting of a three-dimensional network of carbon atoms covalently bound to each other and, covalently bound to said carbon atoms, other atoms selected from hydrogen and fluorine atoms, the composition of said monomeric gas being such as to form a surface coating, wherein the atomic ratio of (H+F) to C is less than about 1.3.

11. A method according to claim 10, wherein said monomers are selected from fluoπnated hydrocarbons and hydrocarbons having 1 to 6 carbon atoms.

12. A method according to claim 11, wherein said monomers are selected from tetrafluoroethylene, hexafluoroethane, methane and ethane.

13. A method according to claim 12, wherein said monomeric gas comprises tetrafluoroethylene in combination with methane and/or hydrogen.

14. A method according to claim 12, wherein said monomeric gas mainly consists of methane.

15. A method according to claim 12, wherein said monomeric gas mainly consists of a mixture of tetrafluoroethylene and methane.

16. A method according to claim 12, wherein said monomeric gas mainly consists of methane and hydrogen.