Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
  • B05D1/00—Processes for applying liquids or other fluent materials
  • B05D1/62—Plasma-deposition of organic layers
• • 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
  • A61L33/0076—Chemical modification of the substrate
  • A61L33/0088—Chemical modification of the substrate by grafting of a monomer onto the substrate

Definitions

• a method of making a biocompatible prosthesis The present invention relates to a method of making a biocompatible hollow artifact with perforated walls made from a substrate of electro-conductive material, such as a metal.
• the surface of said substrate is intended for exposure to living animal tissue or blood.
• 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-à-vis living tissue or blood.
• animal refers in particular to mammals including man.
• 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.
• 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 perform a deposit on the substrate.
• the polymerizable monomers are often constituted by fluorinated hydrocarbons, such as tetrafluoro ethylene.
• the present invention deals exclusively with substrates made of electro-conductive materials, such as metallic materials, and furthermore, substrates which are hollow and have perforated walls.
• the invention is directed to tubular substrates of metallic materials.
• the main object of the present invention is to provide a new method of manufacturing biocompatible hollow artifacts with perforated walls made from a substrate of electro-conductive material by depositing a coating onto said substrate which results in improved biocompatibility at the site of implantation of such prosthesis into a living animal body.
• Another object of the invention is to enable manufacture of tubular artifacts with perforated walls made from a substrate of electro-conductive material using plasma gas discharge in a plasma zone containing a plasma polymerizable monomeric gas to form a biocompatible thin flexible coating on said substrate.
• Yet another object of the invention is to provide pro stheses, the substrates of which are coated with a carbonaceous coating of improved biocompatibility, such as non-thrombogenicity and tissue or blood compatibility.
• Still another object of the invention is to provide techniques for coating expandible tubular stents , such as self-expanding ones, with a thin flexible, strongly adhering coating of excellent biocompatibility.
• a substrate of metallic material whose surface is exposed to living animal tissue or blood is subjected to a plasma gas discharge in a plasma zone containing a plasma polymerizable monomeric gas. Such exposure is performed under relative movement between the plasma zone and the substrate.
• the volume of the plasma zone used must be of such a magnitude in relation to the volume of the substrate as to enable the substrate to move in or through the plasma zone under plasma polymerization without disturbing the plasma generation. It has been found that if the plasma zone volume is of the same order of magnitude as the substrate volume then the plasma generation will automatically cease due to the Fareday's cage phenomenon.
• the substrate volume is the volume contained within an imaginary space surface circumscribing the substrate of metallic material.
• said plasma zone volume is at least about ten times larger than said substrate volume and particularly at least about one hundred times larger than said volume.
• the substrate can be allowed to travel repeatedly into, through and out of said plasma zone, the number of passages being sufficient to provide by deposition a coating of the desired thickness on the substrate.
• the substrate can be moved within said plasma zone for a desired period of time.
• the substrate may be subjected to both translational and rotational movement in relation to the plasma zone. It is particularly preferred to impart to the substrate movement along a circular path.
• the present invention is applicable to the manufacture of any biocompatible tubular and perforated prosthesis based on a substrate of metallic material, it was particularly unexpected that it was possible to effectively coat by plasma polymerization so called stents of the selfexpanding type. Clearly, the coating is subjected to considerable stress and strain in connection with contraction and expansion of such tubular stent and it was therefore surprising that the adherence of the coating was of such a strong nature as to resist manipulation of the stent.
• the self-expanding tubular stent is composed of a plurality of individual rigid but flexible and elastic thread elements each of which extends in helix configuration along and around the centerline of said stent as a common axis, said stent being provided with a first number of thread elements having a common direction of winding and being axially displaced relative to each other, and with a second number of thread elements also axially displaced relative to each other but having an opposite direction of winding thus crossing said first number of thread elements.
• the crossing thread elements are preferably arranged in a braid-like configuration so as to impart stability to the stent. It is clear from said patent specifications that the diameter of the stent is variable under axial movement of the ends of the stent relative to each other.
• monomers selected from fluorinated 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.
• fluorinated hydrocarbons and hydrocarbons having 1, 2 or 3 carbon atoms As examples of such monomers there may be mentioned tetrafluoroethylene, hexafluoroethane, perfluoroprop ⁇ lene, methane, ethane and such monomers can be used in different combinations with or without hydrogen.
• tetrafluoroethylene and methane can be used in roughly equal proportions, and such mixtures may be diluted using hydrogen.
• solely a pure hydrocarbon may be used as a monomeric gas.
• mixtures of methane and hydrogen are also possible to use mixtures of methane and hydrogen.
• 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.
• the monomeric gas is free from oxygen-containing constituents. Due to the presence of un-paired electrones, i.e. free-radicals, in the deposited coating some oxygen from the environment may be found on the surface of the coa ting but will not constitute any problem with regard to biocompatibility of the coating.
• biocompatible has the meaning biologically non-interfering rather than any meaning in the direction of providing any specific bioactivity.
• 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.
• 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 metallic stents 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).
• 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 ba boons as described by Hanson et al. loc.cit.
• the thrombogenicity in regard to platelet adhesion of both untreated and plasma polymer modified artifacts or deplants is determined by dynamaic scintillation camera imaging of the accumulation of autologous blood platelets labeled with Ind ⁇ um-111-ox ⁇ ne 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.
• 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.
• 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.
• Example 2 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 indicates an accumulated thickness of deposition of approximately 100 nm, corresponding to about 30 nm deposition on the rotating stent. The atomic ratio (F+H)/C is approximately 0.9. Five stents coated as described above are tested for a
• Example 2 The same apparatus as used in Example 1 is used and stainless steel stents of the same type as in Example 2 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 ⁇ 100 mm and of 50 mm depth, the cup being connected to two aluminum plates, 100 mm ⁇ 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.
• 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 silicone 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 the atomic ratio (F+H)/C is approximately 0.9.
• the biological properties of the coated stents are si milar to those obtained with the stents treated according to Example 2.
• Example 4 The same procedure as described in Example 1 is used but the stent is mounted on the rotating plate by nylon clips in order to electrically isolate the stent from the rotating disc, which becomes cathode vis-à-vis the anode. With this electrically floating stent coating of plasma polymer is achieved with similar efficiency and the coating obtained has similar biological properties as that of Example 1.

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Hematology (AREA)
• Public Health (AREA)
• Surgery (AREA)
• Physics & Mathematics (AREA)
• Engineering & Computer Science (AREA)
• Plasma & Fusion (AREA)
• Materials For Medical Uses (AREA)
• Media Introduction/Drainage Providing Device (AREA)
• Prostheses (AREA)

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• 1989
  • 1989-06-06 WO PCT/US1989/002379 patent/WO1989011919A1/en not_active Application Discontinuation
  • 1989-06-06 JP JP1506853A patent/JPH04501964A/ja active Pending
  • 1989-06-06 EP EP19890907480 patent/EP0452316A4/en not_active Withdrawn

Non-Patent Citations (1)

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