WO2015062547A1 - 可吸收铁基合金支架 - Google Patents

可吸收铁基合金支架 Download PDF

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Publication number
WO2015062547A1
WO2015062547A1 PCT/CN2014/090110 CN2014090110W WO2015062547A1 WO 2015062547 A1 WO2015062547 A1 WO 2015062547A1 CN 2014090110 W CN2014090110 W CN 2014090110W WO 2015062547 A1 WO2015062547 A1 WO 2015062547A1
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WIPO (PCT)
Prior art keywords
iron
based alloy
stent
degradable polyester
acid
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PCT/CN2014/090110
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English (en)
French (fr)
Inventor
张德元
孙宏涛
陈丽萍
齐海萍
林文娇
秦莉
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先健科技(深圳)有限公司
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Application filed by 先健科技(深圳)有限公司 filed Critical 先健科技(深圳)有限公司
Priority to JP2016526758A priority Critical patent/JP2016534797A/ja
Priority to CN201480056253.9A priority patent/CN105636617A/zh
Priority to NZ720013A priority patent/NZ720013A/en
Priority to EP14858500.3A priority patent/EP3064233B1/en
Priority to KR1020167014074A priority patent/KR102202431B1/ko
Priority to AU2014344308A priority patent/AU2014344308B2/en
Priority to US15/032,100 priority patent/US10058639B2/en
Publication of WO2015062547A1 publication Critical patent/WO2015062547A1/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
    • A61L31/10—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
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
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    • 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
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
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    • 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
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    • 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/9155—Adjacent bands being connected to each other
    • A61F2002/91575—Adjacent bands being connected to each other connected peak to trough
    • 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
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
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    • 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
    • A61F2210/0076—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof multilayered, e.g. laminated structures
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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Definitions

  • the invention belongs to the field of biodegradable implantable medical devices and relates to an absorbable iron-based alloy stent which can be rapidly and controllably degraded within a predetermined period of time.
  • implanted medical devices are typically made from metals and their alloys, ceramics, polymers, and related composite materials.
  • metal materials are particularly favored for their superior mechanical properties, such as high strength and high toughness.
  • iron participates in many biochemical processes, such as the transport of oxygen.
  • Peuster M and other laser-engraving methods of corrosive pure iron stents similar in shape to clinically used metal stents were implanted into the descending aorta of 16 New Zealand rabbits.
  • the results of this animal experiment showed that there was no thrombotic complication within 6-18 months, and no adverse events occurred.
  • Pathological examination confirmed that there was no inflammatory reaction in the local vascular wall, and there was no obvious proliferation of smooth muscle cells, indicating that the degradable iron scaffold has a good application. prospect.
  • the corrosion rate of pure iron in the body environment is slow and needs to be improved.
  • Various techniques for increasing the rate of iron corrosion have been developed, including methods of alloying and altering the metallographic vessels.
  • Degradable polyester mainly includes polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic acid-co-glycolic acid, PLGA), polycaprolactone (polycaprolactone). , PCL) and so on.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA poly(lactic acid-co-glycolic acid
  • PLCA polycaprolactone
  • PCL polycaprolactone
  • the polymer coating can be degraded within 6-9 months; Boston Scientific Synergy drug-eluting stent Pt-Cr alloy is used as the matrix, PLGA is the drug carrier, and Everolimus drug is used.
  • the polymer coating can be degraded within 4 months.
  • many companies use poly-L-lactic acid (PLLA) with slow degradation rate to make fully degradable vascular stents with an absorption period of 2-3 years.
  • PLLA poly-L-lactic acid
  • the hydrogen evolution corrosion rate of the iron-based alloy matrix can be accelerated, the toxicity of the stent at the initial stage of degradation can be reduced, and the rapid endothelialization of the endothelial cells on the stent surface is facilitated.
  • the local micro-acid environment and hydrogen evolution corrosion have not been obtained. It has been confirmed that this report also does not address the compatibility of degradation of degradable polymers with corrosion between iron substrates.
  • Fe(OH) 2 Human blood vessels are aqueous systems. In this environment, iron-based alloys can undergo oxygen absorption and corrosion, and Fe(OH) 2 is formed . Synchronous Fe(OH) 2 is rapidly oxidized to form Fe(OH) 3 precipitates (as shown in Equations 1.1 and 1.2). . Fe(OH) 2 and Fe(OH) 3 are water-insoluble, and their metabolism in human body is mainly achieved by cell phagocytosis and micro-ionization of Fe ions, and the metabolic absorption is slow. At the same time, the corrosion product wrapped around the iron implant will hinder the diffusion of O 2 to the periphery of Fe, reducing the corrosion rate, and is not conducive to further metabolic absorption of iron.
  • this type of corrosion product is a water-soluble iron salt that can be quickly absorbed by the body.
  • the water-soluble iron salt can diffuse to other positions in the body fluid in the body fluid, and there is no solid product around the iron implant which hinders the direct contact of iron with O 2 , which can accelerate the corrosion of Fe.
  • the degradable polyester can accelerate the corrosion of the iron-based alloy and increase the concentration of iron ions by providing the local lactate ion, whether the degradation rate and the corrosion rate of the iron-based alloy match affect the morphology of the final corrosion product and the iron corrosion cycle. length. Specifically, when the corrosion rate is too fast, it will affect the structural integrity and mechanical properties of the iron-based alloy stent in the early stage (such as 3 months) after implantation, and if the iron ion release exceeds the absorption capacity of the blood vessel, it will corrode. The formed iron will be deposited as solid rust again in the peripheral blood vessels outside a certain distance from the implantation site, and will remain in the human body for a long time.
  • the corrosion rate of iron by the degradable polyester is limited, resulting in a long degradation cycle of the iron-based alloy stent.
  • the coronary stent for 3 years after implantation, it cannot be completely degraded and absorbed within 3 years after implantation.
  • peripheral vascular stents it is still not completely degraded and absorbed within 4 years after implantation for 2 years, so it is difficult to highlight the characteristics of degradable absorption of iron-based alloy stents.
  • whether the corrosion cycle of the iron-based alloy matrix matches the degradation cycle of the degradable polyester also seriously affects the overall degradation cycle of the iron stent.
  • the degradable polyester is present only in the early stage of corrosion of the iron-based alloy and accelerates its corrosion, after the degradation of the late degradable polyester is completed, the iron-based alloy is not completely etched away, and the degradation rate of the remaining iron-based alloy is It will be slower and form solid rust, resulting in a longer overall degradation cycle of the iron-based alloy stent, which may still not meet the clinical requirements for degradation and absorption of the degradable stent.
  • Another object of the present invention is to provide an absorbable iron-based alloy stent comprising the degradable polyester.
  • the iron-based alloy in the iron-based alloy stent can be quickly corroded and absorbed in the human body within a predetermined period of time under the action of the polymer coating, and has the mechanical properties required for supporting the blood vessel in the early period of the corrosion cycle. .
  • the iron-based alloy matrix in the iron-based alloy stent can quickly corrode in the human body within a predetermined period of time under the action of the polymer coating, and can meet the requirements of mechanical properties at an early stage, and can also be relatively stable throughout the predetermined period of time. Uniform corrosion causes the rate of formation of corrosion products of the iron-based alloy matrix to be consistent with the rate of absorption in the body, thereby producing less solid products and reducing the accumulation of solid products. Preferably, the resulting iron corrosion product is completely absorbed without any build-up.
  • the quickness means that for an iron-based alloy device with an iron-based alloy support rod thickness of [30, 100) micrometers, the mass loss is more than 10% when implanted in an animal for 3 months, after 1 year of implantation. Within 3 years, the iron-based alloy is completely degraded and completely absorbed; for the iron-based alloy stent rod thickness of [100,300] micrometers, the quality loss is more than 5% when implanted in animals for 3 months. The iron-based alloy was completely corroded and completely absorbed within 4 years after 2 years.
  • the controllable refers to the rapid corrosion of the iron-based alloy by the degradable polyester, which can ensure that the iron-based alloy can maintain good mechanical properties in the early stage after implantation into the human body, for example,
  • the thickness of the stent rod is in the [30-100] micron iron-based alloy stent.
  • the thickness of the degradable polyester coating is between [3, 35] micrometers, and the radial support force is above 80 kPa at 3 months, and is implanted.
  • the iron-based alloy can be completely degraded and completely absorbed within 3 years after 2 years; for the iron-based alloy stent with a stent rod thickness of [100,300] microns, the thickness of the degradable polyester coating is between [10,60] microns.
  • the radial support force is above 40 kPa, and the iron-based alloy can be completely degraded and completely absorbed within 4 years after implantation for 2 years.
  • the complete absorption means that the degradable polyester stent of the present invention (the corresponding bare iron-based alloy stent has a mass M) is implanted into the animal at a predetermined observation time, for example, at 3 months, 6 months, 1 After the year, 2 years, 3 years or even longer, the stent and its blood vessel are taken out, and the stent and its blood vessel are digested with a concentrated nitric acid in a microwave digestion apparatus, and the volume is adjusted to a volume V 0 by water, and the solution after the constant volume is tested.
  • the concentration of iron ions in the medium is C 0 if
  • the specific conditions for testing the iron ion concentration are: Agilent 240FS atomic absorption spectrometer with a wavelength of 248.3 nm, a slit of 0.2 nm, acetylene as a combustion gas, and a flow rate of 2.0 L/min.
  • the degradable polyester refers to a polymer containing an ester group -COO- and which is degradable in vivo to produce a carboxyl group-COOH.
  • the degradable polyester has a weight average molecular weight of [2,100] and a polydispersity coefficient of [1.2, 30]. Further, the weight average molecular weight of the degradable polyester may be between [2, 5) million, or [5, 10) million, or between [10, 20) million, or [20 , 30) million, or [30,40) million, or [40,60) million, or [60,100] million, the polydispersity coefficient may be between [1.2, 5), or [ Between 5, 10), or between [10, 20), or between [20, 30].
  • Each numerical interval follows mathematical common sense, that is, [a, b] means greater than or equal to a, and less than or equal to b; (a, b) means greater than a, and less than or equal to b; [a, b) means greater than or Equal to a, less than b, the same text is the same, no longer repeat.
  • the degradable polyester may be only polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS). ), poly( ⁇ -hydroxybutyrate) (PHB), polycaprolactone (PCL), polyethylene adipate (PEA), polylactic acid-glycolic acid copolymer (PLGA), polyhydroxybutyric acid Any of the ester valerate copolymers (PHBV).
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PBS polysuccinate
  • PBS poly( ⁇ -hydroxybutyrate)
  • PCL polycaprolactone
  • PEA polyethylene adipate
  • PLA polylactic acid-glycolic acid copolymer
  • PHBV polyhydroxybutyric acid Any of the ester valerate copolymers
  • the degradable polyester can also be a mixture of at least two different degradable polyester polymers of different weight average molecular weights.
  • the same type refers to a general term for polymers having the same polymerized monomer (structural unit) but different weight average molecular weights.
  • the foregoing mixture may include a first degradable polyester-based polymer having a weight average molecular weight of [2,5] million, and a second homogeneous degradable polyester having a weight average molecular weight of [6,100] million.
  • a polymer, the second degradable polyester polymer and the first degradable polyester polymer are of the same kind, and the content ratio of the two is between [1:9, 9: 1].
  • the degradable polyester may be selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), and polycaprolactone (PCL). Any one of polyethylene adipate (PEA), polylactic acid-glycolic acid copolymer (PLGA), and polyhydroxybutyrate valerate copolymer (PHBV).
  • the degradable polyester comprises two polylactic acids having different weight average molecular weights, and the weight average molecular weights of the two polylactic acids are between [2, 5] and [6,100], respectively, and The content ratio of the two is between 1:9 and 9:1.
  • the degradable polyester may also be composed of polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), polycaprolactone. (PCL), polyethylene adipate (PEA), polylactic acid-glycolic acid copolymerization At least two of the physical (PLGA) and polyhydroxybutyrate valerate (PHBV) copolymers are physically blended, or are polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), polycaprolactone (PCL), polyethylene adipate (PEA), polylactic acid-glycolic acid copolymer (PLGA) and polyhydroxyl A monomer of at least two of the butyrate valerate (PHBV) copolymers is copolymerized.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PBS poly( ⁇ -hydroxybutyrate)
  • PCL
  • the mixture may include polylactic acid (PLA) and polylactic acid glycolic acid (PLGA), wherein the PLGA weight average molecular weight [2, 30] million, PLA weight average molecular weight [2, 100 10,000, in terms of weight percentage, the ratio of the two is between [1:9, 9:1].
  • PLA polylactic acid
  • PLGA polylactic acid glycolic acid
  • the degradable polyester can also be a blend comprising polymers having different degrees of crystallinity and different degradation cycles. As still another embodiment embodying the spirit of the present invention, it may be a mixture of a crystalline and amorphous degradable polyester polymer, or a blend of a low crystallinity and a high crystallinity degradable polyester polymer, by weight percentage. The content of the polyester having a crystallinity of 5 to 50% is between 10% and 90%.
  • the degradable polyester may be selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), and polycaprolactone (PCL). ), polyethylene adipate (PEA), polylactic acid-glycolic acid copolymer (PLGA), polyhydroxybutyrate valerate copolymer (PHBV).
  • the above polylactic acid may be poly- or poly-L-lactic acid.
  • the degradable polyester may also be mixed with an active pharmaceutical ingredient, the active drug may be a drug that inhibits vascular proliferation such as paclitaxel, rapamycin and derivatives thereof; or the antiplatelet drug is selected from cilostazol (Cilostazol) Or anti-thrombotic drugs such as heparin; or anti-inflammatory drugs such as dexamethasone, etc., the invention is not limited, and is applicable to any drug that can be used in combination with a stent; or a mixture of the foregoing drugs.
  • the active drug may be a drug that inhibits vascular proliferation such as paclitaxel, rapamycin and derivatives thereof; or the antiplatelet drug is selected from cilostazol (Cilostazol) Or anti-thrombotic drugs such as heparin; or anti-inflammatory drugs such as dexamethasone, etc.
  • the invention is not limited, and is applicable to any drug that can be used in combination with a stent; or a mixture of the for
  • the iron-based alloy matrix is selected from the group consisting of pure iron or a medical iron-based alloy.
  • One type can be doped into pure iron to form a medical iron-based alloy.
  • the degradable polyester is coated on the surface of the iron-based alloy substrate; or the iron-based alloy substrate is provided with a slit or a groove, the degradable polyester is embedded in the slit or the groove; or the iron
  • the base alloy matrix has a cavity in which the degradable polyester is filled. That is, the "surface" in the "contact with the surface of the substrate” means not only the outer surface, but also the contact point or contact surface of the degradable polyester or degradable polymer with the iron-based alloy substrate. can.
  • the absorbing iron-based alloy stent provided by the invention adopts a specific degradable polyester, which enables the metal matrix of the iron-based alloy to be controlled and rapidly corroded within a predetermined period of time, and can be implanted into the human body. It plays a mechanical support role in the early stage, and can be gradually degraded within a predetermined period of time and completely absorbed by the body's metabolism, avoiding the long-term risk that may be caused by long-term persistence in the human body.
  • the degradable stent provided by the present invention can produce no or less iron solid corrosion products during its absorption.
  • FIG. 1 is a schematic view of an iron-based alloy stent used in each embodiment and a comparative example of the present invention
  • Example 2 is a photograph of a cross-section iron element distribution spectrum of a metal rod after the biodegradable iron-based alloy stent provided in Example 1 of the present invention is implanted into the rabbit abdominal aorta for 3 months;
  • Example 3 is a photograph of a cross-section iron element distribution spectrum of a metal rod after the biodegradable iron-based alloy stent provided in Example 2 of the present invention is implanted into the rabbit abdominal aorta for 3 months;
  • Example 4 is a photograph of a cross-section iron element distribution spectrum of a metal rod after the biodegradable iron-based alloy stent provided in Example 3 of the present invention is implanted into the rabbit abdominal aorta for 3 months;
  • Figure 5 is a schematic cross-sectional view showing the iron-based alloy stent of the fourth embodiment of the present invention after coating a degradable polyester coating;
  • Example 6 is a photograph of a cross-section iron element distribution spectrum of a metal rod after the biodegradable iron-based alloy stent provided in Example 4 of the present invention is implanted into the rabbit abdominal aorta for 3 months;
  • FIG. 7 is a cross-sectional iron element distribution energy spectrum photograph of an absorbable iron-based alloy stent implanted in a rabbit abdominal aorta for 3 months;
  • Example 8 is a photograph showing the cross-section iron element distribution spectrum of the stent rod after the implantable iron-based alloy stent provided in Example 6 of the present invention is implanted into the abdominal aorta of the rabbit for 3 months;
  • Example 9 is a photograph of a cross-section iron element distribution spectrum of a stent rod after the implantable iron-based alloy stent provided in Example 7 of the present invention is implanted into the rabbit abdominal aorta for 3 months;
  • Example 10 is a photograph showing the cross-section iron element distribution spectrum of the stent rod after the implantable iron-based alloy stent provided in Example 8 of the present invention is implanted into the abdominal aorta of the rabbit for 3 months;
  • Figure 11 is a photograph showing the cross-section iron element distribution spectrum of the stent rod after the implantable iron-based alloy stent provided in Example 9 of the present invention is implanted into the rabbit abdominal aorta for 3 months;
  • FIG. 12 is a cross-sectional iron element distribution energy spectrum photograph of the stent rod after the implantable iron-based alloy stent provided in the embodiment 10 of the present invention is implanted into the pig abdominal aorta for 3 months;
  • Figure 13 is a photograph showing the cross-sectional iron element distribution spectrum of the stent rod after the absorption of the iron-based alloy stent provided in Example 11 of the present invention for 3 months;
  • FIG. 14 is a photograph showing the cross-section iron element distribution spectrum of the stent rod after the implantable iron-based alloy stent provided in the rabbit abdominal aorta for 3 months according to the embodiment 12 of the present invention
  • Figure 15 is a stent rod of an absorbable iron-based alloy stent provided in Example 13 of the present invention after implantation into a rabbit abdominal aorta for 3 months.
  • Figure 16 is a photograph showing the distribution of the iron element distribution of the stent rod after three months of implantation of the pure iron bare stent provided in Comparative Example 1 into the rabbit abdominal aorta;
  • Fig. 17 is a photograph showing the distribution of the iron element distribution of the stent rod after three months of implantation of the nitriding iron stent including the degradable polyester coating provided in Comparative Example 2.
  • the present invention investigates the effect of a degradable polyester coating on the corrosion of an iron-based alloy substrate in an absorbing iron-based alloy stent, including implanting the iron-based alloy stent combined with the degradable polyester coating into an animal.
  • the animal is euthanized, the stent is taken out from the body, and the radial support force and weight loss at the corresponding time point are tested, such as at 3 months, 6 months, 1 year, 2 years, 3 years, X-ray energy spectrometer (EDS) was used to test the stent rod cross section, and the mass of iron ions in the test solution and the bare stent (ie unbound degradable) were tested after the stent and its blood vessels were digested to form a solution.
  • EDS X-ray energy spectrometer
  • the ratio of the mass of the iron-based alloy support of the polyester is less than or equal to 5% is indicative of the rapid, controlled corrosion and complete absorption of the absorbable iron-based alloy stent provided by the present invention during its degradation cycle.
  • the iron-based alloy matrix is selected from the group consisting of pure iron or a medical iron-based alloy. In theory, nutrients and harmless elements in the human body, or less toxic elements such as C, N, O, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, Re,
  • the medical iron-based alloy is formed by doping into pure iron.
  • the test of the radial support force can be carried out by using a radial support force tester produced by MSI, including taking out the stent implanted in the animal body together with the blood vessel at a predetermined observation time point, and directly testing after dehydration and drying. Radial support force.
  • the weight loss test can be carried out by cutting out the blood vessel in which the stent is implanted in the animal at a predetermined observation time point, peeling off the blood vessel, removing the stent, and ultrasonicating in acetonitrile for 20 min to remove the degradable polyester coating. And its product; then the scaffold is ultrasonically cleaned in 3% tartaric acid for at least 20 min to remove the iron-based alloy corrosion product attached to the surface of the stent; the stent is dry and weighed to obtain the weight of the stent body after implantation, and the original body before implantation The bare stent weights are compared and the resulting difference is the weight loss of the iron-based alloy stent. The weight loss is usually expressed as a percentage of the weight difference to the original bare stent weight.
  • the EDS spectrum test is to take out the blood vessel of the stent from the animal body at a predetermined observation time point, fix it with formalin, and dehydrate it, then embedding the blood vessel with methacrylic resin, and cross-section along the axial direction of the stent rod. After slicing and polishing, the gold was sprayed and placed in a scanning electron microscope for observation and testing.
  • the iron ion concentration test comprises: taking a degradable polyester stent (the mass of the bare iron-based alloy stent M) implanted in the animal and the blood vessel therein at a predetermined observation time point, and using the concentrated nitric acid to hold the stent and the blood vessel there Digestion in a microwave digestion apparatus, after forming a volume V 0 solution with water, an Agilent 240FS atomic absorption spectrometer was used to test at a wavelength of 248.3 nm, a slit of 0.2 nm, acetylene as a combustion gas, and a flow rate of 2.0 L/min.
  • the concentration of iron ions in the solution C 0 if
  • the weight average molecular weight of the degradable polyester and its polydispersity coefficient are detected by an eight-angle laser light scattering instrument produced by Wyatt Corporation of the United States.
  • the present invention provides an absorbable iron-based alloy stent comprising an iron-based alloy substrate and a degradable polyester in contact with the surface of the substrate.
  • the degradable polyester which can be used in the absorbable iron-based alloy stent of the present invention is required to satisfy the following conditions:
  • the average molecular weight is between [2,100] and the polydispersity coefficient is between [1.2, 30].
  • the weight average molecular weight of the degradable polyester may be between [2, 5) million, or [5, 10) million, or between [10-20 million], or [20 , 30) between 10,000, or between [30-40) million, or between [40,60) million, or [60,100] million.
  • the polydispersity coefficients may be between [1.2, 5), or between [5, 10), or between [10, 20), or [20, 30], respectively.
  • the degradable polyester may be only polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate, poly( ⁇ -hydroxybutyrate) (PHB), polycaprolactone (PCL). Any one of polyethylene adipate (PEA), polylactic acid-glycolic acid copolymer, and polyhydroxybutyrate valerate copolymer.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PHB poly( ⁇ -hydroxybutyrate)
  • PCL polycaprolactone
  • the degradable polyester polymer may also be a mixture of at least two different weight average molecular weight homogeneous degradable polyester polymers.
  • the foregoing mixture may include a first degradable polyester-based polymer having a weight average molecular weight of [2,5] million, and a second degradable polycondensation having a weight average molecular weight of [6,100] million.
  • An ester polymer, the second degradable polyester polymer is of the same type as the first degradable polyester polymer, and the content ratio of the two is between 1:9 and 9: 1.
  • the degradable polyester-based polymer may be selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), and poly. Ester (PCL), polyethylene adipate (PEA), polylactic acid - Any one of a glycolic acid copolymer (PLGA) and a polyhydroxybutyrate valerate copolymer (PHBV).
  • the degradable polyester may also be composed of polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), polycaprolactone.
  • PLL polylactic acid
  • PGA polyglycolic acid
  • PBS poly( ⁇ -hydroxybutyrate)
  • PCL polycaprolactone
  • the mixture may include polylactic acid (PLA) and polylactic acid glycolic acid (PLGA), wherein the PLGA weight average molecular weight [2,30] million, the PLA weight average molecular weight [2,100] million, in weight percent, two The content ratio is between [1:9, 9:1].
  • PLA polylactic acid
  • PLGA polylactic acid glycolic acid
  • the degradable polyester can also be a blend comprising polymers having different degrees of crystallinity and different degradation cycles.
  • the degradable polyester-based polymer may be selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polysuccinate (PBS), poly( ⁇ -hydroxybutyrate) (PHB), and poly. Ester (PCL), polyethylene adipate (PEA), polylactic acid-glycolic acid copolymer (PLGA) or polyhydroxybutyrate valerate copolymer (PHBV).
  • the above lactic acid may be poly- or poly-L-lactic acid.
  • the degradable polyester may also be mixed with an active pharmaceutical ingredient, and the active drug may be a drug that inhibits vascular proliferation such as paclitaxel, rapamycin and derivatives thereof; or an anti-platelet type
  • the drug is selected from the group consisting of cilostazol; or an antithrombotic drug such as heparin; or an anti-inflammatory drug such as dexamethasone; or a mixture of the foregoing drugs.
  • the degradable polyester may be completely or partially coated on the surface of the iron-based alloy substrate; or the iron-based alloy substrate may have slits or grooves in which the degradable polyester is embedded; or the iron
  • the base alloy substrate is provided with an inner cavity, and the degradable polyester is filled in the inner cavity; or a combination of the above several ways.
  • the absorbing iron-based alloy stent provided by the present invention will be further described below in conjunction with the accompanying drawings and embodiments.
  • the iron-based alloy stents used in the following examples and comparative examples have the same shape and size, as shown in FIG. 1, and it is understood that the following embodiments are merely preferred embodiments of the present invention.
  • the invention is not intended to limit the invention, and any modifications, equivalents and improvements made within the spirit and scope of the invention are intended to be included within the scope of the invention.
  • the surface of the nitrided pure iron stent with a thickness of 60-70 ⁇ m is uniformly coated to a thickness of 8 to 15 ⁇ m and the weight is evenly divided.
  • the polycyclic lactic acid coating having a sub-quantity of 50,000 and a polydispersity coefficient of 2 is dried to obtain an absorbing iron-based alloy stent.
  • the iron-based alloy stent was implanted into the abdominal aorta of the rabbit. The stent was taken out at the corresponding observation time point, the weight loss percentage and radial support force of the stent were tested, and the EDS spectrum test was performed on the axial cross section of the stent rod.
  • the test results show that the weight loss of the stent is 25% for 3 months, the radial support force is 100 kPa, and the EDS spectrum test results are shown in Fig. 2. It can be seen from Fig. 2 that the corrosion products of the three-month iron stent rod are evenly distributed in the blood vessels, and there is no sedimentation of solid products. The iron ion concentration test was 3% after 2.5 years, indicating that the scaffold was completely degraded and absorbed.
  • the surface of the electrodeposited pure iron (550 ° C annealed) stent having a stent rod thickness of 80 to 100 ⁇ m is uniformly coated with a mixture of 15 to 25 ⁇ m thick polycaprolactone (PCL) and paclitaxel, wherein the polycap The ester is a mixture of two polycaprolactones having a weight average molecular weight of 20,000 and a weight average molecular weight of 80,000, and the polycaprolactone has a polydispersity coefficient of 5, and the quality of polycaprolactone and paclitaxel.
  • the ratio is 2:1. After drying, an absorbing iron-based alloy stent is obtained.
  • the iron-based alloy stent was implanted into the rabbit abdominal aorta, and the stent was taken out at the corresponding observation time.
  • the weight loss percentage and radial support force of the stent were tested, and the axial cross-section of the stent rod was tested by EDS.
  • the test results show that the weight loss of the stent is 20% for 3 months, the radial support force is 95 kPa, and the EDS spectrum test results are shown in Fig. 3. It can be seen from Fig. 3 that the corrosion products of the iron stent rods are evenly distributed in the blood vessels for 3 months, and there is no sedimentation of solid products. After 2.5 years, the iron ion concentration test result was 5%, indicating that the scaffold was completely degraded and absorbed.
  • the coating has a thickness of 30 to 40 microns.
  • the poly-L-lactic acid had a weight average molecular weight of 200,000, a polydispersity coefficient of 4, and a crystallinity of 50%. After drying, an absorbing iron-based alloy stent is obtained. The stent was implanted into the rabbit abdominal aorta, and the stent was taken out at the corresponding observation time.
  • the weight loss percentage and radial support force of the stent were tested, and the EDS spectrum was tested on the axial cross section of the stent rod.
  • the test results show that the weight loss of the stent is 8% for 3 months, the radial support force is 60 kPa, and the EDS spectrum test results are shown in Fig. 4. It can be seen from Fig. 4 that the corrosion products of the three-month iron stent rod are evenly distributed in the blood vessels, and there is no sedimentation of the solid product. After 3 years, the iron ion concentration test result was 5%, indicating that the scaffold was completely degraded and absorbed.
  • the bracket rod 1 of the bracket has a thickness of 100 to 120 ⁇ m, and the surface of the bracket rod 1 is provided with a groove 2 .
  • a mixture coating 3 of a degradable polyester-based polymer is uniformly applied to the surface of the stent rod 1 and the groove 2.
  • the coating of the degradable polyester polymer by weight ratio Polylactic acid lactic acid having a weight average molecular weight of 70,000 and a weight average molecular weight of 30,000 polylactic acid glycolic acid (50:50 molar ratio of lactic acid to glycolic acid) are mixed at a ratio of 1:1, and the polylactic acid polydispersity coefficient after mixing At 5, the mixture has a coating thickness of 15 to 25 microns.
  • an absorbing iron-based alloy stent is obtained.
  • the stent was implanted into the rabbit abdominal aorta, and the stent was taken out at the corresponding observation time. The weight loss percentage and radial support force of the stent were tested, and the EDS spectrum was tested on the axial cross section of the stent rod.
  • the test results show that the weight loss of the stent is 11% for 3 months and the radial support force is 80 kPa.
  • the EDS spectrum test results are shown in Fig. 6. It can be seen from Fig. 6 that the corrosion products of the stent rod are evenly distributed in the blood vessels for 3 months. There is no precipitation of solid product. After 3 years, the iron ion concentration test result was 4%, indicating that the stent was completely degraded and absorbed.
  • the inner wall of the stent lumen is not included, and the PLLA coating with a thickness of 5-8 micrometers is uniformly coated.
  • the weight average molecular weight of PLLA is 20,000, and the polydispersity coefficient is 2.
  • the stent was implanted into the abdominal aorta of the rabbit, and the stent was taken out at the corresponding observation time point, and the stent was subjected to weight loss, radial support force and EDS test. As a result, the weight loss of the stent was 28% for 3 months, the radial support force was 90 kPa, and the EDS spectrum test results are shown in Fig. 7.
  • the surface of the sulphurized pure iron support rod having a thickness of 240 to 260 ⁇ m is relatively uniformly coated with a coating having a thickness of 35 to 55 ⁇ m.
  • the coating is divided into two layers, and the thickness of the bottom layer in contact with the support rod is 20 to 25 ⁇ m.
  • the PLLA coating has a weight average molecular weight of 100,000, an amorphous state, and a polydispersity coefficient of 5.
  • the top layer coated on the bottom layer is a mixed coating of PLGA and heparin 1:1, wherein the PLGA has a weight average molecular weight of 30,000.
  • the polydispersity coefficient was 1.8, and the stent was implanted into the rabbit abdominal aorta.
  • the stent was taken out at the corresponding observation time point, and the stent was subjected to weight loss, radial support force and EDS test.
  • the weight loss of the stent was 10% for 3 months
  • the radial support force was 50 kPa
  • the EDS spectrum test results are shown in Fig. 8. It can be seen from Fig. 8 that the corrosion products of the iron stent rods are uniformly distributed in the blood vessels for 3 months, and there is no sedimentation of solid products. After 4 years, the iron ion concentration test result was 5%, indicating that the scaffold was completely degraded and absorbed.
  • the PLLA has a weight average molecular weight of 800,000, a crystallinity of 30%, a polydispersity coefficient of 2, a PLGA weight average molecular weight of 30,000, a polydispersity coefficient of 3, and a crystallinity of 5%.
  • the stent was implanted into the abdominal aorta of the rabbit, and the stent was taken out at the corresponding observation time point, and the stent was subjected to weight loss, radial support force and EDS test. As a result, the weight loss of the stent was 8% for 3 months, and the radial support force was 60 kPa. EDS spectrometry The test results are shown in Figure 9. It can be seen from Fig. 9 that the corrosion product of the iron stent rod for 3 months is evenly distributed in the blood vessel, and there is no sedimentation of the solid product. The iron ion concentration test was 3% after 3 years, indicating that the scaffold was completely degraded and absorbed.
  • a coating having an average thickness of 10 to 20 ⁇ m is applied, and the coating is composed of polylactic acid (PDLLA) and polyglycolic acid (PGA) in a weight ratio of 2: 1 mixed, wherein PDLLA has a weight average molecular weight of 150,000, a PGA weight average molecular weight of 50,000, and a polydispersity coefficient of 10 after mixing.
  • PDLLA polylactic acid
  • PGA polyglycolic acid
  • the weight loss of the stent was 18% for 3 months
  • the radial support force was 80 kPa
  • the EDS spectrum test results are shown in Fig. 10. It can be seen from Fig. 10 that the corrosion product of the iron stent rod for 3 months is evenly distributed in the blood vessel, and there is no sedimentation of the solid product.
  • the iron ion concentration test was 4% after 3 years, indicating that the scaffold was completely degraded and absorbed.
  • an iron-cobalt alloy stent with a thickness of 80-100 ⁇ m, there are two layers of coating thickness of 20-35 ⁇ m, wherein the bottom polylactic acid coating has a polylactic acid weight average molecular weight of 600,000 and a polydispersity coefficient of 7, crystallizing.
  • the amorphous polylactic acid having a degree of 35% and a top molecular weight average molecular weight of 250,000 has a polydispersity coefficient of 1.2, a crystalline polylactic acid, and a ratio of amorphous polylactic acid to rapamycin of 9:1:1.
  • the stent was implanted into the rabbit abdominal aorta and sampled at the corresponding time point.
  • the weight loss of the stent was 20% in 3 months, the radial support force was 85 kPa, and the EDS spectrum was shown in Fig. 11. As can be seen from the figure, The scaffold rod corrosion products are evenly distributed in the blood vessels, and no solid product precipitates. After 2.5 years, the iron ion concentration test result was 3%, indicating that the scaffold was completely degraded and absorbed.
  • An iron-palladium alloy stent having a stent rod thickness of 280-300 micrometers is coated with a mixture of polylactic acid and polyglycolic acid having a thickness of 30-60 micrometers, and the mixing ratio thereof is 9:1, and the weight average molecular weight after mixing is 400,000.
  • the polydispersity coefficient was 20, and the stent was implanted into the abdominal aorta of the pig. The sample was tested at the corresponding time point. The test result was that the radial support force of the stent was 45 kPa and the weight loss was 6% at 3 months.
  • the EDS test results are shown in the figure. As shown in Fig. 12, it can be seen that the stent rod is uniformly corroded, and no solid product precipitates and accumulates. The iron ion concentration test result is 5% at 4 years, indicating that the stent has been completely corroded and absorbed.
  • PHBV polyhydroxybutyrate valerate
  • the polymer has a weight average molecular weight of 300,000.
  • the multi-dispersion coefficient was 25, and the stent was implanted into the abdominal aorta of rabbits.
  • the stents were taken out at 3 months and 3 years respectively, and the test results were as follows: the weight loss of the stent was 12% for 3 months, and the radial support force was 80 kPa.
  • the EDS test results are shown in Figure 13. It can be seen from the figure that the stent rod is uniformly corroded and there is no solid precipitation accumulation.
  • the iron ion concentration test result is 4% at 3 years, indicating that the stent has completely corroded and absorbed.
  • the surface of the iron-nitrogen alloy stent having a thickness of 100-130 ⁇ m is coated with a poly- lactic acid coating having a thickness of 10-20 ⁇ m, the polymer having a weight average molecular weight of 350,000 and a polydispersity coefficient of 15.
  • the stent was implanted into the abdominal aorta of rabbits and tested at 3 months and 3.5 years respectively. The test results showed that the weight loss of the stent was 9% for 3 months and the radial support force was 55 kPa.
  • the EDS test results are shown in Figure 14. It can be seen that the stent rod is uniformly corroded and no solid product is accumulated. After 3.5 years, the iron ion concentration test result is 5%, indicating that the stent has completely corroded.
  • a coating of a blend of polylactic acid and polyglycolic acid is applied, and the coating thickness is 15-20 micrometers, wherein the polylactic acid has a weight average molecular weight of 1 million.
  • the degree is 50%, the content is 70%, the weight average molecular weight of polyglycolic acid is 20,000, the crystallinity is 15%, and the polydispersity coefficient of the blend is 30.
  • the stent is implanted into the porcine coronary artery, respectively, in 3 months and Four years of sampling and corresponding tests, the test results are: 3 months stent weight loss is 13%, radial support force is 90kPa, EDS test results are shown in Figure 15, as can be seen from the figure, the stent is uniformly corroded, no solid products After 4 years, the iron ion concentration test result was 4%, indicating that the stent was completely corroded.
  • a nitriding pure iron stent having a stent rod thickness of 60 to 70 ⁇ m is implanted into the abdominal aorta of the rabbit.
  • the stent was removed, the percent weight loss of the stent and the radial support force were tested, and the EDS spectrum was tested on the axial cross section of the stent rod (see Figure 16).
  • the test results show that the weight loss of the bracket is 5%, the radial supporting force is 120 kPa, and it can be seen from Fig. 11 that the bracket rod remains intact and there is almost no corrosion product around, indicating that the bare pure iron stent has a slow corrosion rate.
  • the iron ion concentration test showed that the stent was not completely absorbed.
  • a 15 ⁇ m thick polylactic acid glycolic acid (50:50 molar ratio of lactic acid to glycolic acid) was uniformly coated on the surface of the nitriding pure iron stent having a stent rod thickness of 60 to 70 ⁇ m. Drying produces an absorbable iron-based alloy stent.
  • the polylactic acid glycolic acid had a weight average molecular weight of 15,000 and a polydispersity coefficient of 1.3.
  • the absorbable iron-based alloy stent was implanted into the rabbit abdominal aorta. Three months later, the stent was removed, the stent weight loss percentage and radial support force were tested, and the EDS spectrum was tested on the axial cross section of the stent rod (see figure 17).

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Abstract

一种可吸收铁基合金支架，其包括铁基合金基体和与该基体表面接触的可降解聚酯，所述可降解聚酯的重均分子量在[2，100]万之间，且多分散系数在[1.2， 30]之间。该可降解聚酯与铁基合金基体匹配，可使该铁基合金在预定时段内快速可控的腐蚀。该可降解支架植入人体后，既能在早期起到力学支撑作用，又能逐渐降解并被人体代谢吸收，降解过程不产生或少产生铁的固体腐蚀产物，最终实现支架植入管腔的结构及舒缩功能恢复至自然状态。

Description

可吸收铁基合金支架 技术领域
本发明属于可降解植入医疗器械领域，涉及可在预定时段内快速、可控降解的可吸收铁基合金支架。
背景技术
当前，植入医疗器械通常采用金属及其合金、陶瓷、聚合物和相关复合材料制成。其中，金属材料以其优越的力学性能，如高强度、高韧性等，尤为受人青睐。
铁作为人体内的重要元素，参与到诸多生物化学过程中，如氧的搬运。Peuster M等采用激光雕刻方法制成的、与临床使用的金属支架形状相似的易腐蚀性纯铁支架，植入到16只新西兰兔的降主动脉处。此动物实验结果表明，在6-18个月内没有血栓并发症，亦无不良事件发生，病理检查证实局部血管壁无炎症反应，平滑肌细胞无明显增殖，初步说明可降解铁支架具有良好的应用前景。但该研究同时发现，纯铁在体内环境下的腐蚀速率较慢，需要改进。各种提高铁腐蚀速度的技术已不断被开发，包括合金化和改变其金相血管的方法。
可降解聚酯主要包括聚乳酸(polylactic acid，PLA)、聚乙醇酸(polyglycolic acid，PGA)、聚乳酸乙醇酸(poly(lactic acid-co-glycolic acid)，PLGA)、聚己内酯(polycaprolactone，PCL)等。该类聚合物具有优良的生物相容性和生物可吸收性，已被广泛地应用于生物医学工程材料，如手术缝合线、骨科固定、及血管修复材料、药物控制释放体系等。其中，Biosensor公司的Biomatrix药物洗脱支架以316L不锈钢为基体，PLA为药物载体，搭载Biolimus药物，该聚合物涂层可在6-9个月内完成降解；Boston Scientific公司的Synergy药物洗脱支架采用Pt-Cr合金为基体，PLGA为药物载体，搭载Everolimus药物，该聚合物涂层可在4个月内完成降解。目前有很多公司采用降解速度慢的聚左旋乳酸(PLLA)制作全降解血管支架，其吸收周期在2-3年。从以上例举可以看出，不同的可降解聚酯有不同降解吸收周期。
有报道指出，若在铁基合金(包括纯铁与医用铁基合金)支架表面涂覆可降解聚酯类涂层，该可降解聚酯类涂层在人体内的降解过程中会产生带有羧基的产物，使得植入位置附近的局部微环境的pH值下降，形成局部微酸性环境，降低铁基合金基体表面析氢反应的过电位，铁基合金基体产生析氢腐蚀，生成降解产物铁盐。该报道认为，通过使用可降解聚酯作为铁基合金基体的涂层，可以加速铁基合金基体的析氢腐蚀速度，降低支架在降解初期的毒性反应，利于内皮细胞在支架表面的快速内皮化。但该局部微酸环境和析氢腐蚀并未得到业 内证实，该报道也未涉及可降解聚合物降解与铁基体之间腐蚀的匹配性。
人体血管为含水体系，铁基合金在该环境下可发生吸氧腐蚀，生成Fe(OH)2，同步Fe(OH)2迅速氧化生成Fe(OH)3沉淀(如公式1.1和1.2所示)。而Fe(OH)2和Fe(OH)3为水不溶物，其在人体中的代谢主要通过细胞吞噬及微量电离Fe离子等方式实现，代谢吸收慢。同时，腐蚀产物包裹在铁植入物周围，会阻碍O2扩散至Fe周围，降低腐蚀速度，不利于铁的进一步代谢吸收。
2Fe+2H2O+O2＝2Fe(OH)2↓             (公式1.1)
4Fe(OH)2+O2+2H2O＝4Fe(OH)3↓    (公式1.2)
我们早期实验表明，在腐蚀环境中通氮去氧后，腐蚀速度大大降低。所以，我们认为，在人体内铁腐蚀并非如前述报道认为的析氢腐蚀，吸氧腐蚀是最可能或最主要的反应。
我们早期实验和理论研究还表明，可降解聚酯在降解过程中产生带有羧基的产物，能与Fe2+配位形成配位化合物，如乳酸亚铁、醋酸亚铁、甘氨酸亚铁等(如公式2.1和2.2所示)，该类腐蚀产物为水溶性铁盐，能快速被人体吸收。同时，水溶性铁盐可在体液中扩散至人体其它位置，铁植入物周围没有固体产物阻碍铁与O2的直接接触，可以加快Fe的腐蚀。
R1COOR2+H2O＝R1COOH+R2OH     (公式2.1)
Fe(OH)2+2RCOO-＝(RCOO)2Fe+2OH-  (公式2.2)
可降解聚酯虽然可以加速铁基合金腐蚀，并通过提供局部乳酸根离子的存在，提高铁离子浓度，但其降解速度和铁基合金的腐蚀速度是否匹配影响最终腐蚀产物的形态和铁腐蚀周期长度。具体而言，当腐蚀速度过快时，会影响该铁基合金支架植入后早期(如3个月)的结构完整性和力学性能，且如果铁离子释放超过了血管的吸收能力，则腐蚀形成的铁会在植入位置一定距离外的周边血管内再次沉积为固体铁锈，而在人体长期存留。当腐蚀速度不足时，可降解聚酯对铁腐蚀速度提升有限，导致铁基合金支架降解周期较长，如对于冠脉支架而言，在植入1年后3年内仍不能完全降解并被吸收，对于外周血管支架而言，在植入2年后4年内仍不能完全降解并被吸收，则难以凸显铁基合金支架可降解吸收的特性。另外，铁基合金基体的腐蚀周期与可降解聚酯的降解周期是否匹配，也严重影响铁支架整体降解周期。例如，如果可降解聚酯只在铁基合金的腐蚀早期存在并加速其腐蚀，则后期可降解聚酯降解完成后，铁基合金还没有完全腐蚀掉，剩下的铁基合金的降解速度就会较慢并形成固体铁锈，导致铁基合金支架整体降解周期较长，可能仍然无法满足临床上对可降解支架降解吸收的时间要求。
因此，有必要提供一种可降解聚酯来匹配铁基合金基体，获得一种可在预定时段内快速、可控地降解的可吸收铁基合金支架。
发明内容
本发明的一目的在于，选定特定的可降解聚酯涂层，将之与铁基合金基体表面接触或填充在其内部，来促进对铁基合金基体在人体内快速腐蚀、速度和周期可控，达成整个周期内铁基合金腐蚀速度和聚合物涂层降解速度的匹配，以使该支架植入人体后，既能在早期起到力学支撑作用，又能逐渐降解并被人体代谢吸收，吸收过程不产生或少产生铁的固体腐蚀产物。
本发明的另一目的在于，提供包括该可降解聚酯的可吸收铁基合金支架。该铁基合金支架中的铁基合金在该聚合物涂层的作用下，既可在预定时段内在人体内快速腐蚀吸收，又能在腐蚀周期的早期时段具有对血管的支撑所要求的力学性能。
本发明的又一目的在于，提供包括可降解聚酯涂层的可吸收铁基合金支架。该铁基合金支架中的铁基合金基体在该聚合物涂层的作用下，既可在预定时段内在人体内快速腐蚀，又能在早期满足力学性能的要求，还能在整个预定时段内相对均匀地腐蚀，使得铁基合金基体腐蚀产物的生成速率与体内的吸收速率一致，从而少生产固体产物，减轻固体产物的堆积。优选地，生成的铁腐蚀产物能完全被吸收，不产生任何堆积。
所述快速是指：对铁基合金支架杆厚度在[30，100)微米的铁基合金器械来说，是植入动物体内3个月时质量损失在10％以上，在植入1年后3年以内铁基合金完全降解并被完全吸收；对铁基合金支架杆厚度在[100，300]微米的器械来说，是植入动物体内3个月时质量损失在5％以上，在植入2年后4年内铁基合金完全腐蚀降解并被完全吸收。
所述可控，是指该可降解聚酯对铁基合金的快速腐蚀，既能保证该铁基合金器械在植入人体后的早期，铁基合金仍然能保持良好的力学性能，例如，对支架杆厚度在[30-100)微米的铁基合金支架，所述可降解聚酯涂层厚度介于[3，35]微米，3个月时径向支撑力在80kPa以上，且在植入2年后3年内铁基合金能够完全降解并被完全吸收；对支架杆厚度在[100，300]微米的铁基合金支架，所述可降解聚酯涂层厚度介于[10，60]微米，3个月时径向支撑力在40kPa以上，且在植入2年后4年内铁基合金能够完全降解并被完全吸收。
所述完全吸收，是指将本发明的可降解聚酯支架(对应的裸铁基合金支架质量为M）植入动物体内，在预定观察时间点，比如在3个月、6个月、1年、2年、3年甚或更长时间后，取出支架及其所在血管，用浓硝酸将支架及其所在血管在微波消解仪中消解，用水定容至体 积V0，测试该定容后溶液中铁离子浓度为C0，如果
Figure PCTCN2014090110-appb-000001
则该支架被完全吸收。
测试铁离子浓度的具体条件为：安捷伦240FS原子吸收光谱仪，波长为248.3nm，狭缝为0.2nm，乙炔为助燃气，流速为2.0L/min。
所述可降解聚酯是指含有酯基-COO-且其能在体内降解产生羧基-COOH的聚合物。所述可降解聚酯的重均分子量在[2，100]万之间，多分散系数在[1.2，30]之间。更进一步地，所述可降解聚酯地重均分子量可以分别介于[2，5)万之间，或[5，10)万之间，或[10，20)万之间，或[20，30)万，或[30，40)万，或[40，60)万，或[60，100]万之间，所述多分散系数可以分别介于[1.2，5)之间，或[5，10)之间，或[10，20)之间，或[20，30]之间。
所述各数值区间遵照数学常识，即[a，b]指大于或等于a，且小于或等于b；(a，b]指大于a，且小于或等于b；[a，b)指大于或等于a，小于b，全文下同，不再赘述。
在满足前述重均分子量范围和多分散系数范围的基础上，作为一种举例，所述可降解聚酯可仅为聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)、聚羟基丁酸酯戊酸酯共聚物(PHBV)中的任一种。
再如，该可降解聚酯还可以是至少两种不同重均分子量的同类可降解聚酯类聚合物的混合物。所述同类，是指具有相同聚合单体(结构单元)，但重均分子量不同的聚合物的统称。前述混合物可以包括重均分子量在[2，5]万之间的第一种可降解聚酯类聚合物，以及重均分子量在[6，100]万之间的第二种同类可降解聚酯类聚合物，所述第二种可降解聚酯类聚合物与所述第一种可降解聚酯类聚合物属于同类，按重量百分比计，两者含量比介于[1∶9，9∶1]。所述可降解聚酯可选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)、聚羟基丁酸酯戊酸酯共聚物(PHBV)中的任一种。作为举例，该可降解聚酯包括两种重均分子量不同的聚乳酸，该两种聚乳酸的重均分子量分别介于[2，5]万之间，[6，100]万之间，且两者含量比介于1∶9-9∶1。
又如，该可降解聚酯还可以由聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚 物(PLGA)和聚羟基丁酸酯戊酸酯(PHBV)共聚物中的至少两种物理共混而成，或者是由聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)和聚羟基丁酸酯戊酸酯(PHBV)共聚物中的至少两种的单体共聚而成。作为体现本发明精神的又一实施方式，该混合物可以包括聚乳酸(PLA)和聚乳酸乙醇酸(PLGA)，其中，PLGA重均分子量[2，30]万，PLA重均分子量[2，100]万，按重量百分比计，两者含量比例介于[1∶9，9∶1]。
还如，该可降解聚酯还可以是包括具有不同结晶度和不同降解周期的聚合物的共混物。作为体现本发明精神的再一实施方式，可以是结晶与非结晶可降解聚酯类聚合物的混合，或低结晶度与高结晶度的可降解聚酯类聚合物的共混，按重量百分比计，其中结晶度为5-50％的聚酯含量在10％-90％之间。所述可降解聚酯可选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)、聚羟基丁酸酯戊酸酯共聚物(PHBV)。
优选地，上述聚乳酸可以是聚消旋乳酸或聚左旋乳酸。
所述可降解聚酯中还可以混合有活性药物成分，活性药物可以是抑制血管增生的药物如紫杉醇、雷帕霉素及其衍生物；或抗血小板类药物选自西洛他唑(Cilostazol)；或抗血栓类药物如肝素；或抗炎症反应的药物如地塞米松等等，本发明不作限定，适用于可与支架配合使用的任何药物；也可以是前述几种药物的混合。
优选地，所述铁基合金基体选自纯铁或医用铁基合金。理论上，人体内营养元素和无害元素，或毒性较小的元素，例如C、N、O、S、P、Mn、Pd、Si、W、Ti、Co、Cr、Cu、Re中的至少一种，都可以掺杂入纯铁中形成医用铁基合金。
所述可降解聚酯涂覆在铁基合金基体表面；或者所述铁基合金基体设有缝隙或凹槽，所述可降解聚酯嵌设于所述缝隙或凹槽中；或者所述铁基合金基体具有腔体，所述可降解聚酯填充在所述腔体内。即，所述“与该基体表面接触”中的“表面”，不仅仅指外表面，只要是所述可降解聚酯或可降解聚合物与所述铁基合金基体有接触点或接触面即可。
与现有技术相比，本发明提供的可吸收铁基合金支架采用特定的可降解聚酯，能够使得铁基合金的金属基体在预定时段内可控快速的腐蚀，植入人体后，既能在早期起到力学支撑作用，而且能够在预定时段内逐渐降解并被人体代谢完全吸收，避免了在人体长期存留可能造成的远期风险。且，本发明提供的可降解支架在其吸收过程中能不产生或少产生铁的固体腐蚀产物。
附图说明
图1是本发明各实施例及对比例采用的铁基合金支架的示意图；
图2是本发明实施例1提供的可降解铁基合金支架植入兔子腹主动脉3个月后金属杆的截面铁元素分布能谱照片；
图3是本发明实施例2提供的可降解铁基合金支架植入兔子腹主动脉3个月后金属杆的截面铁元素分布能谱照片；
图4是本发明实施例3提供的可降解铁基合金支架植入兔子腹主动脉3个月后金属杆的截面铁元素分布能谱照片；
图5是本发明实施例4的铁基合金支架涂覆可降解聚酯涂层后的剖面示意图；
图6是本发明实施例4提供的可降解铁基合金支架植入兔子腹主动脉3个月后金属杆的截面铁元素分布能谱照片；
图7是本发明实施例5提供的可吸收铁基合金支架植入兔子腹主动脉3个月支架杆的截面铁元素分布能谱照片；
图8是本发明实施例6提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图9是本发明实施例7提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图10是本发明实施例8提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图11是本发明实施例9提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图12是本发明实施例10提供的可吸收铁基合金支架植入猪腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图13是本发明实施例11提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图14是本发明实施例12提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆的截面铁元素分布能谱照片；
图15是本发明实施例13提供的可吸收铁基合金支架植入兔子腹主动脉3个月后支架杆 的截面铁元素分布能谱照片；
图16是对比例1提供的纯铁裸支架植入兔子腹主动脉三个月后的支架杆截面铁元素分布能谱照片；
图17是对比例2提供的包括可降解聚酯涂层的渗氮铁支架植入兔子体内三个月后的支架杆截面铁元素分布能谱照片。
具体实施方式
首先需要说明的是，本发明研究可吸收铁基合金支架中可降解聚酯涂层对铁基合金基体腐蚀的影响，包括把该结合可降解聚酯涂层的铁基合金支架植入动物体内后，在预定的观察时间点，诸如3个月，对动物进行安乐处死，从其体内取出支架，通过测试对应时间点的径向支撑力和重量损失，诸如在3个月、6个月、1年、2年、3年，采用X射线能谱仪(EDS)测试支架的支架杆截面，以及将支架及其所在血管消解形成溶液后测试溶液中铁离子质量与裸支架(即未结合可降解聚酯的铁基合金支架)质量的比值是否小于或等于5％来表征本发明提供的可吸收铁基合金支架在其降解周期内快速、可控地腐蚀并被完全吸收。所述铁基合金基体选自纯铁或医用铁基合金。理论上，人体内营养元素和无害元素，或毒性较小的元素，例如C、N、O、S、P、Mn、Pd、Si、W、Ti、Co、Cr、Cu、Re，都可掺杂入纯铁中形成所述医用铁基合金。
所述径向支撑力的测试可使用MSI公司生产的径向支撑力测试仪进行，包括在预定观察时间点将植入动物体内的支架连同血管取出，脱水干燥后直接进行测试，即可得所述径向支撑力。
所述重量损失测试可通过如下方式进行：在预定观察时间点将植入动物体内的支架所在的血管截取出来后，将血管剥离，取出支架，在乙腈中超声20min，除去可降解聚酯涂层及其产物；然后将支架在3％的酒石酸中超声清洗至少20min，除去支架表面附着铁基合金腐蚀产物；将支架干燥称量获得植入后的支架本体重量，将其与植入前的原始裸支架重量进行比较，所得的差值即为铁基合金支架的重量损失。通常用重量差值占原始裸支架重量的百分比来表示重量损失。
所述EDS能谱测试是在预定观察时间点从动物体内取出支架所在的血管，用福尔马林固定后，并脱水处理后，用甲基丙烯酸树脂包埋血管，沿支架杆轴向横截面进行切片打磨抛光，喷金后放入扫描电镜中进行观察测试，其中，能谱仪为Oxford Instruments公司生产，测试条件(处理时间＝5，光谱范围为0-20KeV，通道数为1K)。
所述铁离子浓度测试包括在预定观察时间点，将植入动物体内的可降解聚酯支架(裸铁基合金支架质量为M)及其所在血管取出，用浓硝酸将支架及其所在血管在微波消解仪中消解，用水定容形成体积V0溶液后，采用安捷伦240FS原子吸收光谱仪，在波长为248.3nm，狭缝为0.2nm，乙炔为助燃气，流速为2.0L/min的条件下测试该溶液中铁离子的浓度C0，如果
Figure PCTCN2014090110-appb-000002
则该支架被完全吸收。
所述可降解聚酯重均分子量大小及其多分散系数采用美国怀雅特公司生产的八角度激光光散射仪进行检测。
其次，与本发明相关的实验表明，不同分子结构的可降解聚酯类聚合物有不同的降解速度，如在相同条件下聚乙醇酸(PGA)的降解速度大于聚乳酸(PLA)；对于同类可降解聚酯类聚合物，重均分子量大小和重均分子量分布以及结晶性均可以影响其降解速度。一般而言，重均分子量越大，降解速度越慢；结晶度越高，降解速度越慢。
本发明提供的可吸收铁基合金支架，包括铁基合金基体和与该基体表面接触的可降解聚酯，可用于本发明的可吸收铁基合金支架的可降解聚酯需满足以下条件：重均分子量在[2，100]万之间，多分散系数在[1.2，30]之间。更进一步地，所述可降解聚酯地重均分子量可以分别介于[2，5)万之间，或[5，10)万之间，或[10-20)万之间，或[20，30)万之间，或[30-40)万之间，或[40，60)万之间，或[60，100]万之间。所述多分散系数可以分别介于[1.2，5)之间，或[5，10)之间，或[10，20)之间，或[20，30]之间。
进一步地，所述可降解聚酯可仅为聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物、聚羟基丁酸酯戊酸酯共聚物中的任一种。
或者，该可降解聚酯类聚合物还可以是至少两种不同重均分子量的同类可降解聚酯类聚合物的混合物。例如，前述混合物可以包括重均分子量在[2，5]万之间的第一种可降解聚酯类聚合物，以及重均分子量在[6，100]万之间的第二种可降解聚酯类聚合物，所述第二种可降解聚酯类聚合物与所述第一种可降解聚酯类聚合物属于同类，按重量百分比计，两者含量比介于1∶9-9∶1。所述可降解聚酯类聚合物可选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸- 乙醇酸共聚物(PLGA)、聚羟基丁酸酯戊酸酯共聚物(PHBV)中的任一种。
再者，该可降解聚酯还可以由聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)和聚羟基丁酸酯戊酸酯(PHBV)共聚物中的至少两种物理共混而成，或者是由聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)和聚羟基丁酸酯戊酸酯(PHBV)共聚物中的至少两种的单体共聚而成。例如，该混合物可以包括聚乳酸(PLA)和聚乳酸乙醇酸(PLGA)，其中，PLGA重均分子量[2，30]万，PLA重均分子量[2，100]万，按重量百分比计，两者含量比例介于[1∶9，9∶1]。
还如，该可降解聚酯还可以是包括具有不同结晶度和不同降解周期的聚合物的共混物。例如，结晶与非结晶可降解聚酯类聚合物的混合，或低结晶度与高结晶度的可降解聚酯类聚合物的共混，按重量百分比计，其中结晶度为[5％，50％]的聚酯含量在[10％，90％]之间。所述可降解聚酯类聚合物可选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚丁二酸酯(PBS)、聚(β-羟基丁酸酯)(PHB)、聚已内酯(PCL)、聚己二酸乙二醇酯(PEA)、聚乳酸-乙醇酸共聚物(PLGA)或聚羟基丁酸酯戊酸酯共聚物(PHBV)。
上述乳酸可以是聚消旋乳酸或聚左旋乳酸。
作为药物洗脱支架的一种应用，所述可降解聚酯中还可以混合有活性药物成分，活性药物可以是抑制血管增生的药物如紫杉醇、雷帕霉素及其衍生物；或抗血小板类药物选自西洛他唑(Cilostazol)；或抗血栓类药物如肝素；或抗炎症反应的药物如地塞米松；也可以是前述几种药物的混合。
所述可降解聚酯可以完全或部分涂覆在铁基合金基体表面；或者铁基合金基体具有缝隙或凹槽，所述可降解聚酯镶嵌在所述缝隙或凹槽内；或者所述铁基合金基体设有内腔，所述可降解聚酯填充在所述内腔中；或者以上几种方式的相互组合。
以下结合附图和实施例对本发明提供的可吸收铁基合金支架作进一步说明。特别说明的是，下述各实施例及对比例采用的铁基合金支架具有相同形状及尺寸，见图1，且可以理解的是，下述各实施例仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
实施例1
在支架杆厚度为60～70微米的渗氮纯铁支架表面均匀全涂覆厚度为8～15微米、重均分 子量为5万、多分散系数为2的聚消旋乳酸涂层，干燥，制得可吸收铁基合金支架。将该铁基合金支架植入兔子腹主动脉。相应观察时间点取出支架，测试支架重量损失百分比和径向支撑力，并对支架杆轴向横截面做EDS能谱测试。测试结果表明，3个月支架重量损失25％，径向支撑力为100kPa，EDS能谱测试结果见图2。从图2中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。2.5年后铁离子浓度测试为3％，表明该支架完全降解并被吸收。
实施例2
将支架杆厚度为80～100微米的电沉积纯铁(550℃退火)支架表面均匀全涂覆15～25微米厚的聚己内酯(PCL)与紫杉醇的混合物涂层，其中该聚己内酯由重均分子量为2万和重均分子量为8万的两种聚己内酯1∶1混合而成，混合后的聚己内酯多分散系数为5，聚己内酯与紫杉醇的质量比例均为2∶1。干燥后，制得可吸收铁基合金支架。将该铁基合金支架植入兔子腹主动脉，相应观察时间点取出支架，测试支架重量损失百分比和径向支撑力，并对支架杆轴向横截面做EDS能谱测试。测试结果表明，3个月支架重量损失为20％，径向支撑力为95kPa，EDS能谱测试结果见图3。从图3中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。2.5年后铁离子浓度测试结果为5％，表明该支架完全降解并被吸收。
实施例3
在热处理后的渗碳铁支架外壁表面喷涂聚左旋乳酸和雷帕霉素的混合物涂层，其中该聚合物和雷帕霉素的质量比例为2∶1，支架杆厚度为140～160微米，该涂层厚度为30～40微米。该聚左旋乳酸的重均分子量为20万，多分散系数为4，且结晶度为50％。干燥后，制得可吸收铁基合金支架。将支架植入兔子腹主动脉，相应观察时间点取出支架，测试支架重量损失百分比和径向支撑力，并对支架杆轴向横截面做EDS能谱测试。测试结果表明，3个月支架重量损失为8％，径向支撑力为60kpa，EDS能谱测试结果见图4。从图4中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。3年后铁离子浓度测试结果为5％，表明该支架完全降解并被吸收。
实施例4
打磨Fe-30Mn-6Si合金(固溶处理)支架，使支架表面分布凹槽，如图5所示，该支架的支架杆1厚度为100～120微米，且支架杆1表面设有凹槽2。在支架杆1表面和凹槽2内均匀涂覆可降解聚酯类聚合物的混合物涂层3。按重量比计，该可降解聚酯类聚合物的涂层 为重均分子量均为7万的聚左旋乳酸和重均分子量为3万聚乳酸乙醇酸(乳酸与乙醇酸的摩尔比为50∶50)按1∶1混合，混合后的聚乳酸多分散系数为5，该混合物涂层厚度为15～25微米。干燥后，制得可吸收铁基合金支架。将支架植入兔子腹主动脉，相应观察时间点取出支架，测试支架重量损失百分比和径向支撑力，并对支架杆轴向横截面做EDS能谱测试。测试结果表明，3个月支架重量损失为11％，径向支撑力为80kpa，EDS能谱测试结果见图6，从图6中可以看出3个月支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。3年后铁离子浓度测试结果为4％，表明该支架完全降解并被吸收。
实施例5
在厚度为30～40微米的铁碳合金支架杆外表面，不包括支架管腔内壁，均匀涂覆厚度为5～8微米的PLLA涂层，PLLA重均分子量为2万，多分散系数为2，将该支架植入兔子腹主动脉，相应观察时间点取出支架，对支架进行重量损失，径向支撑力和EDS测试。结果为，3个月支架重量损失28％，径向支撑力为90kPa，EDS能谱测试结果见图7。从图7中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。1.5年后铁离子浓度测试结果为2％，表明该支架完全降解并被吸收。
实施例6
在厚度为240～260微米的渗硫纯铁支架杆表面，相对均匀的涂覆厚度35～55微米的涂层，该涂层分为两层，与支架杆接触的底层厚度为20～25微米的PLLA涂层，重均分子量为10万，无定形态，多分散系数为5，在该底层上涂覆的顶层为PLGA和肝素1∶1的混合涂层，其中PLGA重均分子量为3万，多分散系数为1.8，将支架植入兔子腹主动脉，相应观察时间点取出支架，对支架进行重量损失，径向支撑力和EDS测试。结果为，3个月支架重量损失10％，径向支撑力为50kPa，EDS能谱测试结果见图8。从图8中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。4年后铁离子浓度测试结果为5％，表明该支架完全降解并被吸收。
实施例7
在厚度为120～150微米的铁锰合金支架杆表面，喷涂厚度为20～30微米的涂层，该涂层由PLGA、PLLA、雷帕霉素三者以重量比1∶9∶1混合而成，其中，PLLA重均分子量为80万，结晶度为30％，多分散系数为2，PLGA重均分子量为3万，多分散系数为3，结晶度5％。将支架植入兔子腹主动脉，相应观察时间点取出支架，对支架进行重量损失，径向支撑力和EDS测试。结果为，3个月支架重量损失为8％，径向支撑力为60kPa，EDS能谱测 试结果见图9。从图9中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。3年后铁离子浓度测试为3％，表明该支架完全降解并被吸收。
实施例8
在厚度为70～90微米的渗碳铁支架表面，涂覆平均厚度为10～20微米的涂层，该涂层由聚消旋乳酸(PDLLA)和聚乙醇酸(PGA)以重量比2∶1混合而成，其中PDLLA重均分子量为15万，PGA重均分子量为5万，混合后多分散系数为10。将支架植入兔子腹主动脉，并取样测试，相应观察时间点取出支架，对支架进行重量损失，径向支撑力和EDS测试。结果为，3个月支架重量损失为18％，径向支撑力为80kPa，EDS能谱测试结果见图10。从图10中可以看出3个月铁支架杆的腐蚀产物在血管中均匀分布，没有固体产物的沉淀堆积。3年后铁离子浓度测试为4％，表明该支架完全降解并被吸收。
实施例9
在厚度为80-100微米厚的铁钴合金支架表面，有两层涂层厚度为20-35微米，其中底层聚乳酸涂层，聚乳酸重均分子量为60万，多分散系数为7，结晶度为35％，顶层重均分子量25万的非结晶型聚乳酸，多分散系数为1.2，结晶性聚乳酸，非结晶型聚乳酸与雷帕霉素比例为9∶1∶1。将该支架植入兔子腹主动脉，并在相应时间点取样测试，3个月支架重量损失为20％，径向支撑力为85kPa，EDS能谱见图11，从图中可以看出，该支架杆腐蚀产物在血管中均匀分布，没有固体产物沉淀堆积。2.5年后铁离子浓度测试结果为3％，表明该支架完全降解并被吸收。
实施例10
将支架杆厚度为280-300微米的铁钯合金支架，涂覆厚度为30-60微米的聚乳酸和聚乙醇酸混合物，二者混合比例为9∶1，混合后重均分子量为40万，多分散系数为20，将该支架植入猪腹主动脉，在相应时间点取样测试，测试结果为，3个月时支架径向支撑力为45kPa，重量损失为6％，EDS测试结果见图12所示，从图中可以看出，该支架杆均匀腐蚀，无固体产物沉淀堆积，4年时铁离子浓度测试结果为5％，表明该支架已经完全腐蚀并被吸收。
实施例11
在支架杆厚度为40-50微米的纯铁支架表面，涂覆厚度为3-10微米的聚羟基丁酸酯戊酸酯(PHBV)共聚物涂层，该聚合物重均分子量为30万，多分散系数为25，将该支架植入兔子腹主动脉，分别在3个月和3年取出支架进行相应测试，测试结果为，3个月支架重量损失为12％，径向支撑力为80kPa，EDS测试结果见图13所示，从图中可以看出，该支架杆均匀腐蚀，无固体沉淀堆积，3年时铁离子浓度测试结果为4％，表明该支架已经完全腐蚀并 被吸收。
实施例12
在支架杆厚度为100-130微米的铁氮合金支架表面，涂覆厚度为10-20微米的聚消旋乳酸涂层，该聚合物重均分子量为35万，多分散系数为15，将该支架植入兔子腹主动脉，分别在3个月和3.5年进行相应测试，测试结果为，3个月支架重量损失为9％，径向支撑力为55kPa，EDS测试结果见图14，从图中可以看出，该支架杆均匀腐蚀，无固体产物堆积，3.5年后，铁离子浓度测试结果为5％，表明该支架已经完全腐蚀。
实施例13
在支架杆厚度为120-150微米的纯铁支架表面，涂覆聚乳酸和聚乙醇酸的共混物涂层，涂层厚度为15-20微米，其中聚乳酸重均分子量为100万，结晶度为50％，含量为70％，聚乙醇酸重均分子量为2万，结晶度为15％，共混物多分散系数为30，将该支架植入猪冠脉，分别在3个月和4年取样进行相应测试，测试结果为，3个月支架重量损失为13％，径向支撑力为90kPa，EDS测试结果见图15，从图中可以看出，该支架均匀腐蚀，无固体产物堆积，4年后，铁离子浓度测试结果为4％，表明该支架已经完全腐蚀。
对比例1
将支架杆厚度为60～70微米的渗氮纯铁支架(即表面未覆盖有任何涂层)植入兔子腹主动脉。三个月后，取出支架，测试支架重量损失百分比和径向支撑力，并对支架杆轴向横截面做EDS能谱测试(见图16)。测试结果表明，支架重量损失为5％，径向支撑力为120kpa，且从图11中可以看出，支架杆保持完整，周围几乎没有腐蚀产物，说明裸的纯铁支架腐蚀速度慢。3年后铁离子浓度测试表明，该支架未完全吸收。
对比例2
在支架杆厚度为60～70微米的渗氮纯铁支架表面均匀涂覆15微米厚的聚乳酸乙醇酸(乳酸与乙醇酸的摩尔比为50∶50)。干燥，制得可吸收铁基合金支架。该聚乳酸乙醇酸的重均分子量为1.5万，多分散系数为1.3。将该可吸收铁基合金支架植入兔子腹主动脉，三个月后，取出支架，测试支架重量损失百分比和径向支撑力，并对支架杆轴向横截面做EDS能谱测试(见图17)。测试结果表明，支架重量损失为30％，径向支撑力为60kpa，说明早期腐蚀过快，导致支架早期支撑力的过快下降，不利于植入早期支架对血管的有效支撑。且，从图12中可以看到，早期因铁腐蚀过快，导致过多的铁离子释放超过了血管的吸收能力，在支架杆的原始位置外围形成了新的腐蚀产物沉积层。

Claims (14)

  1. 一种可吸收铁基合金支架，包括铁基合金基体和与该基体表面接触的可降解聚酯，其特征在于，所述可降解聚酯重均分子量在[2，100]万之间，且多分散系数在[1.2，30]之间。
  2. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体的支架杆厚度介于[30，100)微米，所述可降解聚酯涂层厚度在[3，35]微米。
  3. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体的支架杆厚度介于[100，300]微米，所述可降解聚酯涂层厚度介于[10，60]微米。
  4. 如权利要求1-3任一项所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯为聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物、聚羟基丁酸酯戊酸酯共聚物中的任一种。
  5. 如权利要求1-3任一项所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯包括至少两种同类可降解聚酯类聚合物，其中第一种可降解聚酯类聚合物的重均分子量在[2，5]万之间，第二种可降解聚酯类聚合物重均分子量在[6，100]万之间，按重量百分比计，该第一种与第二种可降解聚酯类聚合物的比例介于[1∶9，9∶1]，所述同类可降解聚酯类聚合物选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物中的任一种。
  6. 如权利要求1-3任一项所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯由聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物中的至少两种物理共混而成，或者是由聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物中的至少两种的单体共聚而成。
  7. 如权利要求1-3任一项所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯为具有不同结晶度的可降解聚酯类聚合物的混合物，所述可降解聚酯类聚合物选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚乳酸-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物，其中，按重量百分比计，结晶度为[5％，50％]的聚酯含量在[10％，90％]之间。
  8. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯与所述铁基合 金基体表面接触的方式选自以下至少一种：所述可降解聚酯覆盖在所述铁基合金基体表面；或者所述铁基合金基体设有缝隙或凹槽，所述可降解聚酯设于所述缝隙或凹槽中；或者所述铁基合金基体具有内腔，所述可降解聚酯填充在所述内腔内。
  9. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体选自在纯铁中掺杂有C、N、O、S、P中的至少一种后形成的医用铁基合金。
  10. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体选自纯铁或纯铁中掺杂有Mn、Pd、Si、W、Ti、Co、Cr、Cu、Re中的至少一种后形成的医用铁基合金。
  11. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯中混有活性药物。
  12. 如权利要求1-3任一项所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯的重均重均分子量介于[2，5)万之间，或[5，10)万之间，或[10，20)万之间，或[20，30)万，或[30，40)万，或[40，60)万，或[60，100]万之间。
  13. 如权利要求1-3任一项所述的可吸收铁基合金支架，其特征在于，所述多分散系数介于[1.2，5)之间，或[5，10)之间，或[10，20)之间，或[20，30]之间。
  14. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯类为含有酯基-COO-且能在体内降解产生羧基-COOH的聚合物。
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