WO2017000712A1 - 植入医疗器械预制件、植入医疗器械及其制备方法 - Google Patents

植入医疗器械预制件、植入医疗器械及其制备方法 Download PDF

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WO2017000712A1
WO2017000712A1 PCT/CN2016/083420 CN2016083420W WO2017000712A1 WO 2017000712 A1 WO2017000712 A1 WO 2017000712A1 CN 2016083420 W CN2016083420 W CN 2016083420W WO 2017000712 A1 WO2017000712 A1 WO 2017000712A1
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solution
medical device
metal substrate
implantable medical
ions
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PCT/CN2016/083420
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English (en)
French (fr)
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戚祖强
贾小乐
陈卓
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先健科技(深圳)有限公司
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Priority to US15/579,336 priority Critical patent/US10786599B2/en
Priority to EP16817076.9A priority patent/EP3318287B1/en
Publication of WO2017000712A1 publication Critical patent/WO2017000712A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/01—Filters implantable into blood vessels
    • A61F2/0108—Both ends closed, i.e. legs gathered at both ends
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/01—Filters implantable into blood vessels
    • A61F2002/018—Filters implantable into blood vessels made from tubes or sheets of material, e.g. by etching or laser-cutting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0014—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof using shape memory or superelastic materials, e.g. nitinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0028—Shapes in the form of latin or greek characters
    • A61F2230/006—Y-shaped
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body

Definitions

  • the invention relates to the field of medical instruments, in particular to an implanted medical device preform, an implanted medical device and a preparation method thereof.
  • Pulmonary embolism is a common disease with high mortality. According to statistics, the mortality rate of untreated pulmonary embolism is 20%-30%. The annual new cases account for 0.2% of the total population. With a population of 100 million, there are about 2.7 million new patients each year.
  • Vena cava filters (hereinafter referred to as filters) have been clinically proven to reduce the incidence of pulmonary embolism.
  • the filter is usually made of metal and is divided into a permanent implant filter and a temporary filter. Regardless of the filter, protein adsorption, platelet adhesion, etc. may occur due to contact with blood and vascular endothelium after implantation for a period of time.
  • Endothelial cleft eventually forming a thrombus that causes venous vascular occlusion or causes recurrence of pulmonary embolism.
  • the above-mentioned endothelial climbing also damages the intima of the blood vessel when the filter is taken out, increasing the difficulty of taking out.
  • An anti-endothelial polymer film layer such as a polyethylene glycol-like (PEG-like) film, is applied to the surface of the metal substrate of the filter, and the thickness of the polymer film layer is usually less than 3 micrometers, which can improve the bio-adhesion of the filter surface.
  • the performance of the filter inhibits the interaction between the surface of the filter and the inner wall of the blood vessel and the blood, reduces the creepage and wrapping of the vascular endothelial cells on the surface of the filter, and reduces the possibility of thrombus formation, thereby allowing the filter to remain completely open and further temporary. Good recovery performance of the filter.
  • the polymer film layer (hereinafter may be simply referred to as a film layer) and the metal substrate (hereinafter simply referred to as a substrate) surface of the filter are generally bonded together by a mechanical bond having a small force and a van der Waals force.
  • the film layer directly covers the surface of the filter, the film layer cannot be firmly and effectively adhered to the metal surface, and is easily peeled off from the metal surface. This is especially important for filters.
  • the filter is attached to the delivery cable at the factory and pre-installed in the introducer sheath, typically a smaller 6F introducer sheath.
  • the filter is placed in the delivery sheath prior to implantation of the filter, and the filter is implanted into the body through the delivery sheath.
  • the filter is compressed and filtered. Stronger compression and friction between the various parts of the device, and the filter will inevitably also rub against the inner wall of the delivery sheath when transported in a delivery sheath of about 550 mm in length; if the membrane and the substrate There is not enough bonding force. After this series of extrusion and friction, the film layer will be easy to fall off, and even the large piece may be detached from the substrate.
  • the surface of the metal substrate will be in direct contact with the inner wall of the blood vessel, and the endothelial cells easily climb and wrap the metal surface, which is not conducive to recovery; and the detached membrane layer may block the pulmonary capillaries as the blood flows into the lungs. Or for patients with heart defects, it is possible to enter the brain through the atrial septal defect, block the blood vessels in the brain, and cause life-threatening. Therefore, increasing the bonding force between the film layer and the surface of the metal substrate, preventing the film layer from falling off during and after implantation, is essential for implanted medical devices including a polymer film layer and a metal substrate.
  • the technical problem to be solved by the present invention is to provide an implantable medical device and a preparation method thereof, and a defect that the polymer film layer for preventing endothelium-cracking implanted on the surface of a medical device cannot be stably combined with a metal substrate.
  • the technical solution adopted by the present invention to solve the technical problem thereof is to provide an implanted medical device comprising a metal substrate and an anti-endothelial polymer film layer covering the surface of the metal substrate, at least a part of the surface of the metal substrate A surface modification layer is provided, the surface modification layer comprising an implanted ion, and the metal matrix is connected to the polymer film layer by the doping ions.
  • the doped ions include at least one of oxygen ions, hydroxide ions, carbon ions, nitrogen ions, and carbon nitrogen ions.
  • the thickness of the surface modification layer does not exceed 4 ⁇ m.
  • the surface modification layer has a thickness of 2 nm to 1 ⁇ m.
  • the incorporated ions are chemically bonded to carbon atoms in the polymeric film layer.
  • the doped ions are in the metal matrix
  • the metal element is chemically bonded; or the incorporated ion is located in a lattice gap of the metal substrate.
  • the polymer film layer comprises a polyethylene glycol-like polymer, a polyethylene oxide-like polymer, a polyethylene glycol-like derivative, and a polyoxyethylene derivative. At least one of them.
  • the metal matrix comprises at least one of cobalt, chromium, iron, nickel, molybdenum, titanium, platinum, rhodium.
  • the invention also provides a method for preparing an implanted medical device, comprising: modifying at least a portion of a surface of a metal substrate to form a surface modification layer, wherein the surface modification layer comprises doped ions, and the metal matrix passes through the doping The implanted ions are attached to the polymer film layer.
  • the doping ions include at least one of an oxygen ion, a hydroxide ion, a carbon ion, a nitrogen ion, and a carbon nitrogen ion.
  • the at least a portion of the surface of the metal substrate is modified to form a surface modification layer, including placing the metal substrate in an infusion solution to perform a soaking reaction to form the Surface modified layer.
  • the doping ions include at least one of an oxygen ion and a hydroxide ion.
  • the infusion solution includes a hydrogen peroxide solution, a mixed solution of an aqueous hydrogen peroxide solution and an alkaline solution, a mixed solution of an aqueous hydrogen peroxide solution and an acidic solution, and an alkaline solution.
  • the metal substrate is placed in different soaking liquids to perform at least two soaking reactions to form the surface modified layer.
  • the soaking solution comprises a hydrogen peroxide aqueous solution, a mixed solution of an aqueous hydrogen peroxide solution and an alkaline solution, a mixed solution of an aqueous hydrogen peroxide solution and an acidic solution, an acidic solution, and an alkaline solution.
  • the acidic solution when the soaking liquid includes the acidic solution, includes an HF solution, a HCl solution, a H 2 SO 4 solution, a HNO 3 solution, and H.
  • the at least a portion of the surface of the metal substrate is modified to form a surface modification layer, including implanting the doped ions into the metal substrate by plasma implantation.
  • the surface forms the surface modification layer.
  • the doping ions include at least one of an oxygen ion and a nitrogen ion.
  • the doping ions include at least one of a carbon ion, a nitrogen ion, and a carbon nitrogen ion.
  • the present invention also provides an implantable medical device preform comprising a metal substrate having a surface modification layer disposed on at least a portion of the metal substrate, the surface modification layer including incorporated ions.
  • the incorporated ions can be bonded to carbon atoms in the polymer.
  • the incorporated ions comprise at least one of oxygen ions, hydroxide ions, carbon ions, nitrogen ions, carbon nitrogen ions.
  • the thickness of the surface modification layer does not exceed 4 ⁇ m.
  • the metal matrix comprises at least one of the metallic elements cobalt, chromium, iron, nickel, molybdenum, titanium, platinum, rhodium.
  • an implantable medical device a method of manufacturing the same, and an implanted medical device preform for preparing the implanted medical device, at least a portion of the metal substrate has a surface modification layer in the surface modification layer Including the doping ions, the metal matrix can be connected to the polymer film layer through the doping ions, so that the polymer film layer is not easy to fall off during the transportation process, thereby effectively exhibiting the anti-endothelial climbing in the body.
  • FIG. 1 is a schematic structural view of an implanted medical device according to an embodiment of the present invention.
  • Figure 2 is a schematic cross-sectional view of a portion of Figure 1 in contact with a blood vessel wall;
  • FIG. 3 shows a flow chart of a method of preparing an implantable medical device in accordance with an embodiment of the present invention.
  • the filter 1 in the figure includes a plurality of support rods 11 And a plurality of connecting rods 12 disposed on two sides of the supporting rod 11, each supporting rod 11 is evenly distributed in the circumferential direction, one end of the plurality of connecting rods 12 is connected with the supporting rod 11, and the other ends are collectively aggregated to form a Y-shaped structure and finally form a near-center end. 13 or telecentric end 14.
  • the support rod 11 After the radial deployment, the support rod 11 is in direct contact with the blood vessel wall, and the filter 1 is stably placed in the blood vessel by the radial support force to avoid displacement.
  • the support rod 11 is further provided with an anchor thorn to penetrate the blood vessel wall through the anchor thorn to position the filter.
  • the filter may be other structures.
  • a connecting rod may be provided only on one side of the support rod, one end of each connecting rod is connected with the supporting rod, the other end is gathered together to form a telecentric end, and the other side of the supporting rod is open. structure.
  • At least a portion in contact with the blood vessel wall includes a metal substrate 21 and an endothelium-resistant polymer film layer 22 covering the metal substrate 21;
  • the metal base 21 of this portion has a surface modification layer 211 containing a doped ion, and the metal substrate 21 is connected to the polymer film layer 22 by doping ions.
  • the portion of the implanted medical device that is not in contact with the blood vessel wall, such as the connecting rod 12 in FIG. 1, may have the same structure as the support rod 11. It is also possible to have a metal substrate 21 structure without a surface modification layer, or a metal substrate 21 having no surface modification layer directly covering the polymer film layer 22.
  • the implantable medical device can also be described as being: the implanted medical device comprises an implanted medical device preform and a polymer film layer covering the preform; the preform comprises a metal substrate, the metal substrate at least A portion has a surface modification layer containing incorporated ions, and the incorporated ions in the metal matrix can be bonded to carbon atoms in the polymer.
  • the base body can be radially compressed and pushed into the sheath tube and then transported through the sheath tube to a predetermined position, such as a lumen of the blood vessel; the base body can be restored from the sheath of the conveyor to a radially expanded state, conforming to the lumen
  • the inner wall is fixed in the lumen. After implantation into the lumen, the metal matrix blocks and holds the thrombus, thereby filtering the thrombus.
  • the surface modification layer is the outermost surface of the metal substrate and has a thickness of not more than 4 ⁇ m, and is usually 2 nm to 1 ⁇ m.
  • the doped ions in the surface modification layer include at least one of oxygen ions, hydroxide ions, carbon ions, nitrogen ions, and carbon nitrogen ions, and the doped ions may be combined with the metal element Me in the metal matrix (Me includes Not limited to the metal elements cobalt, chromium, iron, nickel, molybdenum, titanium, platinum, rhodium, may include one or more metal elements) direct bonding, such as forming Me-O, Me-OH, Me-C, Me- One or more of the N, Me-CN bonds; or may be located in the lattice gap of the metal matrix to form a gap filler.
  • the concentration of the incorporated ions gradually decreases from the surface of the metal substrate to the inside of the metal substrate, and the concentration is highest at the outermost surface of the metal substrate.
  • the doped ions at the outer surface of the surface modification layer have no adjacent atoms on the outward side of the surface, so that the doped ions at this point have a part of chemical bonds extending into the space to form dangling bonds.
  • the metal substrate is covered with a polymeric film layer, the dangling bonds will readily bond chemically to the ions/atoms in the polymeric film layer.
  • the thickness of the polymer film layer is usually less than 3 micrometers, and may be at least one of a polyethylene glycol-like polymer, a polyethylene oxide-like polymer, a polyethylene glycol-like derivative, and a polyoxyethylene-like derivative.
  • a polyethylene glycol-like polymer e.g., polyethylene glycol (PEG), polyethylene glycol (PEG-like), polyethylene glycol, crown ether (such as 12-crown ether-4), polyglycol ether, polyvinyl alcohol, poly Vinyl ether, polyethylene oxide (PEO), poly At least one of ethylene oxide alcohol, polyoxyethylene ether, polyoxyethylene alcohol-like, and polyvinylidene oxide-like.
  • the polymer film layer on the outermost surface of the medical device can significantly improve the hydrophilicity of the surface of the device, reduce the roughness, and greatly reduce the adsorption of bacteria and proteins on the surface of the material, prevent endothelial climbing, and also increase the material. Anticoagulant properties.
  • the polymer film layer is rich in carbon atoms.
  • ions such as oxygen ions, hydroxide ions, carbon ions, nitrogen ions, carbon nitrogen ions.
  • the bonding energy of the above chemical bond is 0.5 to 10 eV, which is much larger than the bonding energy between van der Waals forces of 0.1 to 0.5 eV. Therefore, under the bonding energy, the same external force is difficult to separate the metal substrate from the polymer film layer.
  • the metal substrate can be firmly bonded to the polymer film layer to achieve a stable and effective adhesion of the polymer film layer to the metal substrate.
  • the polymer film layer can be effectively connected to the metal substrate by the incorporation of ions, so that the filter enters and exits the sheath tube and after the filter is implanted into the lumen, the filter occurs.
  • the possibility of the polymer film layer falling off is extremely low, and the polymer film layer can effectively function to improve the anti-endothelial climbing performance of the filter.
  • step 101 at least a portion of the surface of the metal substrate is modified to form The surface modification layer forms an implanted medical device preform.
  • the surface modification layer has a thickness of not more than 4 ⁇ m, usually 2 nm to 1 ⁇ m, and includes doping ions, and the doping ions include at least one of oxygen ions, hydroxide ions, carbon ions, nitrogen ions, and carbon nitrogen ions.
  • the concentration of the incorporated ions gradually decreases from the surface of the metal substrate to the inside, and the concentration is greatest at the outer surface.
  • the doped ions at the surface have a part of chemical bonds extending into the space to form dangling bonds, which are easily bonded to other ions/atoms to form new chemical bonds, so that the metal matrix can be attached to the polymer film layer by doping ions.
  • the metal substrate may be surface modified by a chemical surface treatment to form a surface modification layer.
  • the metal substrate can be placed in the infusion solution, and a surface modification layer is formed on the surface by chemical reaction with the infusion solution.
  • the surface modification may be completed by immersing the reaction in only one soaking solution.
  • the optional soaking solution includes a hydrogen peroxide solution, a mixed solution of an aqueous solution of hydrogen peroxide and an alkaline solution, a mixture of an aqueous solution of hydrogen peroxide and an acidic solution, and an alkaline solution.
  • the temperature of the soaking liquid during the reaction may be normal temperature, or may be heated at a high temperature or even at a boiling temperature.
  • the surface modification may also be performed by immersing the reaction multiple times in a plurality of different soaking liquids.
  • the soaking solution used at this time includes a mixed solution of a hydrogen peroxide solution, a hydrogen peroxide solution and an alkaline solution, a mixed solution of a hydrogen peroxide solution and an acidic solution,
  • the acidic solution and the alkaline solution; the temperature of the soaking liquid during the reaction may be normal temperature, or may be heated at a high temperature or even at a boiling temperature.
  • the acidic solution includes HF solution, HCl solution, H 2 SO 4 solution, HNO 3 solution, H 3 PO 4 solution, HClO 4 solution, HBr solution, HI solution, HCN solution, H 2 SO 3 solution, HNO 2 solution, At least one of a CH 3 COOH solution and a H 2 SeO 4 solution; the same basic solution may be used in the above two reaction methods, the alkaline solution including a NaOH solution, a NaHCO 3 solution, a KOH solution, and Ca(OH) 2 solution, Na 2 CO 3 solution, NH 3 .H 2 O solution, NH 4 HCO 3 solution and at least one K 2 CO 3 solution.
  • the original metal substrate may be subjected to a soaking reaction in a H 2 O 2 solution or a boiling water solution containing hydrogen peroxide to form a surface-modified layer containing Me-O and Me-OH bonds on the surface of the metal or alloy.
  • the soaking liquid may also be a mixture of hydrogen peroxide and an alkaline solution, and after the immersion reaction, a surface-modified layer containing Me-O and Me-OH bonds is formed on the surface of the metal substrate.
  • the original metal matrix may be first subjected to a soaking reaction in an aqueous hydrogen peroxide solution to form a surface-modified layer containing Me-O and Me-OH bonds; and then placed in an alkaline solution for secondary soaking reaction, further modified on the surface.
  • Me-O and Me-OH bonds are formed in the layer.
  • the original metal substrate may be first placed in an acidic solution to perform a soaking reaction to activate the surface of the metal substrate; then immediately placed in a boiling alkali solution for a second soaking reaction to form Me in the surface modified layer. -O and Me-OH bonds.
  • the surface modification layer containing Me-O and/or Me-OH bonds may be formed on the surface of the metal substrate by the immersion reaction, and the oxygen ions and hydroxide ions located at the outer surface of the surface modification layer may be combined with the polymer.
  • the doping ions may be implanted into the surface of the metal substrate by a plasma implantation method to form a surface modification layer.
  • a plasma implantation method to form a surface modification layer.
  • the original metal substrate is placed in a vacuum apparatus, and the glow discharge power source is turned on under a preset vacuum degree and an oxygen or nitrogen-containing atmosphere to generate an oxygen plasma or a nitrogen plasma, a highly reactive oxygen plasma.
  • a nitrogen plasma reacts with the metal to form a Me-O or Me-N bond on the surface of the metal substrate to form a surface-modified layer containing a Me-O or Me-N bond.
  • the doping ions may be implanted into the surface of the metal substrate by ion implantation to form a surface modification layer.
  • the original metal substrate can be placed in a high-energy ion implantation apparatus for ion-injection. Specifically, electrons generated by a hot filament (commonly used tungsten filament) source bombard the gas molecules to be injected under a preset vacuum.
  • a hot filament commonly used tungsten filament
  • the bombarded particles gas molecules or atoms, or solid targets
  • the charged ions are subjected to Lorentz forces in the magnetic field, the trajectories are deflected, and the desired ions are Sorting; using the strong electric field of the accelerator to accelerate the ions to obtain the required energy; finally, ions are injected into the surface of the metal substrate through a focusing lens and a beam scanning device.
  • At least one of carbon ions, nitrogen ions, and carbon nitrogen ions can be implanted into the surface of the metal substrate to form a surface modification layer.
  • nitrogen gas may be used as the bombarded gas, and N element may be implanted into the surface of the metal substrate to form a Me-N bond;
  • a hydrocarbon gas such as methane or acetylene may be used as a carbon source to generate C ions, and a C element may be injected into the surface of the metal substrate to form Me.
  • a mixed gas of a hydrocarbon gas such as nitrogen, methane or acetylene may be simultaneously introduced, and C and N elements are simultaneously injected into the surface of the metal substrate to form a Me-CN bond;
  • graphite may be used as a carbon source to inject the surface of the metal substrate The C element is made of graphite as a target, and after being bombarded by electrons, a C ion beam is formed and injected into the surface of the metal substrate to form a Me-C bond.
  • At least one of carbon ions, nitrogen ions, and carbon nitrogen ions located at an outer surface of the surface modification layer may be directly chemically bonded to carbon atoms in the polymer to form at least one of CN, CC, and C-CN bonds, whereby, the metal substrate and the polymer film layer are firmly joined together, so that the polymer film layer is not easily peeled off from the metal substrate.
  • the doping ions can be directly bonded not only to the metal elements in the metal matrix, but also to the interstitial spaces of the metal matrix to form interstitials.
  • the C ions in the surface-modified layer may form a Me-C bond with the metal element or may be located in the lattice gap of the metal substrate.
  • step 102 the surface of the metal substrate having the surface modification layer in step 101 is coated with a polymer film layer to bond the metal substrate and the polymer film layer through the doping ions contained in the surface modification layer.
  • the polymer film layer may be coated on the surface of the transition body and the metal substrate by chemical vapor deposition (for example, radio frequency plasma enhanced chemical vapor deposition RF-PECVD and microwave electron cyclotron resonance plasma assisted chemical vapor deposition ECR-CVD).
  • the obtained polymer film comprises at least one of a polyethylene glycol-like polymer, a polyethylene oxide-like polymer, a polyethylene glycol-like derivative, and a polyoxyethylene-like derivative; specifically, polyethylene glycol, Polyethylene glycol, polyethylene glycol, crown ether, polyethylene glycol, polyvinyl alcohol, polyvinyl ether, polyethylene oxide, polyoxyethylene alcohol, polyoxyethylene ether, polyoxyethylene alcohol, polycondensation At least one of oxyethylene ethers.
  • monomer molecules can be ionized and reacted to form a polymer film layer coated metal substrate.
  • the monomer molecule comprises at least one of ethylene glycol, diethylene glycol, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, and tetraethylene glycol dimethyl ether.
  • the metal substrate may be cleaned prior to step 101.
  • the metal substrate may be placed in the same apparatus as in step 102 to plasma clean the metal substrate under vacuum.
  • the metal substrate can be ultrasonically cleaned in advance.
  • the original metal substrate is firstly plasma-cleaned, the original metal substrate is placed on the sample holder in the vacuum chamber, vacuum is drawn to below 10 Pa, and argon gas having a flow rate of 20 to 200 sccm is introduced to maintain the pressure of the vacuum chamber. Below 10 Pa, the surface of the original metal substrate is plasma cleaned for 5 to 60 minutes under conditions of a radio frequency plasma power of 50 W to 1000 W and a bias voltage of 10 V to 800 V, and then the RF power source is turned off to take out the original metal substrate.
  • the original metal substrate may be ultrasonically cleaned, and the original metal substrate is placed in a container containing ethanol, acetone or other cleaning agent, and then the container is placed in an ultrasonic cleaning tank, and ultrasonically cleaned for 5 to 30 minutes. , take out the original metal matrix and dry it with compressed air or hot air;
  • step 101 an aqueous solution of hydrogen peroxide is used as an soaking liquid to perform a soaking reaction on the cleaned original metal substrate.
  • concentration of H 2 O 2 in the solution is 10 to 35%
  • the immersion reaction time is 1 minute to 180 minutes.
  • the immersion reaction is completed, it is taken out, ultrasonically washed with distilled water for 5 to 30 minutes, and dried by hot air or purified compressed air.
  • a metal substrate having a surface-modifying layer containing Me-O and Me-OH bonds was obtained.
  • a polymer film layer is coated on the outermost surface of the surface of the metal substrate.
  • a radio frequency plasma enhanced chemical vapor deposition (RF-PECVD) method is used, and the polymer film layer is a PEG-like film layer.
  • RF-PECVD radio frequency plasma enhanced chemical vapor deposition
  • argon gas is introduced at a flow rate of 10 to 100 sccm, and the atmospheric pressure in the reaction chamber is controlled to be 2 to 7 Pa, which is 1 to 2 Pa lower than the pressure set by the reaction deposition; and the heating is turned on (the heating temperature is set to 80 to 150 ° C).
  • the needle valve of the triethylene glycol dimethyl ether reaction cylinder adjusts the pressure of the vacuum chamber to the deposition set pressure, and the reaction deposition set pressure is 3 to 9 Pa; the RF power supply is adjusted to 20 W to 200 W, and the bias voltage is 10 V to 200 V.
  • the deposition time under the above conditions is 10 to 60 minutes. After the end, close all reaction gases, RF power and bias, turn off the vacuum pump and take out the filter.
  • a schematic cross-sectional view of the filter prepared in the first embodiment is similar to that of FIG. 2, the surface of the metal substrate 21 of the filter is coated with a PEG-like film layer 22 to prevent endothelial climbing; the surface modification layer 211 of the metal substrate 21 and a PEG-like film
  • the layer 22 is in direct contact, and the atomic layer thickness of the outermost layer of the surface modification layer 211 includes oxygen ions and hydroxide ions with dangling bonds, and the oxygen ions and hydroxide ions are easily associated with the PEG-like film layer 22.
  • the original metal substrate is subjected to two soaking reactions using two different soaking liquids.
  • the first immersion reaction uses a H 2 O 2 solution having a mass concentration of 10 to 35% as a soaking solution, and the immersion reaction time is 1 minute to 60 minutes; the second immersion reaction uses a mass concentration of the alkaline substance of 5 to 35%.
  • the NaOH and KOH mixed solution has a reaction soaking time of 1 minute to 180 minutes.
  • the metal substrate is taken out and washed and dried, thereby obtaining a metal substrate having a surface modified layer containing Me-O bond. And Me-OH bond.
  • the original metal substrate is subjected to two soaking reactions using two different soaking liquids.
  • the first immersion reaction uses a hydrofluoric acid having a mass fraction of 1% to 50% and a mixed solution of nitric acid having a molar concentration of 0.1 to 8 mol/L as a soaking solution, and the immersion reaction time is 0.5 minutes to 10 minutes; the second immersion reaction is used.
  • the NaOH strong alkali solution with a mass concentration of 5 to 35% is used as the soaking solution, and the immersion reaction time is from 1 minute to 180 minutes.
  • the metal substrate is taken out, washed, and then dried by hot air or purified compressed air, thereby obtaining a surface.
  • the surface modification layer comprising a Me-O bond and a Me-OH bond.
  • a mixture of a H 2 SO 4 solution having a molar concentration of 0.1 to 5 mol/L and a H 2 O 2 solution having a molar concentration of 0.1 to 9 mol/L is used as a soaking solution, soaking.
  • the reaction time is from 0.5 minutes to 20 minutes.
  • the metal substrate is taken out and washed and dried, thereby obtaining a metal substrate having a surface-modifying layer containing a Me-O bond and a Me-OH bond.
  • the doping ions are implanted into the original metal substrate by plasma implantation to form a surface modification layer on the surface of the metal substrate.
  • the original metal substrate is placed on the sample holder in the vacuum chamber, and the vacuum chamber is evacuated to 10.0 Pa.
  • argon gas flow rate of 10 ⁇ 100sccm, oxygen flow rate of 20 ⁇ 200sccm, can also be used alone in the flow of 20 ⁇ 200sccm oxygen
  • the vacuum chamber pressure is kept below 20.0Pa, open the RF plasma power supply
  • the surface of the original metal substrate is subjected to oxygen plasma implantation for 5 to 60 minutes under the conditions of a power of 10 W to 1000 W and a bias voltage of 10 V to 800 V.
  • a metal substrate having a surface-modifying layer containing Me-O bonds is thus obtained.
  • a surface modification layer is formed on the surface of the metal substrate by nitrogen plasma implantation.
  • the original metal substrate is placed on a sample holder in a vacuum chamber, and the vacuum chamber is evacuated to below 10.0 Pa, and a mixed gas of argon gas and nitrogen gas is introduced, the flow rate of the argon gas is 10 to 100 sccm, and the flow rate of the nitrogen gas is 20 to 200 sccm.
  • Nitrogen gas with a flow rate of 20 to 200 sccm can be used alone to keep the pressure of the vacuum chamber below 20.0 Pa, and the RF plasma power source can be turned on.
  • the surface of the original metal substrate is subjected to nitrogen at a power of 10 W to 1000 W and a bias voltage of 10 V to 800 V. Plasma injection is 5 to 60 minutes. A metal substrate having a surface-modified layer containing Me-N bonds is thus obtained.
  • the nitrogen ions in the surface modification layer are easily bonded to the carbon atoms in the polymer film layer to form a C-N chemical bond, by which the metal matrix can be firmly bonded to the polymer film layer without being easily peeled off.
  • the original metal substrate is placed on the sample holder in the vacuum chamber of the ion implantation apparatus, and the vacuum chamber is evacuated to 1 ⁇ 10 ⁇ 4 Pa or less, and 5 to 50 sccm of methane gas is introduced to maintain the vacuum.
  • the ion implantation power source is turned on, the ion implantation energy is set to 10 to 500 keV, and the injection time is 3 to 60 minutes.
  • a metal substrate having a surface-modifying layer containing Me-C bonds is thus obtained.
  • the nitrogen ions in the surface modification layer are easily bonded to the carbon atoms in the polymer film layer to form a CC chemical bond, by which the metal matrix can be firmly bonded to the polymer film layer without being easily peeled off.
  • the original metal substrate is placed on a sample holder in a vacuum chamber of the ion implantation apparatus, and the vacuum chamber is evacuated to 1 ⁇ 10 ⁇ 4 Pa or less, and a high-purity graphite target is used as a carbon source to open the ions.
  • the power is injected, the ion implantation energy is set to 10 to 500 keV, and the injection time is 3 to 60 minutes.
  • a metal substrate having a surface modification layer is obtained, and the carbon ions in the surface modification layer are easily bonded to carbon atoms in the polymer film layer to form a CC chemical bond, and the metal matrix can be combined with the polymer film layer by the bonding Firmly connected together, not easy to fall off.
  • the original metal substrate is placed on the sample holder in the vacuum chamber of the ion implantation apparatus, and the vacuum chamber is evacuated to 1 ⁇ 10 ⁇ 4 Pa or less, and 2 to 30 sccm of nitrogen gas and 4 to 60 sccm are introduced.
  • the methane gas is kept at a vacuum of 1 ⁇ 10 -3 Pa or less, and the ion implantation power source is turned on.
  • the ion implantation energy is set to 10 to 500 keV, and the injection time is 3 to 60 minutes.
  • the carbon ions and nitrogen ions in the surface modification layer are easily bonded to carbon atoms in the polymer film layer to form at least one of CC and CN chemical bonds, through the bond
  • the metal substrate can be firmly connected to the polymer film layer without being easily peeled off.
  • the original metal substrate is first surface-modified to form a surface modification layer, and then the metal matrix is coated with an anti-endothelial polymer film layer.
  • the doped ions in the surface modification layer may be bonded to carbon atoms in the polymer film layer to form a CC bond, a CO bond, a C-OH bond, a CN bond, and a C-CN.
  • the bond energy of the chemical bond is much larger than the bond energy and mechanical bond energy between the molecule and the molecule, so that the polymer film layer can be firmly bonded to the metal matrix.
  • the polymer film layer can be firmly connected to the metal substrate, so that the produced filter is not easily peeled off during the process of entering and exiting the sheath and during implantation.

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Abstract

一种植入医疗器械（1）及其制备方法，以及用于制备上述植入医疗器械（1）的植入医疗器械预制件。该植入医疗器械（1）包括金属基体（21）和覆盖金属基体（21）表面的防内皮爬覆的聚合物膜层（22），金属基体（21）的至少一部分表面设有表面改性层（211），表面改性层（211）中包含掺入离子，金属基体（21）通过掺入离子与聚合物膜层（22）连接。由于金属基体（21）可通过掺入离子与聚合物膜层（22）连接，使得聚合物膜层（22）在输送过程中不易脱落，从而能在体内有效发挥防内皮爬覆功能。

Description

植入医疗器械预制件、植入医疗器械及其制备方法 技术领域
本发明涉及医疗器械领域，尤其涉及一种植入医疗器械预制件、植入医疗器械及其制备方法。
背景技术
肺栓塞(PE)是一种常见疾病，病死率高，有资料统计，不经治疗的肺栓塞的死亡率为20％-30％；每年新增病例约占总人口的0.2％，以我国13.5亿人口计算，每年约有270万新增患者。腔静脉滤器(以下简称滤器)在临床上被证实可降低肺栓塞的发生率。滤器通常由金属制成，分为永久植入滤器和临时性滤器，无论是哪种滤器，在植入腔静脉一段时间后，因与血液和血管内皮接触，可能发生蛋白质吸附、血小板粘附等内皮爬覆，最终形成血栓导致静脉血管堵塞，或导致肺栓塞再发生。尤其对于临时性滤器，上述内皮爬覆还会在滤器取出时损伤血管内膜，增加取出难度。
在滤器的金属基体表面附上防内皮爬覆的聚合物膜层，例如类聚乙二醇(类PEG)薄膜，该聚合物膜层的厚度通常小于3微米，可以提高滤器表面抗生物粘附的性能，抑制滤器表面与血管内壁和血液的相互作用，降低血管内皮细胞在滤器表面的爬覆和包裹，以及降低发生促凝形成血栓的可能，从而可以使滤器保持完全开放，并进一步实现临时滤器良好的回收性能。
然而，聚合物膜层(以下可简称为膜层)与滤器的金属基体(以下可简称为基体)表面之间一般通过作用力较小的机械结合和范德华力结合在一起。当膜层直接覆盖于滤器表面上时，膜层无法稳固有效地附着在金属表面上，容易从金属表面上脱落。对于滤器而言这点尤为重要。不同于其它的植入医疗器械，例如封堵器或支架，出厂时，滤器与输送钢缆连接，预装在导引鞘内，通常为较小的6F导引鞘。手术中，在植入滤器之前，需将滤器装入输送鞘内，并通过输送鞘将滤器植入人体。在将滤器收入输送鞘的过程中滤器受力被压缩，滤 器各部位之间会发生比较强烈的挤压和摩擦，再加上滤器在通常长度为550mm左右的输送鞘中输送时不可避免地也将与输送鞘的内壁产生摩擦；如若膜层与基体之间的结合力不够，经过这一系列挤压和摩擦后膜层将易于脱落，甚至可能大片从基体上脱离。
膜层脱离后的金属基体表面将与血管内壁直接接触，内皮细胞容易爬覆和包裹金属表面，从而不利于回收；并且脱落的膜层可能随着血流进入肺部而堵塞肺部毛细血管，或者对于心脏缺损患者，有可能通过房间隔缺损进入大脑，堵塞脑部血管，引起生命危险。因此，提高膜层与金属基体表面之间的结合力，防止膜层在输送过程中和植入后脱落，对于包括聚合物膜层和金属基体的植入医疗器械至关重要。
发明内容
本发明要解决的技术问题在于，针对现有技术植入医疗器械表面的防内皮爬覆的聚合物膜层无法与金属基体稳固结合的缺陷，提供了一种植入医疗器械及其制备方法、以及用于制备上述植入医疗器械的植入医疗器械预制件。
本发明解决其技术问题所采用的技术方案是：提供了一种植入医疗器械，包括金属基体和覆盖所述金属基体表面的防内皮爬覆的聚合物膜层，所述金属基体的至少一部分表面设有表面改性层，所述表面改性层中包含掺入离子，所述金属基体通过所述掺入离子与所述聚合物膜层连接。
在依据本发明实施例的植入医疗器械中，所述掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种。
在依据本发明实施例的植入医疗器械中，所述表面改性层的厚度不超过4μm。
在依据本发明实施例的植入医疗器械中，所述表面改性层的厚度为2nm～1μm。
在依据本发明实施例的植入医疗器械中，所述掺入离子与所述聚合物膜层中的碳原子化学键合。
在依据本发明实施例的植入医疗器械中，所述掺入离子与所述金属基体中 的金属元素化学键合；或者所述掺入离子位于所述金属基体的晶格间隙中。
在依据本发明实施例的植入医疗器械中，所述聚合物膜层包括类聚乙二醇聚合物、类聚氧化乙烯聚合物、类聚乙二醇衍生物、类聚氧化乙烯衍生物中的至少一种。
在依据本发明实施例的植入医疗器械中，所述金属基体包括钴、铬、铁、镍、钼、钛、铂、钽中的至少一种。
本发明还提供了一种植入医疗器械的制备方法，包括对金属基体的至少一部分表面改性形成表面改性层，所述表面改性层中包含掺入离子，所述金属基体通过所述掺入离子与所述聚合物膜层连接。
在依据本发明实施例的植入医疗器械的制备方法中，所述掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种。
在依据本发明实施例的植入医疗器械的制备方法中，所述对金属基体的至少一部分表面改性形成表面改性层，包括将所述金属基体置于浸泡液中进行浸泡反应形成所述表面改性层。
在依据本发明实施例的植入医疗器械的制备方法中，所述掺入离子包括氧离子和氢氧根离子中的至少一种。
在依据本发明实施例的植入医疗器械的制备方法中，所述浸泡液包括双氧水溶液、双氧水溶液与碱性溶液的混合液、双氧水溶液与酸性溶液的混合液、以及碱性溶液。
在依据本发明实施例的植入医疗器械的制备方法中，将所述金属基体分别置于不同的所述浸泡液中进行至少两次浸泡反应形成所述表面改性层。
在依据本发明实施例的植入医疗器械的制备方法中，所述浸泡液包括双氧水溶液、双氧水溶液与碱性溶液的混合液、双氧水溶液与酸性溶液的混合液、酸性溶液、以及碱性溶液。
在依据本发明实施例的植入医疗器械的制备方法中，当所述浸泡液包括所述酸性溶液时，所述酸性溶液包括HF溶液、HCl溶液、H2SO4溶液、HNO3溶液、H3PO4溶液、HClO4溶液、HBr溶液、HI溶液、HCN溶液、H2SO3溶液、HNO2溶液、CH3COOH溶液、和H2SeO4溶液中的至少一种；所述碱性溶 液包括NaOH溶液、NaHCO3溶液、KOH溶液、Ca(OH)2溶液、Na2CO3溶液、NH3.H2O溶液、NH4HCO3溶液和K2CO3溶液中的至少一种。
在依据本发明实施例的植入医疗器械的制备方法中，所述对金属基体的至少一部分表面改性形成表面改性层，包括采用等离子体注入法将所述掺入离子注入所述金属基体表面形成所述表面改性层。
在依据本发明实施例的植入医疗器械的制备方法中，所述掺入离子包括氧离子和氮离子中的至少一种。
在依据本发明实施例的植入医疗器械的制备方法中，所述对金属基体的至少一部分表面进行改性形成表面改性层，包括采用离子注入法将所述掺入离子注入所述金属基体表面形成所述表面改性层。
在依据本发明实施例的植入医疗器械的制备方法中，所述掺入离子包括碳离子、氮离子和碳氮离子中的至少一种。
本发明还提供了一种植入医疗器械预制件，包括金属基体，所述金属基体的至少一部分上设有表面改性层，所述表面改性层中包括掺入离子。
在依据本发明实施例的植入医疗器械预制件中，所述掺入离子可与聚合物中的碳原子键合。
在依据本发明实施例的植入医疗器械预制件中，所述掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种。
在依据本发明实施例的植入医疗器械预制件中，所述表面改性层的厚度不超过4μm。
在依据本发明实施例的植入医疗器械预制件中，所述表面改性层的厚度为2nm～1μm。
在依据本发明实施例的植入医疗器械预制件中，所述金属基体包括金属元素钴、铬、铁、镍、钼、钛、铂、钽中的至少一种。
在依据本发明实施例的植入医疗器械及其制备方法、以及用于制备上述植入医疗器械的植入医疗器械预制件中，金属基体的至少一部分具有表面改性层，表面改性层中包含掺入离子，金属基体可通过该掺入离子与聚合物膜层连接，使聚合物膜层在输送过程中不易脱落，从而能在体内有效发挥防内皮爬覆 功能。
附图说明
下面将结合附图及实施例对本发明作进一步说明，附图中：
图1是本发明实施例的植入医疗器械的结构示意图；
图2是图1中与血管壁接触的部分的截面示意图；
图3示出了依据本发明实施例的植入医疗器械的制备方法的流程图。
具体实施方式
为了对本发明的技术特征、目的和效果有更加清楚的理解，现以滤器为例，对照附图详细说明本发明的具体实施方式。本领域的普通技术人员应当知晓，以滤器为例并不是对本发明的限制，其他任何植入医疗器械(例如管腔支架和封堵器)，只要基于本发明的教导实现，均落在本发明的保护范围之内。
如图1所示，依据本发明实施例的植入医疗器械1(以滤器为例)至少一部分需在植入体内后与血管壁直接接触，例如，图中的滤器1包括多个支撑杆11和设于支撑杆11两侧多个连接杆12，各支撑杆11沿周向均布，多个连接杆12的一端与支撑杆11连接，另一端一并汇聚形成Y型结构并最终形成近心端13或远心端14。径向展开后，上述支撑杆11与血管壁直接接触，通过径向支撑力使得滤器1稳定地设于血管中，避免发生移位。支撑杆11上还设有锚刺，以通过锚刺刺入血管壁内，定位滤器。当然，图中示出的结构仅用作举例，并不是对本发明的限制。滤器还可为其他结构，例如，可仅在支撑杆的一侧设置连接杆，各连接杆的一端与支撑杆连接，另一端一并汇聚形成远心端，而支撑杆的另一侧为开放结构。
参见图2，植入医疗器械中，至少与血管壁接触的部分(例如图1中的支撑杆11)包括金属基体21和包覆金属基体21的防内皮爬覆的聚合物膜层22；其中该部分的金属基体21具有表面改性层211，表面改性层211中包含掺入离子，金属基体21通过掺入离子与聚合物膜层22连接。植入医疗器械中未与血管壁接触的部分，例如图1中的连接杆12，可采用与支撑杆11相同的结构， 也可为不具有表面改性层的金属基体21结构，或者也可为不具有表面改性层的金属基体21上直接覆盖聚合物膜层22。
结构不变的情况下，还可将上述植入医疗器械阐述为：植入医疗器械包括植入医疗器械预制件和覆盖该预制件的聚合物膜层；预制件包括金属基体，金属基体的至少一部分具有表面改性层，表面改性层中包含掺入离子，金属基体中的掺入离子可与聚合物中的碳原子键合。
金属基体(以下可简称为基体)可由生物相容性较好的316L不锈钢、镍钛合金、金属钛、Phynox合金(钴、铬、铁、镍、钼合金)、钽合金中的一种制备而成，可通过设置基体的结构或采用记忆合金材料(例如镍钛合金)制备基体，使基体具有径向压缩状态和径向展开状态。可将基体径向压缩、并推入鞘管内，然后经由鞘管输送至预定位置如血管管腔内；基体从输送器的鞘管中释放后可恢复形变至径向展开状态，贴合管腔内壁以固定于管腔内。植入管腔后，金属基体可阻挡并置留血栓，从而实现对血栓的过滤。
表面改性层为金属基体的最外层表面，厚度不超过4μm，通常为2nm～1μm。表面改性层中的掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种，该掺入离子可与金属基体中的金属元素Me(Me包括但不限于金属元素钴、铬、铁、镍、钼、钛、铂、钽，可以包括一种或多种金属元素)直接键合，例如形成Me-O、Me-OH、Me-C、Me-N、Me-CN键中的一种或多种；也可以位于金属基体的晶格间隙中，形成填隙子。
掺入离子的浓度从金属基体的表面向金属基体内部逐渐减少，在金属基体的最外层表面处浓度最高。该表面改性层外表面处的掺入离子在表面向外的一侧没有近邻原子,因此该处的掺入离子有一部分化学键伸向空间形成悬空键。当金属基体上覆盖聚合物膜层时，该悬空键将易于与聚合物膜层中的离子/原子化学键合。
具体而言，聚合物膜层的厚度通常小于3微米，可以是类聚乙二醇聚合物、类聚氧化乙烯聚合物、类聚乙二醇衍生物、类聚氧化乙烯衍生物中的至少一种。具体可以是聚乙二醇(PEG)、类聚乙二醇(PEG-like)、聚乙二醚、冠醚(例如12-冠醚-4)、类聚乙二醚、聚乙烯醇、聚乙烯醚、聚氧化乙烯(PEO)、聚 氧化乙烯醇、聚氧化乙烯醚、类聚氧化乙烯醇、类聚氧化乙烯醚中的至少一种。医疗器械最外层表面覆盖的聚合物膜层可显著改善器械表面的亲水性，降低粗糙度，并能极大地减少细菌和蛋白质在材料表面的吸附，防止内皮爬覆，同时还可以增加材料的抗凝血性。
聚合物膜层中富含碳原子，当聚合物膜层覆盖金属基体而与金属基体直接接触后，掺入离子(例如氧离子、氢氧根离子、碳离子、氮离子、碳氮离子)易于与聚合物膜层中的碳原子直接化学键合。金属基体外表面处的掺入离子的悬空键与聚合物膜层中的碳原子键合，形成C-C键、C-O键、C＝O键、C-OH键、C-N键、C-CN等化学键中的至少一种，使得聚合物膜层与金属基体之间通过该化学键(例如共价键)连接。上述化学键的键合能为0.5～10eV，远远大于范德华力之间的键合能量0.1～0.5eV，因此，在此键合能下，相同的外力难于将金属基体与聚合物膜层分离，金属基体可以稳固地与聚合物膜层结合在一起，从而实现聚合物膜层稳固有效地附着在金属基体上。
依据本发明的滤器在植入管腔后，因聚合物膜层可以通过掺入离子稳固而有效地与金属基体连接，所以在滤器进出鞘管的过程中以及在滤器植入管腔后，发生聚合物膜层脱落的可能极低，聚合物膜层可以有效发挥作用，提高滤器的抗内皮爬覆性能。
图3示出了依据本发明实施例的植入医疗器械(以滤器为例)的制备方法100的流程图，如图3所示，步骤101中，对金属基体的至少一部分表面进行改性形成表面改性层，形成植入医疗器械预制件。该表面改性层的厚度不超过4μm，通常为2nm～1μm，包含掺入离子，该掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种，掺入离子的浓度从金属基体的表面向内部逐渐减少，在外表面处浓度最大。表面处的掺入离子有一部分化学键伸向空间形成悬空键，该悬空键易与其它离子/原子键合形成新的化学键，因此金属基体可通过掺入离子与聚合物膜层连接。
可采用化学表面处理法对金属基体进行表面改性形成表面改性层。具体地，可将金属基体置于浸泡液中，通过与浸泡液进行化学反应在表面形成表面改性层。可只在一种浸泡液中浸泡反应一次完成表面改性，此时可选用的浸泡 液包括双氧水溶液、双氧水溶液与碱性溶液的混合液、双氧水溶液与酸性溶液的混合液、以及碱性溶液；反应时浸泡液的温度可以是常温，也可以高温加热甚至达沸腾温度。也可在多种不同的浸泡液中分别浸泡反应多次完成表面改性，此时所使用的浸泡液包括双氧水溶液、双氧水溶液与碱性溶液的混合液、双氧水溶液与酸性溶液的混合液、酸性溶液以及碱性溶液；反应时浸泡液的温度可以是常温，也可以高温加热甚至达沸腾温度。其中，酸性溶液包括HF溶液、HCl溶液、H2SO4溶液、HNO3溶液、H3PO4溶液、HClO4溶液、HBr溶液、HI溶液、HCN溶液、H2SO3溶液、HNO2溶液、CH3COOH溶液、和H2SeO4溶液中的至少一种；上述两种反应方法中可使用相同的碱性溶液，该碱性溶液包括NaOH溶液、NaHCO3溶液、KOH溶液、Ca(OH)2溶液、Na2CO3溶液、NH3.H2O溶液、NH4HCO3溶液和K2CO3溶液中的至少一种。
例如，可将原始的金属基体在H2O2溶液或者含双氧水的沸水溶液进行浸泡反应，使金属或合金表面形成含Me-O和Me-OH键的表面改性层。浸泡液还可以采用双氧水和碱性溶液的混合液，浸泡反应后在金属基体的表面形成含Me-O和Me-OH键的表面改性层。也可以首先将原始的金属基体在双氧水溶液中进行浸泡反应，形成含Me-O和Me-OH键的表面改性层；随后再置于碱性溶液中进行二次浸泡反应，进一步在表面改性层中形成Me-O和Me-OH键。类似地，可首先将原始的金属基体置于酸性溶液中进行浸泡反应以对金属基体的表面进行活化处理；随后立刻置于沸腾碱溶液中进行二次浸泡反应，在表面改性层中形成Me-O和Me-OH键。
上述通过浸泡反应可以在金属基体的表面形成包含Me-O和/或Me-OH键的表面改性层，位于表面改性层外表面处的氧离子和氢氧根离子可与聚合物中的碳原子直接化学键合，形成C-O、C-OH和C＝O键中的至少一种，从而稳固地将金属基体与聚合物膜层连接在一起，使得聚合物膜层不易从金属基体上脱落。
可采用等离子体注入法将掺入离子注入到金属基体表面形成表面改性层。例如，将原始的金属基体置于真空设备内，在预设的真空度和含氧气或氮气气氛下，开启辉光放电电源，产生氧等离子体或氮等离子体，高活性氧等离子体 或氮等离子体与金属反应，在金属基体表面形成Me-O或Me-N键，从而形成含Me-O或Me-N键的表面改性层。位于表面改性层外表面处的氧离子和氮离子可与聚合物中的碳原子直接化学键合，形成C-O、C＝O和C-N键中的至少一种，从而稳固地将金属基体与聚合物膜层连接在一起，使得聚合物膜层不易从金属基体上脱落。
可采用离子注入法将掺入离子注入到金属基体表面形成表面改性层。例如，可将原始的金属基体置于高能离子注入设备中进行掺入离子的注入，具体地，在预设真空度下，采用热灯丝(常用钨丝)源产生的电子轰击待注入的气体分子或原子、或固体靶材，被轰击的粒子(气体分子或原子、或固体靶材)离化形成离子；带电离子在磁场中受洛伦兹力的作用，运动轨迹发生偏转，将所需离子分选出来；利用加速器的强电场使离子加速获得所需的能量；最后通过聚焦透镜和束流扫描装置将离子注入金属基体的表面。
通过该方法，可将碳离子、氮离子和碳氮离子中的至少一种注入到金属基体表面形成表面改性层。例如，可使用氮气作为被轰击气体，向金属基体表面注入N元素，形成Me-N键；可使用甲烷、乙炔等烃类气体作为碳源产生C离子，向金属基体表面注入C元素，形成Me-C键；可同时通入氮气、甲烷、乙炔等烃类气体的混合气体，向金属基体的表面同时注入C和N元素，形成Me-CN键；可使用石墨作为碳源向金属基体表面注入C元素，将石墨做成靶材，经电子轰击后形成C离子束，注入金属基体表面，形成Me-C键。
位于表面改性层外表面处的碳离子、氮离子和碳氮离子中的至少一种可与聚合物中的碳原子直接化学键合，形成C-N、C-C和C-CN键中的至少一种，从而稳固地将金属基体与聚合物膜层连接在一起，使得聚合物膜层不易从金属基体上脱落。
当然，掺入离子不仅可以直接与金属基体中的金属元素键合，还可位于金属基体的晶格间隙中，形成填隙子。以C掺入离子为例，表面改性层中的C离子既可以与金属元素形成Me-C键，也可位于金属基体的晶格间隙中。
步骤102中，采用聚合物膜层包覆步骤101中具有表面改性层的金属基体表面，从而通过表面改性层中包含的掺入离子连接金属基体和聚合物膜层。
可采用化学气相沉积法(例如射频等离子增强化学气相沉积RF-PECVD和微波电子回旋共振等离子体辅助化学气相沉积ECR-CVD)在过渡体和金属基体表面覆盖聚合物膜层。制得的聚合物膜包括类聚乙二醇聚合物、类聚氧化乙烯聚合物、类聚乙二醇衍生物、类聚氧化乙烯衍生物中的至少一种；具体可以是聚乙二醇、类聚乙二醇、聚乙二醚、冠醚、类聚乙二醚、聚乙烯醇、聚乙烯醚、聚氧化乙烯、聚氧化乙烯醇、聚氧化乙烯醚、类聚氧化乙烯醇、类聚氧化乙烯醚中的至少一种。
例如，在采用化学气相沉积法制备聚合物膜层过程中，可使单体分子发生电离并反应聚合形成聚合物膜层包覆金属基体。其中，单体分子包括乙二醇、二乙二醇、乙二醇二甲醚、二乙二醇二甲醚、三乙二醇二甲醚、以及四乙二醇二甲醚中的至少一种。
为了进一步提高滤器的性能，还可在步骤101之前先对金属基体进行清洗，例如可将金属基体置于实施步骤102的同一装置中，在真空条件下等离子清洗金属基体。除此之外，还可以对金属基体事先进行超声波清洗。
实施例一
在步骤101之前首先对原始的金属基体进行等离子清洗，将原始的金属基体放入真空室内的样品架上，抽真空至10Pa以下，通入流量为20～200sccm的氩气，使真空室压力保持在10Pa以下，在射频等离子功率为50W至1000W、偏压10V至800V的条件下，对原始的金属基体表面使用等离子清洗5～60分钟，然后关闭射频电源，取出原始的金属基体。或者也可对原始的金属基体进行超声波清洗，将原始的金属基体放入装有乙醇、丙酮或其它清洗剂的容器内，然后将该容器放入超声波清洗槽内，超声清洗5～30分钟后，取出原始的金属基体并使用压缩空气或热风吹干干燥；
步骤101中，采用双氧水溶液作为浸泡液，对清洗后的原始金属基体进行浸泡反应。该溶液中H2O2的质量浓度为10～35％，浸泡反应时间为1分钟至180分钟，浸泡反应结束后取出，采用蒸馏水超声清洗5～30min，用热风或净化压缩空气吹干干燥，由此获得具有表面改性层的金属基体，该表面改性层中包含Me-O和Me-OH键。
步骤102中，在金属基体表面的最外层包覆聚合物膜层，本实施例中采用射频等离子增强的化学气相沉积(RF-PECVD)法，该聚合物膜层为类PEG膜层。具体地，以流量10～100sccm通入氩气，控制反应室内的气氛压力为2～7Pa，比反应沉积设定的压力低1～2Pa；打开经加热(加热温度设定为80～150℃)的三乙二醇二甲醚反应气瓶的针阀调节真空室压力至沉积设定压力，反应沉积设定压力为3～9Pa；调节射频电源功率至20W～200W、偏压10V～200V，在上述条件下沉积时间10～60分钟。结束后关闭所有反应气体、射频电源及偏压，关闭真空泵并取出滤器成品。
实施例一中制得的滤器的截面示意图与图2类似，该滤器的金属基体21表面包覆类PEG膜层22，以防止内皮爬覆；金属基体21的表面改性层211与类PEG膜层22直接接触，表面改性层211最外层的几个原子层厚度内包含带悬空键的氧离子和氢氧根离子，该氧离子和氢氧根离子易与类PEG膜层22中的碳原子键合，形成C-O、C＝O和C-OH化学键中的至少一种，通过该键合，金属基体21可以与类PEG膜层22稳固地连接在一起，而不易脱落。
实施例二
与实施例一不同的是，本实施例的步骤101中使用H2O2和NaOH溶液的混合液作为浸泡液，该混合液中H2O2的质量浓度为10～35％，碱性物质的质量浓度为5～35％，浸泡反应时间为1分钟至180分钟，浸泡反应后取出金属基体，采用蒸馏水超声清洗5～30min，最后室温干燥，由此获得具有表面改性层的金属基体，该表面改性层中包含Me-O键和Me-OH键。表面改性层中的氧离子和氢氧根离子易与聚合物膜层中的碳原子键合，形成C-O、C＝O和C-OH化学键中的至少一种，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例三
与实施例一不同的是，本实施例的步骤101中使用两种不同的浸泡液分别对原始的金属基体进行两次浸泡反应。第一浸泡反应使用质量浓度为10～35％的H2O2溶液作为浸泡液，浸泡反应时间为1分钟至60分钟；第二次浸泡反应使用碱性物质的质量浓度为5～35％的NaOH和KOH混合溶液，反应浸泡 时间为1分钟至180分钟，浸泡反应后取出金属基体，并清洗干燥，由此获得具有表面改性层的金属基体，该表面改性层中包含Me-O键和Me-OH键。表面改性层中的氧离子和氢氧根离子易与聚合物膜层中的碳原子键合，形成C-O、C＝O和C-OH化学键中的至少一种，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例四
与实施例一不同的是，本实施例的步骤101中使用两种不同的浸泡液分别对原始的金属基体进行两次浸泡反应。第一浸泡反应使用质量分数为1％～50％的氢氟酸和摩尔浓度为0.1～8mol/L的硝酸混合溶液作为浸泡液，浸泡反应时间为0.5分钟至10分钟；第二次浸泡反应使用质量浓度为5～35％的NaOH强碱溶液作为浸泡液，浸泡反应时间为1分钟至180分钟，浸泡反应后取出金属基体，清洗后进行热风或净化压缩空气吹干干燥，由此获得具有表面改性层的金属基体，该表面改性层中包含Me-O键和Me-OH键。表面改性层中的氧离子和氢氧根离子易与聚合物膜层中的碳原子键合，形成C-O、C＝O和C-OH化学键中的至少一种，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例五
与实施例一不同的是，本实施例的步骤101中使用摩尔浓度为0.1～5mol/L的H2SO4溶液和0.1～9mol/L的H2O2溶液的混合液作为浸泡液，浸泡反应时间为0.5分钟至20分钟，浸泡反应后取出金属基体，并清洗干燥，由此获得具有表面改性层的金属基体，该表面改性层中包含Me-O键和Me-OH键。表面改性层中的氧离子和氢氧根离子易与聚合物膜层中的碳原子键合，形成C-O、C＝O和C-OH化学键中的至少一种，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例六
与实施例一不同的是，本实施例的步骤101中采用等离子体注入法将掺入离子注入至原始的金属基体中，从而在金属基体的表面形成表面改性层。实施中将原始的金属基体置于真空室内的样品架上，真空室内抽真空至10.0Pa以 下；通入氩气及氧气混合气体，氩气流量10～100sccm，氧气流量为20～200sccm，也可单独使用流量为20～200sccm氧气，使真空室压力保持在20.0Pa以下，开启射频等离子电源，在功率为10W至1000W、偏压为10V至800V的条件下，对原始的金属基体表面进行氧等离子注入5～60分钟。由此获得具有表面改性层的金属基体，该表面改性层中包含Me-O键。表面改性层中的氧离子易与聚合物膜层中的碳原子键合，形成C-O、C＝O化学键中的至少一种，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例七
与实施例六不同的是，本实施例的101步骤中采用氮等离子体注入在金属基体的表面形成表面改性层。具体地，将原始的金属基体置于真空室内的样品架上，真空室抽真空至10.0Pa以下，通入氩气及氮气混合气体，氩气流量10～100sccm，氮气流量为20～200sccm，也可单独使用流量为20～200sccm的氮气，使真空室压力保持在20.0Pa以下，开启射频等离子电源，在功率为10W至1000W、偏压10V至800V的条件下，对原始的金属基体表面进行氮等离子注入5～60分钟。由此获得具有表面改性层的金属基体，该表面改性层中包含Me-N键。表面改性层中的氮离子易与聚合物膜层中的碳原子键合，形成C-N化学键，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例八
与实施例一不同的是，本实施例的步骤101中采用离子体注入法将掺入离子注入至原始的金属基体中，从而在金属基体的表面形成表面改性层。实施中，将原始的金属基体置于离子注入设备的真空室内的样品架上，真空室抽真空至1×10-4Pa以下，通入5～50sccm的氮气，保持真空在1×10-3Pa以下，开启离子注入电源，离子注入能量设定为10～500keV，注入时间为3～60分钟。由此获得具有表面改性层的金属基体，该表面改性层中包含Me-N键。表面改性层中的氮离子易与聚合物膜层中的碳原子键合，形成C-N化学键，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例九
与实施例八不同的是，将原始的金属基体置于离子注入设备的真空室内的样品架上，真空室抽真空至1×10-4Pa以下，通入5～50sccm甲烷气体，保持真空在1×10-3Pa以下，开启离子注入电源，离子注入能量设定为10～500keV，注入时间3～60分钟。由此获得具有表面改性层的金属基体，该表面改性层中包含Me-C键。表面改性层中的氮离子易与聚合物膜层中的碳原子键合，形成C-C化学键，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例十
与实施例八不同的是，将原始的金属基体置于离子注入设备的真空室内的样品架上，真空室抽真空至1×10-4Pa以下，使用高纯石墨靶作为碳源，开启离子注入电源，离子注入能量设定为10～500keV，注入时间3～60分钟。由此获得具有表面改性层的金属基体，该表面改性层中一部分注入的碳元素与金属元素Me形成Me-C键，一部分注入的碳元素作为填隙子位于金属基体的晶格间隙中。由此获得具有表面改性层的金属基体，表面改性层中的碳离子易与聚合物膜层中的碳原子键合，形成C-C化学键，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
实施例十一
与实施例八不同的是，将原始的金属基体置于离子注入设备的真空室内的样品架上，真空室抽真空至1×10-4Pa以下，通入2～30sccm的氮气和4～60sccm的甲烷气体，保持真空在1×10-3Pa以下，开启离子注入电源，离子注入能量设定为10～500keV，注入时间3～60分钟。由此获得具有表面改性层的金属基体，表面改性层中的碳离子和氮离子易与聚合物膜层中的碳原子键合，形成C-C和C-N化学键中的至少一种，通过该键合，金属基体可以与聚合物膜层稳固地连接在一起，而不易脱落。
从以上可以看出，本发明的植入器械的制备方法中，首先对原始的金属基体进行表面改性形成表面改性层，再在该金属基体上包覆防内皮爬覆的聚合物膜层；由此制得的植入器械中，表面改性层中的掺入离子可与聚合物膜层中的碳原子键合形成C-C键、C-O键、C-OH键、C-N键、C-CN等化学键中的至 少一种，该化学键的键合能远大于分子与分子之间的键合能和机械结合能，因此聚合物膜层可以稳固地与金属基体结合。这样，通过掺入离子作为媒介，聚合物膜层可以与金属基体稳固连接，使得所制得的滤器在进出鞘、以及植入过程中，其表面的聚合物膜层均不易脱落。
以上的具体实施例仅用作举例，并不是对本发明的限制，本领域的普通技术人员基于本发明中的教导，可以采用任意适合的方式来制备滤器，所制备的滤器具有聚合物膜层不易脱落、抗内皮爬覆性能好、以及安全取出时间窗口长的特点。

Claims (26)

  1. 一种植入医疗器械，包括金属基体和覆盖所述金属基体表面的防内皮爬覆的聚合物膜层，其特征在于，所述金属基体的至少一部分表面设有表面改性层，所述表面改性层中包含掺入离子，所述金属基体通过所述掺入离子与所述聚合物膜层连接。
  2. 根据权利要求1所述的植入医疗器械，其特征在于，所述掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种。
  3. 根据权利要求1所述的植入医疗器械，其特征在于，所述表面改性层的厚度不超过4μm。
  4. 根据权利要求1所述的植入医疗器械，其特征在于，所述表面改性层的厚度为2nm～1μm。
  5. 根据权利要求1所述的植入医疗器械，其特征在于，所述掺入离子与所述聚合物膜层中的碳原子化学键合。
  6. 根据权利要求1所述的植入医疗器械，其特征在于，所述掺入离子与所述金属基体中的金属元素化学键合；或者所述掺入离子位于所述金属基体的晶格间隙中。
  7. 根据权利要求1所述的植入医疗器械，其特征在于，所述聚合物膜层包括类聚乙二醇聚合物、类聚氧化乙烯聚合物、类聚乙二醇衍生物、类聚氧化乙烯衍生物中的至少一种。
  8. 根据权利要求1所述的植入医疗器械，其特征在于，所述金属基体包括钴、铬、铁、镍、钼、钛、铂、钽中的至少一种。
  9. 一种植入医疗器械的制备方法，其特征在于，包括对金属基体的至少一部分表面改性形成表面改性层，所述表面改性层中包含掺入离子，所述金属基体通过所述掺入离子与所述聚合物膜层连接。
  10. 根据权利要求9所述的植入医疗器械的制备方法，其特征在于，所述掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种。
  11. 根据权利要求9所述的植入医疗器械的制备方法，其特征在于，所 述对金属基体的至少一部分表面改性形成表面改性层，包括将所述金属基体置于浸泡液中进行浸泡反应形成所述表面改性层。
  12. 根据权利要求11所述的植入医疗器械的制备方法，其特征在于，所述掺入离子包括氧离子和氢氧根离子中的至少一种。
  13. 根据权利要求11所述的植入医疗器械的制备方法，其特征在于，所述浸泡液包括双氧水溶液、双氧水溶液与碱性溶液的混合液、双氧水溶液与酸性溶液的混合液、以及碱性溶液。
  14. 根据权利要求11所述的植入医疗器械的制备方法，其特征在于，将所述金属基体分别置于不同的所述浸泡液中进行至少两次浸泡反应形成所述表面改性层。
  15. 根据权利要求14所述的植入医疗器械的制备方法，其特征在于，所述浸泡液包括双氧水溶液、双氧水溶液与碱性溶液的混合液、双氧水溶液与酸性溶液的混合液、酸性溶液、以及碱性溶液。
  16. 根据权利要求13或15所述的植入医疗器械的制备方法，其特征在于，当所述浸泡液包括所述酸性溶液时，所述酸性溶液包括HF溶液、HCl溶液、H2SO4溶液、HNO3溶液、H3PO4溶液、HClO4溶液、HBr溶液、HI溶液、HCN溶液、H2SO3溶液、HNO2溶液、CH3COOH溶液、和H2SeO4溶液中的至少一种；所述碱性溶液包括NaOH溶液、NaHCO3溶液、KOH溶液、Ca(OH)2溶液、Na2CO3溶液、NH3.H2O溶液、NH4HCO3溶液和K2CO3溶液中的至少一种。
  17. 根据权利要求9所述的植入医疗器械的制备方法，其特征在于，所述对金属基体的至少一部分表面改性形成表面改性层，包括采用等离子体注入法将所述掺入离子注入所述金属基体表面形成所述表面改性层。
  18. 据权利要求17所述的植入医疗器械的制备方法，其特征在于，所述掺入离子包括氧离子和氮离子中的至少一种。
  19. 根据权利要求9所述的植入医疗器械的制备方法，其特征在于，所述对金属基体的至少一部分表面进行改性形成表面改性层，包括采用离子注入法将所述掺入离子注入所述金属基体表面形成所述表面改性层。
  20. 据权利要求19所述的植入医疗器械的制备方法，其特征在于，所述掺入离子包括碳离子、氮离子和碳氮离子中的至少一种。
  21. 一种植入医疗器械预制件，包括金属基体，其特征在于，所述金属基体的至少一部分上设有表面改性层，所述表面改性层中包括掺入离子。
  22. 根据权利要求21所述的植入医疗器械预制件，其特征在于，所述掺入离子可与聚合物中的碳原子键合。
  23. 根据权利要求21所述的植入医疗器械预制件，其特征在于，所述掺入离子包括氧离子、氢氧根离子、碳离子、氮离子、碳氮离子中的至少一种。
  24. 根据权利要求21所述的植入医疗器械预制件，其特征在于，所述表面改性层的厚度不超过4μm。
  25. 根据权利要求21所述的植入医疗器械预制件，其特征在于，所述表面改性层的厚度为2nm～1μm。
  26. 根据权利要求21所述的植入医疗器械预制件，其特征在于，所述金属基体包括金属元素钴、铬、铁、镍、钼、钛、铂、钽中的至少一种。
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US20180185545A1 (en) 2018-07-05

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