WO2016188342A1 - 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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WO2016188342A1
WO2016188342A1 PCT/CN2016/082311 CN2016082311W WO2016188342A1 WO 2016188342 A1 WO2016188342 A1 WO 2016188342A1 CN 2016082311 W CN2016082311 W CN 2016082311W WO 2016188342 A1 WO2016188342 A1 WO 2016188342A1
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metal substrate
transition body
medical device
implantable medical
film layer
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PCT/CN2016/082311
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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 US15/575,928 priority Critical patent/US10933162B2/en
Priority to EP16799231.2A priority patent/EP3299039B1/en
Publication of WO2016188342A1 publication Critical patent/WO2016188342A1/zh

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    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/084—Carbon; Graphite
    • 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
    • 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
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • 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
    • A61L27/28—Materials for coating prostheses
    • A61L27/30—Inorganic 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
    • A61L27/50—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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—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
    • 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
    • A61L33/06—Use of macromolecular materials
    • A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/10—Materials for lubricating medical devices
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more 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
    • 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
    • A61L27/422—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of carbon
    • 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
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time

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 should be placed in the delivery sheath before the filter is implanted.
  • the filter is implanted into the body through the delivery sheath.
  • the filter is compressed, and intense compression and friction occur between the various parts of the filter.
  • the filter is inevitably transported in a delivery sheath of about 550 mm in length. It will rub against the inner wall of the conveying sheath; if the bonding force between the film layer and the substrate is insufficient, the film layer will be easily peeled off after this series of pressing and rubbing, 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, a preparation method thereof, and a method for the defect that the polymer film layer for preventing endothelium-cracking implanted on the surface of the medical device cannot be stably combined with the metal substrate.
  • the polymer film layer of the implanted medical device and the metal substrate are firmly connected by the transition body.
  • 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, the implant medical device further comprising a transition body between the metal substrate and the polymer film layer covering at least a portion of a surface of the metal substrate, the transition body connecting the polymer film layer and the metal substrate.
  • the transition body covers a part of a surface of the metal substrate, and the transition body has a thickness of 1 to 100 nm.
  • the transition body covers the entire surface of the metal substrate, and the transition body has a thickness of 1 to 100 nm.
  • the transition body includes at least one of amorphous carbon, titanium oxide, titanium nitride, titanium carbide, and titanium carbonitride.
  • the polymer film comprises a polyethylene glycol-like polymer At least one of a compound, a polyoxyethylene-like polymer, a polyethylene glycol-like derivative, and a polyoxyethylene-like derivative.
  • the polymer film layer comprises polyethylene glycol, polyethylene glycol-like, polyethylene glycol, crown ether, polyethylene-like ether, polyvinyl alcohol, poly At least one of vinyl ether, polyethylene oxide, polyoxyethylene alcohol, polyoxyethylene ether, polyoxyethylene alcohol-like, and polyvinylidene oxide-like.
  • the metal matrix and the transition body are connected by chemical bonds.
  • the invention also provides a method for preparing an implanted medical device, comprising covering at least part of a surface of a metal substrate with a transition body; covering the transition body with a polymer film layer resistant to endothelium and covering the surface of the metal substrate; Wherein the transition body connects the metal matrix and the polymer film layer.
  • the transition body includes at least one of amorphous carbon, titanium oxide, titanium nitride, titanium carbide, and titanium carbonitride.
  • the transition body is covered on the surface of the metal substrate by vapor deposition.
  • the polymer film layer is covered on the surface of the transition body and the metal substrate by chemical vapor deposition; the polymer film layer includes a poly-B At least one of a diol polymer, a polyethylene oxide-like polymer, a polyethylene glycol-like derivative, and a polyoxyethylene-like derivative.
  • the surface of the metal substrate covers the transition body, and the polymer film layer covers the transition body and covers the surface of the metal substrate, in the same
  • the device is completed in situ.
  • the preparation method further includes washing the metal substrate before the surface of the metal substrate covers the transition body; the cleaning the metal substrate, and The surface of the metal substrate is covered with a transition body and is completed in situ in the same apparatus.
  • the device includes a radio frequency power source or a microwave power source.
  • the invention also provides an implanted medical device preform comprising a metal substrate, the implanted medical device
  • the instrument preform further includes a transition body covering at least a portion of the surface of the metal substrate, the metal matrix being coupled to the transition body by a chemical bond.
  • the transition body covers a portion of the surface of the metal substrate, the transition body having a thickness of 1 to 100 nm.
  • the transition body covers the entire surface of the metal substrate, the transition body having a thickness of 1 to 100 nm.
  • the transition body comprises at least one of amorphous carbon, titanium oxide, titanium nitride, titanium carbide, and titanium carbonitride.
  • a method of manufacturing the same, and an implanted medical device preform for preparing the implanted medical device further includes providing a transition body connecting the polymer film layer and The metal matrix makes the polymer film layer not easy to fall off during transportation, so that the anti-endothelial climbing function can be effectively exerted 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. 4 is a schematic view showing a transition body covering the entire surface of a metal substrate in an embodiment of the present invention
  • Figure 5 is a schematic cross-sectional view showing a filter in an embodiment of the present invention.
  • FIG. 6 shows a flow chart of a method of preparing an implanted medical device in accordance with an embodiment of the present invention
  • Figure 7 shows an optical micrograph of Sample 2 after an in vitro simulation experiment in 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 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, and A transition body 23 between the metal substrate 21 and the polymer film layer 22 and covering the surface of the metal substrate 21, the transition body 23 is connected to the polymer film layer 22 and the metal substrate 21.
  • 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 be the same structure as the support rod 11, or may be only the metal base 21 structure, or may be directly on the metal base 21
  • the polymer film layer 22 is covered.
  • the implantable medical device may also be described as being: the implanted medical device comprises an implanted medical device preform and a polymeric film layer covering the preform; the preform comprises a metal substrate and partial or full coverage The transition body of the metal matrix, the metal matrix and the transition body are connected by a chemical bond.
  • the base body can be radially compressed and pushed into the sheath tube, and then delivered into the lumen through the sheath tube; after the matrix is released from the sheath of the conveyor, the deformation can be restored to a radially expanded state, and the inner wall of the lumen is attached to be fixed to the lumen.
  • the metal matrix blocks and holds the thrombus, thereby filtering the thrombus.
  • the bond between the surface of the metal substrate and the transition body includes not only mechanical bonding and physical bonding but also chemical bonding.
  • the metal element Me Me including but not limited to cobalt, chromium, iron, nickel, molybdenum, titanium, platinum, rhodium
  • Me-C Me- At least one of O, Me-N and Me-CN chemical bonds, which may be an ionic bond, a covalent bond, or a metal bond.
  • amorphous carbon transition body As an example, after the amorphous carbon deposition covers the surface of the metal substrate, a chemical bond Me-C is formed between the carbon element and the metal element, and exists as an ionic bond. At the same time, the concentration of carbon atoms deposited on the surface of the substrate is high. Due to the concentration gradient, the carbon atoms have a driving force for infiltration into the metal matrix, and the carbon atoms penetrating into the metal matrix will form an ionic bond with the metal elements. The carbon atoms on the surface of the substrate and the carbon atoms penetrating into the interior of the matrix will bond in a covalent bond.
  • the aforementioned metal element and the aforementioned non-metal element are chemical bonds formed between atoms and atoms, and the bonding energy 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. With this bonding force, the same external force makes it more difficult to separate the transition body from the surface of the metal substrate, and the transition body can be firmly bonded to the metal substrate.
  • the transition body covering the metal substrate can also effectively prevent the release of metal ions in the body, which is especially important for the nickel-titanium alloy filter, which effectively prevents harmful nickel ions in the nickel-titanium alloy by isolating the substrate.
  • the release of tissue and blood around the tissue further enhances the biocompatibility of the filter and reduces the production of inflammation.
  • 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, preventing endothelial climbing, while still It can increase the anticoagulant properties of the material.
  • the entire surface of the metal substrate 21 is covered with the transition body 23, in which case the filter comprises a metal substrate 21, a transition body 23 covering the metal substrate 21 in its entirety, and a metal substrate 21 coated on the outermost layer.
  • the polymer film layer 22 of the transition body 23 At least one of a covalent bond such as a C-C bond, a C-O bond, and a C-N bond may be formed between the polymer film layer 22 and the transition body 23 such that the polymer film layer 22 and the transition body 23 are connected by a covalent bond.
  • the bonding energy of the covalent 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.
  • the transition body includes at least one of amorphous carbon, titanium oxide (TiO 2 ), titanium nitride (TiN), titanium carbide (TiC), and titanium carbonitride (TiCN), and the amorphous carbon may be formed by a vapor deposition technique.
  • At least one transition body of titanium oxide (TiO 2 ), titanium nitride (TiN), titanium carbide (TiC), and titanium carbonitride (TiCN) covers the surface of the substrate.
  • Vapor deposition techniques utilize physical or chemical processes occurring in the gas phase to form functional or decorative metallic, non-metallic or compound coatings on the surface of the workpiece. According to the film formation mechanism, vapor deposition technology can be divided into chemical vapor deposition (CVD) and physical vapor deposition (PVD).
  • the transition body can be controlled on the metal matrix by adjusting the deposition power and deposition time. As shown in FIG. 3, the amount of deposition of the surface is controlled to partially cover the surface of the metal substrate 21 uniformly, and the thickness of the transition body 23 is 1 to 100 nm. Since the polymer film layer is formed of a polymer containing a chain structure, even if the transition body 23 is only partially partially covered, the transition body 23 can still effectively connect the polymer film layer and the metal substrate 21 by the entanglement constraint between the chain structures. To prevent the polymer film layer from falling off the metal substrate. In general, the higher the coverage of the transition body on the metal substrate, the better the connection between the substrate and the polymer film layer. As shown in FIG. 4, the transition body 23 can also be controlled to cover the entire surface of the metal substrate 21 to form an integral film layer having a thickness of 1 to 100 nm, which allows the transition body to effectively connect the polymer film layer and the metal substrate.
  • step 120 the surface of the metal substrate covered with the transition body in step 110 is coated with a polymer film layer such that the transition body connects the metal substrate and the polymer film 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.
  • steps 110 and 120 can be performed in the same apparatus by the same method (e.g., vapor deposition method), and the apparatus can include a radio frequency power source and a microwave power source.
  • the deposition of the amorphous carbon transition body can be completed by using hydrocarbon gas as a gas source in step 110; then, in step 120, triethylene glycol dimethyl ether is replaced as a gas source.
  • the coating of the polymer film layer is completed in the same reaction chamber, and the metal matrix does not need to be displaced during the two steps. Since the above two steps can be completed in situ in the same device, the metal substrate does not need to be displaced throughout the process, so that no secondary pollution is caused, and the process is simple, the production efficiency is improved, and the device cost is saved.
  • a carbon-carbon gas is used as a carbon source, and an amorphous carbon transition body is deposited on the surface of the metal substrate by chemical vapor deposition.
  • a metal substrate can be placed in a reaction chamber, using a hydrocarbon gas as a carbon source to generate carbon and/or hydrocarbon ions, which are then directed to the metal substrate by a magnetic field or bias, and deposited on the surface of the metal substrate to form hydrogen or no Hydrogen amorphous carbon transition body.
  • Chemical vapor deposition methods include radio frequency plasma enhanced chemical vapor deposition (RF-PECVD) and microwave electron cyclotron resonance plasma assisted chemical vapor deposition (ECR-CVD).
  • the thickness is from 1 to 100 nm.
  • 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 PEG-like.
  • Membrane layer Specifically, 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.
  • the cross-sectional view of the filter prepared in the first embodiment is similar to that of FIG. 5.
  • the surface of the metal substrate 21 of the filter is coated with an amorphous carbon transition body 23 as a film layer covering the metal substrate 21 as a whole;
  • the surface of 23 is coated with a PEG-like film layer 22 to prevent endothelial grafting.
  • step 110 of the present embodiment graphite is used as a carbon source, and an amorphous carbon transition body is deposited on the surface of the metal substrate by physical vapor deposition.
  • a metal substrate may be placed in a reaction chamber, and graphite may be used as a carbon source, and amorphous carbon may be deposited on the surface of the metal substrate by vacuum evaporation, arc ion plating, or sputtering.
  • the amorphous carbon does not have a crystal structure, and is a short-range ordered, long-range disordered carbon allotrope, including diamond-like, glassy carbon, and amorphous carbon; and using graphite as a carbon source will produce non-hydrogen-free Crystal carbon.
  • the surface of the metal substrate is covered with a transition body by a reactive deposition method.
  • metal titanium is used as a target, and an inert gas such as argon is introduced into the vacuum chamber to ionize and accelerate the flying direction under an electric field such as direct current, intermediate frequency, radio frequency or cathode multiple arc.
  • an electric field such as direct current, intermediate frequency, radio frequency or cathode multiple arc.
  • a reactive gas such as at least one of O 2 , N 2 , CO 2 , and CH 4 is introduced into the vacuum reaction chamber while sputter coating, thereby obtaining a compound of the target and the reaction gas, such as TiO 2 , TiN, TiC. At least one of TiCN.
  • reaction gases such as a mixed gas of N 2 and CO 2 , or a mixed gas of N 2 and CH 4 , or a mixed gas of N 2 , CO 2 and CH 4 , may be introduced Generate TiCN.
  • at least one of titanium oxide, titanium nitride, titanium carbide, and titanium carbonitride can be coated on the surface of the substrate as a transition body.
  • the filter (sample 1 or sample 2), the guiding sheath, the conveying sheath and the conveying cable are first immersed in water at 37 ° C, and the simulation experiment is completed in the normal body temperature of the human body; the length of the conveying cable is 85 mm.
  • Figure 7 shows an optical micrograph of sample 2 after an in vitro simulation experiment with a magnification of 200 times.
  • Fig. 7 in the above-mentioned in vitro simulation experiment, after the surface of the filter was in direct contact with and rubbed against the inner wall of the sheath, a large piece of peeling occurred on the PEG-like film layer 1a (see the marked area of 2a).
  • Figure 8 shows an optical micrograph of Sample 1 after an in vitro simulation experiment, the magnification is also 200 times. It can be seen from Fig.
  • sample 1 and sample 2 were implanted into the inferior vena cava of the same ram, and sample 3 was implanted together.
  • Sample 3 included only the same metal matrix as Sample 1 and Sample 2, no amorphous carbon transition body and polymer film layer. After four weeks of implantation, the endothelial grafting of the above three samples in the inferior vena cava was observed.
  • the sample 3 only includes the metal matrix, after the implantation, the surface of the filter is covered with the endothelium, and the portion of the metal substrate that is in contact with the blood vessel wall is completely covered, the filter cannot be successfully removed by the blood vessel recovery method, even if it is forcibly taken out, Will damage the vessel wall.
  • the surface portion of the sample 2 has an endothelial climbing layer because the surface of the metal substrate is coated with a PEG-like film layer, which can inhibit endothelial climbing, but the PEG film layer is directly coated on the metal substrate, between the two The bonding force is small.
  • the PEG-like film layer is easy to fall off, and the exposed metal matrix does not have the effect of preventing the endothelial climbing after the shedding. Therefore, the endothelial resurfacing of the exposed portion is more serious. If the filter is recovered intravascularly, the endothelium of the endothelium may be greatly damaged when the endothelium is torn, and may not be successfully removed.
  • sample 1 has almost no endothelium-clip surface. This is because the PEG-like film layer is firmly bonded to the metal matrix through the deposited amorphous carbon transition layer. Therefore, the PEG-like film layer does not fall off substantially during the process of entering and exiting the sheath and after implantation. Effectively inhibiting endothelial resuscitation, the filter can be successfully removed by intravascular recovery without being damaged by the endovascular membrane.
  • the transition body is first covered on the surface of the metal substrate, and then the polymer film layer for preventing the endothelium is coated on the transition body and the metal substrate;
  • the non-metal element in the transition body forms a chemical bond with the metal element in the metal matrix, and the bonding energy is much larger than the bonding energy between the molecule and the molecule, so that the transition body can be firmly bonded to the metal
  • the matrix is bonded;
  • the outermost layer of the metal substrate is coated with a polymer film layer, and the polymer film layer forms a chemical bond with the non-metal element in the transition body, and the bonding energy is also large, which can make the transition The body is firmly bonded to the polymer film layer.
  • 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

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Abstract

一种植入医疗器械、其制备方法、以及用于制备该植入医疗器械的植入医疗器械预制件。植入医疗器械包括金属基体(21)和覆盖金属基体(21)表面的防内皮爬覆的聚合物膜层(22)，还包括位于金属基体(21)与聚合物膜层(22)之间、且覆盖金属基体(21)至少部分表面的过渡体(23)，过渡体(23)连接聚合物膜层(22)和金属基体(21)。通过设置过渡体(21)连接聚合物膜层(22)和金属基体(21)，使聚合物膜层(22)在植入人体过程中及在人体内发挥功效过程中不易脱落。

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，该植入医疗器械的聚合物膜层与金属基体通过过渡体稳固连接在一起。
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，所述植入医疗器械还包括位于所述金属基体与所述聚合物膜层之间、且覆盖所述金属基体至少部分表面的过渡体，所述过渡体连接所述聚合物膜层和所述金属基体。
在依据本发明实施例的植入医疗器械中，所述过渡体覆盖所述金属基体的部分表面，所述过渡体的厚度为1～100nm。
在依据本发明实施例的植入医疗器械中，所述过渡体覆盖所述金属基体的全部表面，所述过渡体的厚度为1～100nm。
在依据本发明实施例的植入医疗器械中，所述过渡体包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种。
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。
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。
在依据本发明实施例的植入医疗器械中，所述金属基体与所述过渡体通过化学键连接。
本发明还提供了一种植入医疗器械的制备方法，包括在金属基体的至少部分表面覆盖过渡体；采用防内皮爬覆的聚合物膜层覆盖所述过渡体并覆盖所述金属基体的表面；其中，所述过渡体连接所述金属基体和所述聚合物膜层。
在依据本发明实施例的植入医疗器械的制备方法中，所述过渡体包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种。
在依据本发明实施例的植入医疗器械的制备方法中，采用气相沉积法在所述金属基体的表面覆盖所述过渡体。
在依据本发明实施例的植入医疗器械的制备方法中，采用化学气相沉积法在所述过渡体和所述金属基体表面覆盖所述聚合物膜层；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的制备方法中，所述在金属基体的表面覆盖过渡体、以及所述采用聚合物膜层覆盖所述过渡体并覆盖所述金属基体表面，在同一设备中原位完成。
在依据本发明实施例的植入医疗器械的制备方法中，在所述在金属基体的表面覆盖过渡体之前，所述制备方法还包括清洗所述金属基体；所述清洗所述金属基体、以及所述在金属基体的表面覆盖过渡体，在同一设备中原位完成。
在依据本发明实施例的植入医疗器械的制备方法中，所述设备包括射频电源或微波电源。
本发明还提供了一种植入医疗器械预制件，包括金属基体，所述植入医疗 器械预制件还包括覆盖所述金属基体至少部分表面的过渡体，所述金属基体与所述过渡体通过化学键连接。
在依据本发明实施例的植入医疗器械预制件中，所述过渡体覆盖所述金属基体的部分表面，所述过渡体的厚度为1～100nm。
在依据本发明实施例的植入医疗器械预制件中，所述过渡体覆盖所述金属基体的全部表面，所述过渡体的厚度为1～100nm。
在依据本发明实施例的植入医疗器械预制件中，所述过渡体包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种。
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，还包括设有过渡体，该过渡体连接聚合物膜层和金属基体，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是本发明实施例中过渡体覆盖金属基体部分表面的示意图；
图4是本发明实施例中过渡体覆盖金属基体全部表面的示意图；
图5是本发明实施例中滤器的截面示意图；
图6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；
图7示出了本发明实施例中样品2在体外模拟实验后的光学显微镜照片；
图8示出了本发明实施例中样品1在体外模拟实验后的光学显微镜照片。
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。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、以及位于金属基体21与聚合物膜层22之间且覆盖于金属基体21表面的过渡体23，过渡体23连接聚合物膜层22和金属基体21。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，也可仅为金属基体21结构，或者也可为金属基体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以及部分或全面覆盖该金属基体的过渡体，金属基体与过渡体通过化学键连接。
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。
过渡体包括非晶碳、氧化钛(TiO2)、氮化钛(TiN)、碳化钛(TiC)和碳 氮化钛(TiCN)中的至少一种。参见图3，过渡体可覆盖金属基体的部分表面，即过渡体未形成完整的一体结构，而是暴露出部分金属基体，单处过渡体的厚度为1～100nm。参见图4，过渡体还可整体覆盖金属基体的全部表面，形成一体膜层，过渡体的厚度为1～100nm。
此处，金属基体的表面与过渡体之间的结合不仅包括机械结合和物理结合，还包括化学结合。具体而言，金属基体中的金属元素Me(Me包括但不限于钴、铬、铁、镍、钼、钛、铂、钽)可与过渡体中的非金属元素结合形成Me-C、Me-O、Me-N和Me-CN化学键中的至少一种，该化学键既可以是离子键，也可以是共价键，还可以是金属键。以非晶碳过渡体为例，非晶碳沉积覆盖金属基体表面后，碳元素与金属元素之间形成化学键Me-C，以离子键形式存在。同时，基体表面所沉积的碳原子浓度高，由于浓度梯度的存在，使碳原子具有向金属基体体内渗透的驱动力，渗透到金属基体内的碳原子将与金属元素之间形成离子键，而基体表面的碳原子与渗透到基体内部的碳原子将以共价键形式结合。已经知晓，前述金属元素与前述非金属元素之间是原子与原子之间形成的化学键，且键合能为0.5～10eV，远远大于范德华力之间的键合能0.1～0.5eV，因此，在此键合能下，相同的外力更难于将过渡体与金属基体的表面分离，过渡体可以稳固地与金属基体结合在一起。
另一方面，覆盖在金属基体上的过渡体还可有效防止金属离子在体内的释放，这一点对于镍钛合金滤器尤为重要，该过渡体通过隔离基体从而有效防止镍钛合金中的有害镍离子在周围组织和血液的释放，从而进一步增强滤器的生物相容性，并减少炎症的产生。
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。
如图5所示，以过渡体23覆盖金属基体21的全部表面为例，此时，滤器包括金属基体21、全面覆盖金属基体21的过渡体23、以及在最外层包覆金属基体21和过渡体23的聚合物膜层22。聚合物膜层22与过渡体23之间可形成C-C键、C-O键和C-N键等共价键中的至少一种，使得聚合物膜层22与过渡体23之间通过共价键连接。同样地，该共价键的键合能为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，相同的外力难于将过渡体与聚合物膜层分离，过渡体可以稳固地与聚合物膜层结合在一起。前文已经提及，过渡体可以通过化学键稳固地与金属基体结合在一起，结合过渡体可以稳固地与聚合物膜层通过共价键结合在一起，由此通过过渡体可以提高聚合物膜层与金属基体表面之间的结合力，实现聚合物膜层稳固有效地附着在金属基体上。
通过本发明的上述制备方法所制得的滤器在植入管腔后，因聚合物膜层可以通过过渡体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。另一方面，在滤器植入管腔后，即使亲水的聚合物膜层随着时间水解，金属基体表面稳固连接的过渡体也可有效防止金属元素在管腔内的释放，降低滤器对人体的损伤。
图6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6所示，步骤110中，首先在金属基体的表面覆盖过渡体，形成植入医疗器械预制件。
过渡体包括非晶碳、氧化钛(TiO2)、氮化钛(TiN)、碳化钛(TiC)和碳氮化钛(TiCN)中的至少一种，可采用气相沉积技术将上述非晶碳、氧化钛(TiO2)、氮化钛(TiN)、碳化钛(TiC)和碳氮化钛(TiCN)中的至少一种过渡体覆盖在基体表面。气相沉积技术是利用气相中发生的物理或化学过程，在工件表面形成功能性或装饰性的金属、非金属或化合物涂层。气相沉积技术按照成膜机理，可分为化学气相沉积(CVD)和物理气相沉积(PVD)。
气相沉积中可通过调节沉积功率和沉积时间来控制过渡体在金属基体表 面的沉积量，如图3所示，控制过渡体23均匀地部分覆盖金属基体21表面，各处过渡体23的厚度为1～100nm。由于聚合物膜层由包含链状结构的聚合物形成，即使过渡体23只是离散地部分覆盖，但是通过链状结构间的缠绕约束，过渡体23仍然可以有效连接聚合物膜层和金属基体21，防止聚合物膜层从金属基体上脱落。通常情况下，过渡体在金属基体上的覆盖率越高，基体与聚合物膜层之间的连接效果越好。如图4所示，还可控制过渡体23覆盖全部金属基体21表面形成一体膜层，该过渡体膜层的厚度为1～100nm，该厚度使得过渡体能有效连接聚合物膜层与金属基体。
步骤120中，采用聚合物膜层包覆步骤110中覆盖有过渡体的金属基体表面，从而过渡体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。此处，因可采用相同的方法(例如气相沉积法)实施步骤110和120，所以步骤110和120可在同一装置中原位完成，该装置可包括射频电源和微波电源。例如，以非晶碳过渡体为例，可在步骤110中采用碳氢气体作为气源，完成非晶碳过渡体的沉积；随后在步骤120中换成三乙二醇二甲醚作为气源，在同一反应室内完成聚合物膜层的包覆，两个步骤过程中金属基体无需移位。因上述两个步骤可在同一装置中原位完成，金属基体在整个过程中无需移位，因此不会造成二次污染，且工序简单，提高了生产效率，并节约了装置成本。
为了进一步提高滤器的性能，还可在步骤110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110和120的同一装置中，在真空条件下等离子清洗金属基体。这样，即使对金属基体进行清洗，也可在同一设备中原位完成。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
本实施例中采用碳氢气体作为碳源、通过化学气相沉积法在金属基体的表面沉积覆盖非晶碳过渡体。例如，可将金属基体置于反应室中，采用碳氢气体作为碳源，产生碳和/或碳氢离子，然后通过磁场或偏压引向金属基体，沉积于金属基体表面形成含氢或无氢非晶碳过渡体。化学气相沉积方法包括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)，所采用的碳氢气体碳源包括甲烷、乙烷、乙炔、丁烷、苯中的至少一种。沉积中，可通入氢气与上述碳氢气体混合成反应气体，从而提高C-H键比例。还可采用氩气作为辅助气体与碳氢气体混合，或者与碳氢气体以及氢气混合，从而有助于产生等离子体。该非晶碳不具有晶体结构，为短程有序、长程无序的碳的同素异形体，包括类金刚石、玻璃碳、以及无定型碳。
具体而言，在步骤110之前先等离子清洗用于制备滤器的金属基体，具体地，将滤器放入真空室内的样品架上，抽真空至8.0Pa以下；通入流量为20～200sccm的氩气，使真空室压力保持在10.0Pa以下，开启射频或微波电源使气体电离并对金属基体施加10-500V的偏压，在此条件下对金属基体表面等离子清洗5～60分钟。
步骤110中，采用化学气相法在金属基体表面沉积非晶碳过渡体。具体地，以流量10～50sccm通入碳氢气体甲烷，为提高等离子量，在通入甲烷的同时混合辅助气体氩气，氩气流量为50～200sccm，同时保持反应室内的真空压力低于10.0Pa。调节射频功率至200W～1000W、偏压10V～500V，在上述条件下沉积时间1～60分钟，然后关闭反应气体、射频电源以及偏压，此时非晶碳过渡体覆盖金属基体的全部表面，厚度为1～100nm。
步骤120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5类似，该滤器的金属基体21表面包覆一层非晶碳过渡体23，该过渡体23作为膜层整体覆盖金属基体21；在过渡体23的表面包覆类PEG膜层22，以防止内皮爬覆。
实施例二
与实施例一不同的是，本实施例的步骤110中采用石墨作为碳源、通过物理气相沉积法在金属基体的表面沉积覆盖非晶碳过渡体。例如，可将金属基体置于反应室中，以石墨为碳源，采用真空蒸镀、电弧离子镀或者溅射镀膜等方法，在金属基体的表面沉积非晶碳。该非晶碳不具有晶体结构，为短程有序、长程无序的碳同素异形体，包括类金刚石、玻璃碳、以及无定型碳；而采用石墨作为碳源，将产生不含氢的非晶碳。
实施例三
与实施例一不同的是，本实施例的步骤110中采用蒸发镀膜在金属基体的表面覆盖过渡体。具体而言，在真空条件下，用加热蒸发的方法使镀料转化为气相，镀料包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种；加热蒸发的方法包括电阻加热、电子束加热和高频感应加热等。然后将蒸发后的镀料凝聚在基体表面，实现过渡体覆盖基体。该方法的优点是设备和工艺简单，蒸发过程不产生等离子体，基体温度低。
实施例四
与实施例一不同的是，本实施例的步骤110中采用反应沉积法在金属基体的表面覆盖过渡体。具体而言，在真空室中，采用金属钛作为靶材，向真空室内通入惰性气体，例如氩气，使其在直流、中频、射频或阴极多弧等电场作用下发生电离并加速飞向金属靶材，靶材上的钛原子由此获得足够的能量而溅出 形成气相。在溅射镀膜的同时向真空反应室内通入反应气体，如O2、N2、CO2、CH4中的至少一种，从而获得靶材与反应气体的化合物，如TiO2、TiN、TiC、TiCN中的至少一种。其中，如果通入两种或两种以上的反应气体，如N2和CO2的混合气体，或者N2与CH4的混合气体，或者N2、CO2和CH4的混合气体，则可以生成TiCN。由此，可在基体的表面覆盖氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种作为过渡体。
将上述实施例一中制备的滤器标记为样品1，制备另一滤器样品2与之对比，样品2采用实施例一中相同金属基体、以及相同的清洗步骤和步骤120制成，未采用步骤110，因此样品2仅包括金属基体和包覆该金属基体的类PEG膜层。将样品1和样品2在相同的条件下进行体外模拟实验，模拟滤器推入输送鞘管、并从鞘管中释放和回收的过程。
具体地，首先将滤器(样品1或样品2)、导引鞘、输送鞘及输送钢缆浸泡在37℃的水中，模拟实验在人体正常体温的水中完成；将输送钢缆穿过长度为85mm的6F导引鞘；再将滤器通过滤器上的连接螺母固定在输送钢缆上；回撤输送钢缆，将滤器收入6F导引鞘；将导引鞘插入长度为550mm的6F输送鞘内，推动输送钢缆将滤器推入输送鞘中；持续推送钢缆，直至将滤器推送到输送鞘的另一端；用手握住滤器，逆时针旋转，将滤器从输送钢缆上取下；用滤纸吸干滤器上的水，放在光学显微镜下观察聚合物膜层脱落情况。
图7示出了样品2在体外模拟实验后的光学显微镜照片，放大倍数为200倍。从图7可以看出，在上述体外模拟实验中，滤器表面与鞘管内壁直接接触和摩擦后，类PEG膜层1a上出现大片脱落(见2a标示区域)。图8示出了样品1在体外模拟实验后的光学显微镜照片，放大倍数同样为200倍。从图8可以看出，在上述体外模拟实验中，滤器表面与鞘管内壁直接接触和摩擦后，类PEG膜层1b未见脱落，图8中的白亮区域2b为光线反射所致。比较图7和图8可知，样品2中因金属基体表面上直接沉积的类PEG膜层(采用1a标示)与金属基体之间的结合力较小，类PEG膜层易于从金属基体表面脱落；样品1中因金属基体表面与类PEG膜层1b之间通过非晶碳过渡体稳固结合在一起，因此类PEG膜层不易脱落。
为了验证采用本发明的制备方法制得的滤器的抑制内皮爬覆的效果，将上述样品1和样品2植入同一头公绵羊的下腔静脉血管中，同时一起植入的还有样品3，样品3仅包括与样品1和样品2相同的金属基体，无非晶碳过渡体和聚合物膜层。在植入四周后，观察上述三个样品在下腔静脉血管中的内皮爬覆情况。
因样品3仅包括金属基体，因此在植入后滤器表面长满内皮，将金属基体接触血管壁的部分全部包覆这种情况下，通过血管回收方法将无法成功取出滤器，即使强行取出，也将损伤血管壁。
样品2的表面部分有内皮爬覆，这是因为其金属基体表面包覆有类PEG膜层，可以抑制内皮爬覆，但是该类PEG膜层直接包覆于金属基体上，两者之间的结合力较小，在滤器与输送鞘管的摩擦过程中，类PEG膜层易于脱落，脱落后裸露的金属基体不具有阻止内皮爬覆的作用，因此，该裸露部分的内皮爬覆比较严重。如果通过血管内回收该滤器，则在撕裂内皮爬覆部分时会对血管内膜造成较大伤害，甚至无法成功取出。
样品1表面几乎无内皮爬覆，这是由于类PEG膜层通过沉积的非晶碳过渡层与金属基体稳固结合,因此类PEG膜层在进出鞘以及植入后的过程中基本无脱落，可以有效抑制内皮爬覆，该滤器植入体内四周以上仍然可以通过血管内回收方法成功取出，而不会损伤血管内膜。
从以上可以看出，现有的临时滤器(例如上述样品2和样品3)在植入四周后即发生了较为严重的内皮爬覆，为了能将滤器安全地从血管中回收，现有滤器的安全取出时间窗口通常为14天左右。对于采用本发明中的制备方法所制得的滤器(例如样品1)，因聚合物膜层可以稳固包覆金属基体，而该聚合物膜层又能有效防止内皮爬覆，因此滤器安全取出时间窗口可延长到至少为一个月。延长安全取出时间窗口可以延长临床观察时间，并扩大适用人群范围。例如，依据本发明实施例的滤器可适应需长期植入滤器的患者，避免此类患者多次植入传统的临时滤器或植入永久性滤器。
从以上可以看出，本发明的植入器械的制备方法中，首先在金属基体的表面覆盖过渡体，再在该过渡体和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，过渡体中的非金属元素与金属基体中的金属元素形成化学键，该键合能远大于分子与分子之间的键合能，因此过渡体可以稳固地与金属基体结合；另一方面，最后在金属基体的最外层包覆聚合物膜层，该聚合物膜层与过渡体中的非金属元素之间形成化学键，键合能同样较大，可以使得过渡体与聚合物膜层稳固结合。这样，通过过渡体作为媒介，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 (18)

  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，所述植入医疗器械还包括位于所述金属基体与所述聚合物膜层之间、且覆盖所述金属基体至少部分表面的过渡体，所述过渡体连接所述聚合物膜层和所述金属基体。
  2. 根据权利要求1所述的植入医疗器械，其特征在于，所述过渡体覆盖所述金属基体的部分表面，所述过渡体的厚度为1～100nm。
  3. 根据权利要求1所述的植入医疗器械，其特征在于，所述过渡体覆盖所述金属基体的全部表面，所述过渡体的厚度为1～100nm。
  4. 根据权利要求1所述的植入医疗器械，其特征在于，所述过渡体包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种。
  5. 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。
  6. 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。
  7. 根据权利要求1所述的植入医疗器械，其特征在于，所述金属基体与所述过渡体通过化学键连接。
  8. 一种植入医疗器械的制备方法，其特征在于，包括在金属基体的至少部分表面覆盖过渡体；采用防内皮爬覆的聚合物膜层覆盖所述过渡体并覆盖所述金属基体的表面；其中，所述过渡体连接所述金属基体和所述聚合物膜层。
  9. 根据权利要求8所述的植入医疗器械的制备方法，其特征在于，所述过渡体包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种。
  10. 根据权利要求8所述的植入医疗器械的制备方法，其特征在于，采用气相沉积法在所述金属基体的表面覆盖所述过渡体。
  11. 聚合物膜根据权利要求8所述的植入医疗器械的制备方法，其特征在于，采用化学气相沉积法在所述过渡体和所述金属基体表面覆盖所述聚合物膜层；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。
  12. 根据权利要求8所述的植入医疗器械的制备方法，其特征在于，所述在金属基体的表面覆盖过渡体、以及所述采用聚合物膜层覆盖所述过渡体并覆盖所述金属基体表面，在同一设备中原位完成。
  13. 根据权利要求12所述的植入医疗器械的制备方法，其特征在于，在所述在金属基体的表面覆盖过渡体之前，所述制备方法还包括清洗所述金属基体；所述清洗所述金属基体、以及所述在金属基体的表面覆盖过渡体，在同一设备中原位完成。
  14. 根据权利要求12或13所述的植入医疗器械的制备方法，其特征在于，所述设备包括射频电源或微波电源。
  15. 一种植入医疗器械预制件，包括金属基体，其特征在于，所述植入医疗器械预制件还包括覆盖所述金属基体至少部分表面的过渡体，所述金属基体与所述过渡体通过化学键连接。
  16. 根据权利要求15所述的植入医疗器械预制件，其特征在于，所述过渡体覆盖所述金属基体的部分表面，所述过渡体的厚度为1～100nm。
  17. 根据权利要求15所述的植入医疗器械预制件，其特征在于，所述过渡体覆盖所述金属基体的全部表面，所述过渡体的厚度为1～100nm。
  18. 根据权利要求15所述的植入医疗器械预制件，其特征在于，所述过渡体包括非晶碳、氧化钛、氮化钛、碳化钛和碳氮化钛中的至少一种。
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