WO2017113657A1 - 可吸收铁基合金内固定植入医疗器械 - Google Patents

可吸收铁基合金内固定植入医疗器械 Download PDF

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WO2017113657A1
WO2017113657A1 PCT/CN2016/087292 CN2016087292W WO2017113657A1 WO 2017113657 A1 WO2017113657 A1 WO 2017113657A1 CN 2016087292 W CN2016087292 W CN 2016087292W WO 2017113657 A1 WO2017113657 A1 WO 2017113657A1
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iron
based alloy
degradable
group
acid
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PCT/CN2016/087292
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French (fr)
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林文娇
张德元
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先健科技(深圳)有限公司
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Priority to US15/775,137 priority Critical patent/US11819591B2/en
Priority to EP16880462.3A priority patent/EP3398622B1/en
Publication of WO2017113657A1 publication Critical patent/WO2017113657A1/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
    • A61L31/02—Inorganic materials
    • A61L31/028—Other inorganic materials not covered by A61L31/022 - A61L31/026
    • 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
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing 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
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A61L17/12—Homopolymers or copolymers of glycolic acid or lactic acid
    • 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
    • A61L31/02—Inorganic materials
    • A61L31/022—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
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—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
    • 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
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
    • 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
    • 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
    • A61L31/148—Materials at least partially resorbable by the body
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/08—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained otherwise than by reactions only involving unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
    • C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
    • 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
    • A61L27/042—Iron or iron alloys

Definitions

  • the invention belongs to the field of absorbable implant medical devices, in particular to an absorbable iron-based alloy internal fixation implanted medical device.
  • the fracture healing time varies with the location of the injury, the degree of injury, and even the treatment method, usually 2 to 6 months, which requires the internal fixation of the implanted medical device to have a certain initial mechanical properties.
  • the initial bending strength of the nail should be more than 350 MPa
  • the tensile strength of the suture should be 400 MPa or more.
  • the materials currently used for the manufacture of internal fixation implanted medical devices for wound repair mainly include permanent metals such as stainless steel, titanium-based alloys, cobalt-based alloys, and absorbable materials such as polymers and magnesium-based alloys.
  • permanent metals have excellent mechanical properties and biocompatibility. They will remain in the human body for a long time after the damaged bones heal. There is a potential long-term biological risk. If taken, it will increase the patient's pain and economic burden. At the same time, it may cause secondary damage (such as slippery teeth in the residual body).
  • Absorbable polymers such as polylactic acid, polylactone, etc. have accumulated a large amount of clinical data with good biocompatibility. Generally, within a certain range, the higher the molecular weight and crystallinity of the polymer, the better the comprehensive mechanical properties, but at the same time, the more difficult the polymer is to dissolve in the organic solvent. Therefore, the finished product can only be produced by heating it into a flowing melt and then molding, injection molding, drawing or extrusion molding. Structures that do not require high mechanical properties, such as absorbable polymer coatings for medical devices, are typically coated with a low molecular weight polymer and dissolved in an organic solvent to coat the surface or interior of the medical device. The processing method of the high molecular weight polymer is usually melted and then processed, so that the high molecular weight polymer is suitable for making an internal fixation implanted medical device for wound repair with a certain mechanical strength.
  • the flexural strength of magnesium-based alloy implanted medical devices can reach about 300 MPa, but the mechanical properties of magnesium-based alloys still fall short of the level of permanent metal implant materials. Currently, they can only be used for non-weight bearing and activities. Location, for example, small The internal fixation of bone and bone fragments has a limited clinical application; in addition, the magnesium-based alloy has a faster corrosion rate, and the implanted medical device will lose its effective support and fixation prematurely, and the local pH of the implant site will increase when corroded. Bone growth has an adverse effect and is prone to poor bone union.
  • the mechanical properties of the absorbing iron-based alloy can be close to that of permanent stainless steel, cobalt-chromium alloy and titanium alloy, and have better mechanical properties than the absorbable polymer and the magnesium-based alloy, but the corrosion rate of the iron-based alloy is slow.
  • CN104587534 discloses that in an acidic micro-environment formed after degradation of a polymer material such as a degradable polyester, the corrosion rate of the iron-based alloy can be remarkably improved, thereby significantly shortening the corrosion period of the iron-based alloy, but absorbing the iron-based alloy by oxygen absorption.
  • the corrosion products produced by corrosion are usually hydroxides or oxides of insoluble iron.
  • the corrosion products of these insoluble irons may be metabolized and absorbed by the body for several years or more. Although their biocompatibility is very good, their long-term existence aggravates the organization. The burden of metabolism. Therefore, it is necessary to reduce the insoluble corrosion products of the absorbing iron-based alloy internal fixation implanted medical device while taking into consideration the mechanical properties.
  • the invention provides an absorbing iron-based alloy internal fixation implanted medical instrument, which has better initial mechanical properties under the premise of reducing the amount of the iron-based alloy matrix, and the amount of the hardly-corroded corrosion product of the iron-based alloy in the later stage of implantation is better. Less, reducing the burden on tissues for their metabolism.
  • An absorbable iron-based alloy internal fixation implanted medical device the base of which comprises an iron-based alloy and a degradable polymer
  • the mass ratio of the iron-based alloy to the degradable polymer is [1:4, 4:1
  • the degradable polymer has a weight average molecular weight of [15,300] and a polydispersity coefficient of [1,6].
  • the mass ratio of the iron-based alloy to the degradable polymer is preferably between [1:4, 1:1].
  • the absorbing iron-based alloy internal fixation implant medical device further comprises an antioxidant selected from the group consisting of butylated hydroxyanisole, dibutylhydroxytoluene, tert-butyl hydroquinone, propyl gallate, At least one of vitamin A, carotenoids, ubiquinone, glutathione, water-soluble polyphenols, tocopherol, sodium tripolyphosphate, sodium ascorbate, lipoic acid salt, ascorbyl palmitate, said water-soluble The polyphenol is selected from the group consisting of white reed alcohol and flavonoids.
  • the degradable polymer comprises a degradable polyester, or a mixture of the degradable polyester and at least one of a degradable polyanhydride, a degradable polyamino acid, a degradable polyphosphate, or at least one A copolymer of a monomer of a degradable polyester and at least one monomer forming the degradable polyanhydride, degradable polyamino acid or degradable polyphosphate.
  • the degradable polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, polycaprolactone, polyhydroxyalkanoate, polyethylene adipate, polylactic acid-glycolic acid copolymer, poly Any one of hydroxybutyrate valerate copolymers, or selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, polycaprolactone, polyhydroxyalkanoate, polyethylene adipate a physical blend of at least two of a polylactic acid-glycolic acid copolymer and a polyhydroxybutyrate valerate copolymer, or forming the foregoing a copolymer of at least two monomers in a monomer that degrades polyester;
  • the degradable polyanhydride is selected from the group consisting of crosslinked polyanhydrides, aromatic polyanhydrides, aliphatic polyanhydrides, heterocyclic polyanhydrides, polyacyl anhydrides, poly Any one of an
  • the iron-based alloy is a pure iron or iron-based alloy having a carbon content of not more than 2.11 wt.%.
  • the absorbable iron-based alloy internal fixation implanted medical device is a bone nail or a suture.
  • the invention adopts an iron-based alloy as a load-bearing skeleton or a reinforcing phase of an internal fixation implanted medical device, so that the device has good initial mechanical properties under the premise of reducing the amount of the iron-based alloy matrix;
  • the mass ratio and combination of the degradable polymer accelerates the corrosion rate of the iron-based alloy matrix at the same time as the implant, and reduces the amount of the hardly soluble corrosion products of the iron-based alloy, and reduces the burden of the structure on the corrosion of the corrosion product;
  • the oxidant further reduces the amount of poorly soluble corrosion products of the iron-based alloy.
  • Example 1 is a schematic view showing the structure of a bone nail prepared in Example 1.
  • Example 2 is a schematic view showing the structure of a bone nail prepared in Example 2.
  • Example 3 is a schematic cross-sectional view of a composite bar for making a bone nail prepared in Example 5.
  • the base material of the absorbing iron-based alloy internal fixation implanted medical device of the present invention comprises an iron-based alloy and a degradable polymer, and the mass ratio of the iron-based alloy to the degradable polymer is [1:4, 4: Between 1], the device has good initial mechanical properties under the premise of reducing the amount of the iron-based alloy matrix, and can rapidly degrade and degrade the amount of the poorly soluble corrosion product in the later stage of implantation, thereby reducing the metabolic burden of the tissue.
  • the composite of the iron-based alloy and the degradable polymer composite includes:
  • the iron-based alloy is distributed in the degradable polymer in the form of a solid or hollow whisker, a filament, a rod, an irregular stent or a mesh; or
  • the iron-based alloy and the degradable polymer respectively form a layer and the iron-based alloy layer and the polymer layer alternate with each other;
  • the iron-based alloy is stranded on the degradable polymer filament in a filament form
  • the iron-based alloy has grooves, voids, slits or hollow lumens, and the degradable polymer is filled in the grooves, pores, slits or hollow lumens.
  • the iron-based alloy and the degradable polymer adopt the above composite method, and can reduce the initial mechanical properties of the permanent metal material (such as stainless steel, cobalt chromium alloy and titanium-based alloy) while reducing the initial mechanical properties of the iron-based alloy substrate.
  • the amount used thereby reducing the amount of poorly soluble corrosion products that may be formed.
  • the degradable polymer comprises a degradable polyester, or a mixture of the degradable polyester and at least one of a degradable polyanhydride, a degradable polyamino acid, a degradable polyphosphate, or at least one A copolymer of a monomer of a degradable polyester and at least one monomer forming the degradable polyanhydride, degradable polyamino acid or degradable polyphosphate.
  • the degradable polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, polycaprolactone, polyhydroxyalkanoate, polyethylene adipate, polylactic acid-glycolic acid copolymer, poly Any one of hydroxybutyrate valerate copolymers, or selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, polycaprolactone, polyhydroxyalkanoate, polyethylene adipate a physical blend of at least two of a polylactic acid-glycolic acid copolymer, a polyhydroxybutyrate valerate copolymer, or a copolymer of at least two of the monomers forming the aforementioned degradable polyester;
  • the degradable polyanhydride is selected from the group consisting of a cross-linked polyanhydride, an aromatic polyanhydride, an aliphatic polyanhydride, a heterocyclic polyanhydride, a polyamic anhydride,
  • the iron-based alloy matrix gradually corrodes in the physiological solution to form a primary corrosion product Fe 3+ or Fe 2+ , Fe 3+ or Fe 2+ subsequently in the environment
  • the OH - reaction produces a poorly soluble corrosion product such as Fe(OH) 2 or Fe(OH) 3 .
  • the degradable polyester, the degradable polyanhydride, the degradable polyamino acid, and the degradable polyphosphate degrade and release hydrogen ions, which can effectively inhibit the reaction of Fe 3+ or Fe 2+ and OH ⁇ ; degradable polyester, representing OH generated after the environment biodegradable polyanhydrides, polyamino acid degradable and biodegradable polyphosphate degradation complex ions (ligand) - preferentially with Fe 3+ or Fe 2+ to form a stable coordination reaction
  • the soluble iron complex can further reduce or prevent the reaction of Fe 3+ or Fe 2+ with OH - in the physiological environment to form a poorly soluble corrosion product.
  • the mass ratio of the iron-based alloy to the degradable polymer in the device is between [1:4, 4:1], preferably between [1:4, 1:1], so that the device can be obtained
  • the desired mechanical properties simultaneously reduce the amount of poorly soluble corrosion products.
  • the absorbing iron-based alloy internal fixation implant medical device further comprises an antioxidant selected from the group consisting of butylated hydroxyanisole, dibutylhydroxytoluene, tert-butyl hydroquinone, propyl gallate, At least one of vitamin A, carotenoids, ubiquinone, glutathione, water-soluble polyphenols, tocopherol, sodium tripolyphosphate, sodium ascorbate, lipoic acid salt, ascorbyl palmitate, said water-soluble The polyphenol is selected from the group consisting of white reed alcohol and flavonoids.
  • the antioxidant may be coated on the surface of the iron-based alloy; when the iron-based alloy has a slit, a groove or a cavity, the antioxidant may be disposed in the gap, the groove and the inner cavity of the iron-based alloy Further, the antioxidant may be dispersed in the degradable polymer.
  • the solubility of the poorly soluble corrosion product in the physiological environment is small, a small amount of ions still enter the solution, and ions entering the solution are deposited on the solid surface.
  • the equilibrium constant is called dissolution.
  • Fe 3+ and OH - generated by corrosion products insoluble Fe (OH) 3 is far below the solubility product for Fe 2+ and OH - generated corrosion products insoluble Fe (OH) 2 solubility product, i.e., into the solution of The amount of Fe 3+ is much lower than the amount of Fe 2+ entering the solution.
  • the corrosion product of ferric iron is more difficult to metabolize in the body, and adding an antioxidant to the absorbable iron-based alloy internal fixation implanted medical device can inhibit the conversion of Fe 2+ to Fe 3+ , thereby reducing the poor solubility of three
  • the formation of ferrous corrosion products increases the solubility of iron.
  • a complexing agent selected from the group consisting of monodentate ligands and/or multidentate ligands.
  • the hydroxyl group on the fused ring aromatic hydrocarbon is selected from a phenolic hydroxyl group; the aromatic heterocyclic group is selected from a furyl group Pyrrolyl Thienyl Imidazolyl Triazolyl Thiazolyl Pyridyl Pyridone Pyranyl Pyrone Pyrimidinyl Pyridazinyl Pyrazinyl Quinoline Isoquinolinyl Pyridazinyl Acridine Base Base Phenanthroline
  • the monodentate ligand is selected from the group consisting of gluconic acid, glucoheptonic acid, glycolic acid, and derivatives or salts thereof.
  • the polydentate ligand of the hydroxyl group on the fused ring aromatic hydrocarbon is selected from the group consisting of 8-hydroxyquinoline, 8-hydroxyquinaldine, sodium 4,5-dihydroxybenzene-1,3-disulfonate, 4-[3 , 5-dihydroxyphenyl-1H-1,2,4-triazole]-benzoic acid (destasis);
  • the thiol-containing polydentate ligand is selected from the group consisting of 8-mercaptoquinoline, thioglycolic acid, Methyl 5-methyl-2-mercaptobenzoate;
  • the amine group-containing polydentate ligand is selected from the group consisting of ethylenediamine, triethylenetetramine, ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetate, N' -[5-[[4-[[5-(acetylhydroxylamino)pentyl]amino]
  • the carbonyl-containing polydentate ligand is further selected from the group consisting of oxalic acid, tartaric acid, malic acid, succinic acid, and oxaloacetic acid. , fumaric acid, maleic acid, citric acid, triammonium citrate, ammonia triacetic acid, diethylene triamine pentacarboxylic acid, alginic acid, glutamic acid, aspartic acid, ornithine, lysine, potassium citrate Calcium citrate, glyceryl citrate, acetylsalicylic acid, sulfosa salicylamide, polyaspartic acid, polyglutamic acid, polyornithine, polylysine, polymaleic anhydride.
  • the complexing agent may be coated on the surface of the iron-based alloy; when the iron-based alloy has a slit, a groove or a cavity, the complexing agent may be disposed in the gap, the groove of the iron-based alloy, In the inner cavity; in addition, the complexing agent may also be dispersed in the degradable polymer.
  • the complexing agent can provide a lone pair of electrons or ⁇ -electrons, complexing with Fe 2+ and/or Fe 3+ to form a water-soluble iron complex, compared with a water-soluble iron complex.
  • the insoluble solid corrosion products of iron-based alloys can be metabolized/absorbed by the body more quickly.
  • the iron complex has a greater stability than Fe(OH) 2 and/or Fe(OH) 3 and does not convert into insoluble Fe(OH) 2 and/or Fe(OH) 3 in a physiological solution.
  • the absorbing iron-based alloy internal fixation implant medical device further comprises a biocompatible good degradable binder selected from the group consisting of polyester hot melt adhesive, polyamide hot melt adhesive, and starch. At least one of a cyclodextrin, a lignin, or a copolymer selected from at least two of the monomers forming a polyester hot melt adhesive, a polyamide hot melt adhesive, a starch, a cyclodextrin, and a lignin.
  • a biocompatible good degradable binder selected from the group consisting of polyester hot melt adhesive, polyamide hot melt adhesive, and starch.
  • the present invention performs an in vitro accelerated corrosion test on the device: after etching the device in a 100 ml PBS solution for three weeks at 80 ° C, the iron-based alloy is corroded.
  • the soluble corrosion product formed is fully dissolved in PBS solution, and the infusion solution is filtered with an aqueous membrane having a pore size of 0.22 ⁇ m, and then the concentration of dissolved iron in the filtrate is measured by atomic absorption spectrometry (AAS), and the solubility in the PBS solution is dissolved.
  • AAS atomic absorption spectrometry
  • the mass of iron m 1 cV, where V is the volume of the solution; the instrument is taken out, the rust is removed, and the weighing is washed, and the weight loss of the iron-based alloy portion is calculated as ⁇ m, which is the mass of iron in the corrosion product of the iron-based alloy;
  • the mass percentage W of soluble iron in the corrosion products of the base alloy is as shown in formula (1):
  • the invention investigates the initial mechanical properties of the absorbable iron-based alloy internal fixation implanted medical device by testing the bending strength or the tensile strength, and the initial fixed implant medical device prepared by the invention has an initial bending strength of not less than 350 MPa, and the tensile strength The strength is not less than 400 MPa, which is regarded as the standard for achieving internal fixation of implanted medical devices for load-bearing parts.
  • the invention adopts the C43.504 model universal material testing machine produced by MTS Company, and tests the three-point bending strength of the sample according to the YBT 5349-2006 metal material bending mechanical property test standard.
  • the invention adopts the C43.504 model universal material testing machine produced by MTS Company, and tests the tensile strength of the sample according to the GBT 228.1-2010 tensile test standard.
  • the mass percentage of soluble iron corrosion products in the corrosion products of the iron-based alloy actually detected due to the normal fluctuation of the product's own performance within the design permission range and the systematic error that the test method inevitably introduces. Will fluctuate within a certain range.
  • a low-alloy high-strength steel with an alloy content of ⁇ 6 wt.% is cast to form a billet, and the billet is cold-drawn into an ultra-fine steel wire having a diameter of 0.2 mm and heat-treated, and the steel wire having a diameter of 0.2 mm prepared in the above step is cut into lengths. A small section is then coated with a complexing agent, triammonium citrate.
  • a polylactic acid glycolic acid (PLGA) billet having a weight average molecular weight of 1.2 million and a polydispersity factor of 1.1 to a molten state
  • the antioxidant vitamin A is dispersed; the treated steel wire segment is aligned and added to the molten PLGA billet as a reinforcing phase, condensed and solidified, extruded into a rod, and machined into a sheet as shown in FIG.
  • the nail 10 is shown.
  • the mass ratio of the steel wire reinforcing phase 11 to the polylactic acid glycolic acid phase is 20:80.
  • the initial bending strength of the bone nail prepared in this example was 350 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after the accelerated corrosion in three weeks in vitro was 45 wt.%.
  • a low-alloy high-strength steel with an alloy content of ⁇ 6wt.% is prepared into a billet by powder metallurgy, then hot rolled into a wire rod, cold drawn into a hollow steel wire, and then filled with an antioxidant ascorbyl palmitate in the core of the hollow steel wire.
  • a plurality of strands of steel wire are twisted into a steel strand and a layer of hydroxamic acid deferoxamine complexing agent is prepared on the surface thereof.
  • a polylactic acid (PLA) having a weight average molecular weight of 3 million, a polydispersity coefficient of 1.2, and a polylactic acid-methionine having a molecular weight of 250,000 were used as a blend blank; the steel strand prepared in the above step was placed in the molten poly As a reinforcing phase in the blend of lactic acid (PLA) and polylactic acid-methionine, after solidification, it is machined into a compression nail 20 as shown in FIG. 2, wherein the strand reinforcing phase 21 and polylactic acid (PLA) The mass ratio of the polylactic acid-methionine blend phase 22 was 30:70.
  • the initial bending strength of the material of the compression nail prepared in this embodiment was 450 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after three weeks of accelerated corrosion in vitro was 35 wt.%.
  • the low alloy high strength steel with alloy content ⁇ 6wt.% is obtained by powder metallurgy method, then hot rolled into wire rod, cold drawn into hollow steel wire and filled with complexing agent acetylsalicylic acid, and stranded steel wire After being woven into a two-dimensional mesh, a hydroxyapatite layer is prepared on the surface of the two-dimensional mesh and coated with an anti-oxidant ubiquinone.
  • the polylactic acid billet having a weight average molecular weight of 2 million and a polydispersity factor of 1.5 is heated to a molten state, and a multi-layer two-dimensional mesh is added thereto, uniformly mixed, condensed and solidified, and machined into a bone nail, and all the two dimensions in the nail.
  • the mesh extends in the same direction, and the mass ratio of the two-dimensional mesh to the polylactic acid blank is 25:75.
  • the initial bending strength of the material of the bone nail prepared in this embodiment is 400 MPa, and the mass percentage of soluble iron in the soluble corrosion product of the iron-based alloy after three weeks of accelerated corrosion in vitro is 35 wt.%.
  • the as-cast pure iron billet is hot-rolled into a wire rod, which is cold-drawn into a hollow iron wire, and the inner cavity of the wire is filled with a complexing agent sodium gluconate and an antioxidant sodium tripolyphosphate; the weight average molecular weight obtained by melt polymerization is 500,000.
  • a lactic acid-phosphate copolymer blank having a polydispersity factor of 5 and drawn into a wire, and the copolymer and the wire are stranded together to form a strand having a larger wire diameter, and a cyclodextrin is added thereto and compacted.
  • the mass ratio of the iron wire to the lactic acid-phosphate copolymer in the suture was 50:50.
  • the initial tensile strength of the suture prepared in this example was 400 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after the accelerated corrosion in three weeks in vitro was 25 wt.%.
  • the medium carbon steel having a carbon content of 0.3 wt.% was obtained by casting to obtain a billet and further heat-treated; and the medium carbon steel and the polylactic acid (PLA) dispersed with sodium ascorbate having a weight average molecular weight of 2.6 million and a polydispersity coefficient of 2 were obtained.
  • the blanks are co-extruded to form a multilayer composite bar having a cross section as shown in FIG. 3, wherein 51 is a medium carbon steel layer, 52 is a polymer layer, and a poly layer is added between the medium carbon steel layer 51 and the polymer layer 52.
  • the ester hot melt adhesive is then processed into a solid bone nail by mechanical processing, wherein the medium carbon steel and the polylactic acid have a mass ratio of 50:50.
  • the initial bending strength of the bone nail prepared in this example was 450 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after the accelerated corrosion in three weeks in vitro was 15 wt.%.
  • the low alloy high strength steel with alloy content ⁇ 6wt.% is obtained by casting, then hot rolled into wire rod, cold drawn into hollow steel wire, filled with the complexing agent sodium gluconate in the inner cavity of the steel wire; the weight average molecular weight is 300 a lactic acid (PLA)-maleic anhydride copolymer having a polydispersity coefficient of 1.2 is drawn into a filament, and an antioxidant butylhydroxyanisole is further dispersed in the copolymer; the steel wire and the copolymer yarn are twisted together to form a composite twist In the process of making the strands and strands, a polyamide hot melt adhesive is added between the steel wire and the copolymer yarn; finally, the stranding machine is processed into a compression nail, and the mass ratio of the steel wire to the copolymer yarn in the pressure nail is 65: 35.
  • PLA lactic acid
  • maleic anhydride copolymer having a polydispersity coefficient of 1.2 is drawn into a filament, and an
  • the initial bending strength of the compression nail prepared in this example was 500 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after the accelerated corrosion in three weeks in vitro was 15 wt.%.
  • a low carbon low alloy steel having a carbon content of 0.1 wt.% is formed into a billet by powder metallurgy and further heat-treated; a polylactic acid having a weight average molecular weight of 2 million, a polydispersity factor of 1.8, and a polycondensation having a weight average molecular weight of 150,000
  • a blend of maleic anhydride-glycine copolymer a low carbon low alloy steel billet is extruded into a hollow nail and a blend of polylactic acid and polymaleic anhydride-methionine copolymer
  • the oxidant glutathione and the complexing agent sodium hexametaphosphate are filled in the inner cavity of the nail, wherein the mass ratio of the low carbon low alloy steel to the blend is 80:20.
  • the initial bending strength of the material of the bone nail prepared in this embodiment is 600 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after the accelerated corrosion in vitro is 10 wt.%.
  • the as-cast pure iron billet is hot rolled into a wire rod, cold drawn into a wire, and the wire is stranded into a stitch.
  • the initial tensile strength of the suture was 600 MPa.
  • the mass percentage of soluble iron in the corrosion products of the iron-based alloy after accelerated corrosion in vitro is 0.
  • a low carbon low alloy steel having a carbon content of 0.1 wt.% is formed into a billet by powder metallurgy and further heat-treated; a polylactic acid having a weight average molecular weight of 2 million, a polydispersity factor of 1.8, and a polycondensation having a weight average molecular weight of 150,000 Maleic anhydride-glycine copolymerization
  • the mixture is made into a blend; the low carbon low alloy steel blank is extruded and machined into hollow nails, and a blend of polylactic acid and polymaleic anhydride-methionine copolymer is filled in the inner cavity of the nail, Among them, the mass ratio of low carbon low alloy steel to blend is 95:5.
  • the initial bending strength of the material of the bone nail is 650 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after the accelerated corrosion in three weeks in vitro is 2 wt.%. .
  • a low-alloy high-strength steel having an alloy content of ⁇ 6 wt.% was cast to form a billet, and the billet was cold-drawn into an ultra-fine steel wire having a diameter of 0.2 mm and heat-treated.
  • a polylactic acid glycolic acid (PLGA) billet having a weight average molecular weight of 100,000 and a polydispersity factor of 15 is heated to a molten state; the 0.2 mm diameter steel wire prepared in the above step is cut into small lengths of different lengths and aligned to be melted.
  • the PLGA billet is used as a reinforcing phase, condensed and solidified, extruded into a rod, and machined into a nail 10 as shown in FIG.
  • the mass ratio of the steel wire reinforcing phase 11 to the polylactic acid glycolic acid phase is 20:80.
  • the initial bending strength of the material of the nail is 60 MPa, and the mass percentage of soluble iron in the corrosion product of the iron-based alloy after three weeks of accelerated corrosion in vitro is 10 wt.%.
  • the absorbable internal fixation implanted medical instruments prepared in the respective examples have an initial bending strength of not less than 350 MPa or a tensile strength of not less than 400 MPa, and all have excellent properties.

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Abstract

一种可吸收铁基合金内固定植入医疗器械，基体包括铁基合金和可降解聚合物，铁基合金与可降解聚合物的质量比在[1:4，4:1]之间，可降解聚合物的重均分子量在[15，300]万之间，多分散系数在[1，6]之间。可吸收铁基合金内固定植入医疗器械还包括抗氧化剂。铁基合金作为器械的承重骨架或增强相。通过调节铁基合金与可降解聚合物的质量比和组合方式，在加快铁基合金在植入后期的腐蚀速率的同时，减少了铁基合金难溶性腐蚀产物的量。向器械中添加抗氧化剂进一步降低了铁基合金难溶性腐蚀产物的量。

Description

可吸收铁基合金内固定植入医疗器械 技术领域
本发明属于可吸收植入医疗器械领域，尤其涉及一种可吸收铁基合金内固定植入医疗器械。
背景技术
骨折愈合时间因受伤部位、受伤程度甚至治疗方法的不同而不同，通常为2～6个月，这要求内固定植入医疗器械具有一定的初始力学性能。例如通常骨钉的初始抗弯曲强度需达350MPa以上，缝线的抗拉强度需达400MPa以上。目前用于制造创伤修复用内固定植入医疗器械的材料主要有永久性金属如不锈钢、钛基合金、钴基合金，和可吸收材料如聚合物、镁基合金等。其中，永久性金属具有优异的力学性能和生物相容性，在受损骨愈合后将长期留在人体内，会存在潜在的长期生物学风险，若取出则会增加病人的痛苦和经济负担，同时有可能造成二次损伤(如滑牙折断残留体内)。
可吸收聚合物如聚乳酸、聚几内酯等具有良好的生物相容性已经积累了大量的临床数据。通常在一定范围内，聚合物的分子量和结晶度越高，其综合力学性能越好，但同时聚合物便越难溶于有机溶剂。因此只能通过将其加热为流动的熔融体后，再经模压、注塑、拉伸或挤出成型制成成品。对力学性能要求不高的结构，如医疗器械的可吸收聚合物涂层，通常是选用低分子量的聚合物并经有机溶剂溶解后，涂覆在医疗器械表面或内部。高分子量聚合物的加工方法通常是熔融后再加工成型，因此高分子量聚合物适用于制成具有一定力学强度的创伤修复用内固定植入医疗器械。
用高分子量聚乳酸制作的可吸收骨钉的抗弯强度虽可达150MPa以上，但与传统的永久性金属材料相比，存在以下缺点：力学性能差，通常仅适用于各种非承重部位的松质骨、关节骨或活动较少的骨的固定，以防过分受力或者活动频繁导致植入医疗器械的失效；聚乳酸降解会产生酸性环境，容易导致植入部位产生较严重的炎症反应；此外，显影性不好。这些缺点都制约了可吸收聚合物基内固定植入医疗器械的应用。
镁基合金内固定植入医疗器械的抗弯强度可达300MPa左右，但镁基合金的力学性能仍达不到永久性金属植入材料的水平，目前仍然只能用于非承重和活动较少的位置，例如对小 骨和骨片的内固定，临床应用范围有限；此外，镁基合金腐蚀速率较快，植入医疗器械会过早丧失有效支撑和固定作用，且腐蚀时会使植入部位局部pH增高，对骨生长有不良影响，容易造成骨结合不好。
可吸收铁基合金的力学性能可接近永久性不锈钢、钴铬合金以及钛合金，相对可吸收聚合物和镁基合金具有更好的力学性能，但铁基合金的腐蚀速率缓慢。CN104587534公开了在可降解聚酯等高分子材料降解后形成的酸性微环境中，铁基合金的腐蚀速度可以显著提高，从而显著缩短铁基合金的腐蚀周期，但可吸收铁基合金通过吸氧腐蚀生成的腐蚀产物通常都是难溶的铁的氢氧化物或氧化物。在体内软硬组织中，这些难溶的铁的腐蚀产物被机体代谢和吸收的时间可能长达数年甚至更久，虽然它们的生物相容性很好，但是其长期存在加重了组织对其代谢的负担。因此，有必要在兼顾力学性能的同时，减少可吸收铁基合金内固定植入医疗器械的难溶性腐蚀产物。
发明内容
本发明提供了一种可吸收铁基合金内固定植入医疗器械，其在减少铁基合金基体用量的前提下具有较好的初始力学性能，且植入后期铁基合金难溶性腐蚀产物量较少，减轻了组织对其代谢的负担。
一种可吸收铁基合金内固定植入医疗器械，其基体包括铁基合金和可降解聚合物，所述铁基合金与所述可降解聚合物的质量比在[1:4，4:1]之间，所述可降解聚合物的重均分子量在[15，300]万之间，多分散系数在[1，6]之间。
所述铁基合金与所述可降解聚合物的质量比优选在[1:4，1:1]之间。
所述可吸收铁基合金内固定植入医疗器械中还包括抗氧化剂，所述抗氧化剂选自丁基羟基茴香醚、二丁基羟基甲苯、叔丁基对苯二酚、没食子酸丙酯、维生素A、类胡萝卜素、泛醌、谷胱甘肽、水溶性多酚、生育酚、三聚磷酸钠、抗坏血酸钠、硫辛酸盐、抗坏血酸棕榈酸酯中的至少一种，所述水溶性多酚选自白芦藜醇、黄酮类。
所述可降解聚合物包括可降解聚酯，或所述可降解聚酯与可降解聚酸酐、可降解聚氨基酸、可降解聚磷酸酯中的至少一种的混合物，或至少一种形成所述可降解聚酯的单体与至少一种形成所述可降解聚酸酐、可降解聚氨基酸或可降解聚磷酸酯的单体的共聚物。
所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚已内酯、聚羟基脂肪酸酯、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意一种，或者选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚已内酯、聚羟基脂肪酸酯、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至少两种的物理共混物，或形成前述可 降解聚酯的单体中的至少两种单体的共聚物；所述可降解聚酸酐选自交联聚酸酐、芳香族聚酸酐、脂肪族聚酸酐、杂环聚酸酐、聚酰酸酐、聚酰胺酸酐、含磷聚酸酐中的任意一种，或者选自交联聚酸酐、芳香族聚酸酐、脂肪族聚酸酐、杂环聚酸酐、聚酰酸酐、聚酰胺酸酐、含磷聚酸酐中至少两种的物理共混物；所述可降解聚氨基酸选自聚甘氨酸、聚蛋氨酸、聚硫代氨酸、聚天冬氨酸中的至少一种。
所述铁基合金为含碳质量百分比不高于2.11wt.％的纯铁或铁基合金。
所述可吸收铁基合金内固定植入医疗器械为骨钉或缝线。
相比现有技术，本发明采用铁基合金作为内固定植入医疗器械的承重骨架或增强相，使器械在减少铁基合金基体用量的前提下具有良好的初始力学性能；通过设置铁基合金与可降解聚合物的质量比和组合方式，在加快植入后期铁基合金基体腐蚀速率的同时，减少了铁基合金难溶性腐蚀产物的量，减轻了组织对腐蚀产物代谢的负担；添加抗氧化剂进一步降低了铁基合金难溶性腐蚀产物的量。
附图说明
图1为实施例1制备的骨钉的结构示意图。
图2为实施例2制备的骨钉的结构示意图。
图3为实施例5制备的用于制作骨钉的复合棒材的截面示意图。
具体实施方式
为了便于理解本发明，下面将参照相关附图对本发明进行更全面的描述。附图中给出了本发明的首选实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使本发明的公开内容更加透彻全面。
除非另有定义，本文所使用的所有技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
本发明的可吸收铁基合金内固定植入医疗器械的基体材料包括铁基合金和可降解聚合物，所述铁基合金与所述可降解聚合物的质量比在[1:4，4:1]之间，使得器械在减少铁基合金基体用量的前提下具有良好初始力学性能，在植入后期能够较快地腐蚀降解并减少了难溶性腐蚀产物的量，减轻了组织的代谢负担。
减少所述器械难溶性腐蚀产物的量的途径主要有两条：一是减少铁基合金基体的用量；二是减少铁基合金腐蚀产物中难溶性腐蚀产物的质量百分比，即提高铁基合金腐蚀产物中可 溶性铁的质量百分比。
所述铁基合金和可降解聚合物复合材料的复合方式包括：
所述铁基合金以实心或中空须状、丝状、棒状、不规则支架或网状的形式分布在所述可降解聚合物中；或
所述铁基合金与所述可降解聚合物分别形成层状物且铁基合金层与聚合物层相互交替；或
所述铁基合金以丝状绞合在所述可降解聚合物丝上；或
所述铁基合金具有凹槽、孔隙、缝隙或中空内腔，所述可降解聚合物填充在所述凹槽、孔隙、缝隙或中空内腔中。
所述铁基合金和可降解聚合物采用上述复合方式，可以在获得接近或媲美永久性金属材料(如不锈钢、钴铬合金和钛基合金)器械的初始力学性能的同时减少铁基合金基体的用量，从而降低了可能生成的难溶性腐蚀产物的量。
所述可降解聚合物包括可降解聚酯，或所述可降解聚酯与可降解聚酸酐、可降解聚氨基酸、可降解聚磷酸酯中的至少一种的混合物，或至少一种形成所述可降解聚酯的单体与至少一种形成所述可降解聚酸酐、可降解聚氨基酸或可降解聚磷酸酯的单体的共聚物。
所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚已内酯、聚羟基脂肪酸酯、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意一种，或者选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚已内酯、聚羟基脂肪酸酯、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至少两种的物理共混物，或形成前述可降解聚酯的单体中的至少两种单体的共聚物；所述可降解聚酸酐选自交联聚酸酐、芳香族聚酸酐、脂肪族聚酸酐、杂环聚酸酐、聚酰酸酐、聚酰胺酸酐、含磷聚酸酐中的任意一种，或者选自交联聚酸酐、芳香族聚酸酐、脂肪族聚酸酐、杂环聚酸酐、聚酰酸酐、聚酰胺酸酐、含磷聚酸酐中至少两种的物理共混物；所述可降解聚氨基酸选自聚甘氨酸、聚蛋氨酸、聚硫代氨酸、聚天冬氨酸中的至少一种。
可吸收铁基合金内固定植入医疗器械植入人体后，铁基合金基体在生理溶液中逐渐腐蚀生成初级腐蚀产物Fe3+或Fe2+，Fe3+或Fe2+随后与环境中的OH-反应，生成Fe(OH)2、Fe(OH)3等难溶性腐蚀产物。所述可降解聚酯、可降解聚酸酐、可降解聚氨基酸及可降解聚磷酸酯降解后释放出氢离子，可以有效抑制Fe3+或Fe2+与OH-的反应；此外，所述可降解聚酯、可降解聚酸酐、可降解聚氨基酸和可降解聚磷酸酯降解后生成的络离子(配体)较环境中的OH-优先与Fe3+或Fe2+配位反应生成稳定的可溶性铁络合物，从而能够进一步减少或者防止Fe3+或Fe2+与生理环境中的OH-反应生成难溶性腐蚀产物。所述器械中铁基合金与可降解聚合物 的质量比越小，产生的离子或可溶性铁络合物形式的铁的量占铁基合金腐蚀产物中铁的质量比越高。但所述铁基合金与可降解聚合物的质量比越小，所述器械的力学性能便越差。因此，本发明铁基合金与可降解聚合物的质量比在[1:4，4:1]之间，优选在[1:4，1:1]之间，可以使所述器械能够在获得理想的力学性能的同时，减少难溶性腐蚀产物的量。
所述可吸收铁基合金内固定植入医疗器械中还包括抗氧化剂，所述抗氧化剂选自丁基羟基茴香醚、二丁基羟基甲苯、叔丁基对苯二酚、没食子酸丙酯、维生素A、类胡萝卜素、泛醌、谷胱甘肽、水溶性多酚、生育酚、三聚磷酸钠、抗坏血酸钠、硫辛酸盐、抗坏血酸棕榈酸酯中的至少一种，所述水溶性多酚选自白芦藜醇、黄酮类。
所述抗氧化剂可以涂覆在所述铁基合金表面；当铁基合金具有缝隙、凹槽或内腔时，所述抗氧化剂还可设于所述铁基合金的缝隙、凹槽、内腔中；此外，所述抗氧化剂可分散于所述可降解聚合物中。
尽管难溶性腐蚀产物在生理环境中的溶解度很小，但仍然存在少量离子进入溶液，同时进入溶液的离子又会在固体表面沉积下来，当难溶性腐蚀产物达到溶解平衡时，平衡常数称为溶度积常数(沉淀平衡常数)，即溶度积。Fe3+和OH-生成的难溶性腐蚀产物Fe(OH)3的溶度积远远低于Fe2+和OH-生成的不溶腐蚀产物Fe(OH)2的溶度积，即进入溶液的Fe3+的量远低于进入溶液的Fe2+的量。因此三价铁的腐蚀产物在体内的代谢更加困难，向所述可吸收铁基合金内固定植入医疗器械中添加抗氧化剂，可以抑制Fe2+向Fe3+转化，从而能够减少难溶性三价铁腐蚀产物的生成，提高铁的溶解度。
所述可吸收铁基合金内固定植入医疗器械中还包括络合剂，所述络合体选自单齿配体和/或多齿配体。所述单齿配体含有单个配位基团，所述多齿配体含有至少两个配位基团，所述配位基团选自：稠环芳烃上的羟基、巯基(-SH)、胺基
Figure PCTCN2016087292-appb-000001
芳杂环基团、亚硝基(O＝N－)、羰基
Figure PCTCN2016087292-appb-000002
磺基
Figure PCTCN2016087292-appb-000003
磷酸基团
Figure PCTCN2016087292-appb-000004
有机膦基团
Figure PCTCN2016087292-appb-000005
所述稠环芳烃上的羟基选自酚羟基；所述芳杂环基团选自呋喃基
Figure PCTCN2016087292-appb-000006
吡咯基
Figure PCTCN2016087292-appb-000007
噻吩基
Figure PCTCN2016087292-appb-000008
咪唑基
Figure PCTCN2016087292-appb-000009
三唑基
Figure PCTCN2016087292-appb-000010
噻唑基
Figure PCTCN2016087292-appb-000011
吡啶基
Figure PCTCN2016087292-appb-000012
吡啶酮基
Figure PCTCN2016087292-appb-000013
吡喃基
Figure PCTCN2016087292-appb-000014
吡喃酮基
Figure PCTCN2016087292-appb-000015
嘧啶基
Figure PCTCN2016087292-appb-000016
哒嗪基
Figure PCTCN2016087292-appb-000017
吡嗪基
Figure PCTCN2016087292-appb-000018
喹啉基
Figure PCTCN2016087292-appb-000019
异喹啉基
Figure PCTCN2016087292-appb-000020
酞嗪基
Figure PCTCN2016087292-appb-000021
喋啶基
Figure PCTCN2016087292-appb-000022
吲哚基
Figure PCTCN2016087292-appb-000023
嘌呤基
Figure PCTCN2016087292-appb-000024
菲咯啉基
Figure PCTCN2016087292-appb-000025
所述单齿配体选自葡萄糖酸、葡庚糖酸、乙醇酸，及其衍生物或盐类。
所述含稠环芳烃上的羟基的多齿配体选自8-羟基喹啉、8-羟基喹哪啶、4,5-二羟基苯-1,3-二磺酸钠、4-[3,5-二-羟苯基-1H-1,2,4-三唑]-苯甲酸(去铁斯若)；所述含巯基的多齿配体选自8-巯基喹啉、巯基乙酸、5-甲基-2-巯基苯甲酸甲酯；所述含胺基的多齿配体选自乙二胺、三乙烯四胺、乙二胺四乙酸、乙二胺四乙酸四钠、N'-[5-[[4-[[5-(乙酰羟胺基)戊基]氨]-1,4-二氧丁基]羟胺]戊基]-N-(5-氨基戊基)-N-羟基琥珀酰胺(去铁胺)；所述含芳杂环基团的多齿配体选自邻菲罗啉、联吡啶、卟啉、卟吩、叶绿素、血红蛋白、1,2-二甲基-3-羟基-4-吡啶酮(去铁酮)；所述含亚硝基的多齿配体选自1-亚硝基-2-萘酚、1-亚硝基-2-萘酚-6-磺酸钠；所述含羰基的多齿配体选自多元羧酸及其盐、酸酐、酯、酰胺、聚羧酸、聚酸酐；所述含磺基的多齿配体选自磺基水杨酸、8-羟基喹啉-5-磺酸；所述含磷酸基团的多齿配体选自焦磷酸、三聚磷酸、六偏聚磷酸、多聚磷酸、焦磷酸钠、六偏聚磷酸钠、多聚磷酸铵；所述含有机膦基团的多齿配体选自二乙烯三胺五甲叉膦酸钾、乙二胺四甲叉膦酸钠，所述含羰基的多齿配体进一步选自草酸、酒石酸、苹果酸、琥珀酸、草酰乙酸、延胡索酸、马来酸、柠檬酸、柠檬酸三铵、氨三乙酸、二乙烯三胺五羧酸、海藻酸、谷氨酸、天冬氨酸、鸟氨酸、赖氨酸、柠檬酸钾、柠檬酸钙、柠檬酸甘油酯、乙酰水杨酸、磺基水杨酰胺、聚天冬氨酸、聚谷氨酸、聚鸟氨酸、聚赖氨酸、聚马来酸酐。
所述络合剂可以涂覆在所述铁基合金表面；当铁基合金具有缝隙、凹槽或内腔时，所述络合剂还可设于所述铁基合金的缝隙、凹槽、内腔中；此外，所述络合剂还可分散于所述可降解聚合物中。
在生理环境下，络合剂能提供孤对电子或π电子，与Fe2+和/或Fe3+发生络合反应，生成可水溶的铁络合物，水溶性铁络合物相比于铁基合金的难溶性固体腐蚀产物，能更快地被机体代谢/吸收。所述铁络合物的稳定性大于Fe(OH)2和/或Fe(OH)3，在生理溶液中不会转变成难溶的Fe(OH)2和/或Fe(OH)3。
所述可吸收铁基合金内固定植入医疗器械还包括生物相容性良好的可降解粘结剂，所述可降解粘结剂选自聚酯热熔胶、聚酰胺热熔胶、淀粉、环糊精、木质素中的至少一种，或选自由形成聚酯热熔胶、聚酰胺热熔胶、淀粉、环糊精、木质素的单体中的至少两种的共聚物。
为了考察可吸收铁基合金内固定植入医疗器械的腐蚀情况，本发明对器械进行体外加速腐蚀试验：在80℃条件下，将器械浸泡在100ml PBS溶液中腐蚀三周后，铁基合金腐蚀后生成的可溶性腐蚀产物充分溶解在PBS溶液中，用孔径为0.22μm的水性膜过滤浸泡液，然后采用原子吸收光谱仪(AAS)测试滤液中溶解的铁元素的浓度c，PBS溶液中溶解的可溶性铁的质量m1＝cV，其中V为溶液体积；将器械取出，去除铁锈后洗净称重，计算得到铁基合金部分的失重为△m，即为铁基合金腐蚀产物中铁的质量；铁基合金腐蚀产物中可溶性铁的质量百分比W如公式(1)所示：
W＝m1/△m×100％   (1)
W—铁基合金腐蚀产物中可溶性铁腐蚀产物的质量百分比
m1—PBS溶液中的可溶性铁的质量
△m—铁基合金腐蚀产物中铁的质量
W越高，表明铁基合金腐蚀产物中形成的可溶性腐蚀产物越多，即难溶性腐蚀产物越少，组织代谢的负担越小。
本发明通过测试弯曲强度或抗拉强度对可吸收铁基合金内固定植入医疗器械的初始力学性能进行考察，本发明制备的内固定植入医疗器械初始抗弯曲强度不低于350MPa，抗拉强度不低于400MPa，视为达到用于承重部位的内固定植入医疗器械的标准。
本发明采用MTS公司生产的C43.504型号的万能材料试验机，根据YBT 5349-2006金属材料弯曲力学性能试验标准对试样的三点弯曲强度进行测试。
本发明采用MTS公司生产的C43.504型号的万能材料试验机，根据GBT 228.1-2010拉伸试验标准测试试样的抗拉强度。
需要指出的是，以下各实施例中，由于产品自身性能在设计许可范围内的正常波动以及测试方法不可避免引入的系统误差，实际检测到的铁基合金腐蚀产物中可溶性铁腐蚀产物的质量百分比会在一定范围内波动。
实施例1
将合金含量<6wt.％的低合金高强度钢铸造形成坯料，将坯料冷拔成直径为0.2mm的超细钢丝并进行热处理，将上述步骤制备的直径0.2mm的钢丝剪成长度不等的小段，然后在其上涂覆络合剂柠檬酸三铵。
将重均分子量为120万、多分散系数为1.1的聚乳酸乙醇酸(PLGA)坯料加热到熔融状 态，PLGA坯料中分散有抗氧化剂维生素A；将上述处理后的钢丝段钢丝定向排列加入到熔融的PLGA坯料中作为增强相，冷凝固化后挤压成棒材，再机加工成如图1所示的骨钉10。其中钢丝增强相11与聚乳酸乙醇酸相12质量比为20:80。
本实施例制备的骨钉的材料初始弯曲强度为350MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为45wt.％。
实施例2
采用粉末冶金的方法将合金含量<6wt.％的低合金高强度钢制备成坯料，然后热轧成盘条，冷拔成空心钢丝，然后在空心钢丝芯部填充抗氧化剂抗坏血酸棕榈酸酯，将多股钢丝绞合成钢绞线并在其表面制备羟肟酸去铁胺络合剂层。
将重均分子量为300万、多分散系数为1.2的聚乳酸(PLA)和25万分子量的聚乳酸-蛋氨酸制成共混物坯料；将上述步骤制备的钢绞线置于所述熔融的聚乳酸(PLA)和聚乳酸-蛋氨酸的共混物坯料中作为增强相，固化后将其机加工成如图2所示的加压钉20，其中钢绞线增强相21与聚乳酸(PLA)和聚乳酸-蛋氨酸共混物相22的质量比为30:70。
本实施例制备的加压钉的材料初始弯曲强度为450MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为35wt.％。
实施例3
将合金含量<6wt.％的低合金高强度钢采用粉末冶金的方法获得坯料，然后热轧成盘条，冷拔成空心钢丝并在内填充络合剂乙酰水杨酸，将多股钢丝绞合后编织成二维网片，并在二维网片表面制备羟基磷灰石层再涂覆抗氧化剂泛醌。
将重均分子量为200万、多分散系数为1.5的聚乳酸坯料加热到熔融状态后将多层二维网片加入其中，混合均匀后冷凝固化并机加工成骨钉，骨钉中所有二维网片的延伸方向一致，且二维网片与聚乳酸坯料的质量比为25:75。
本实施例制备的骨钉的材料初始弯曲强度为400MPa，体外加速腐蚀三周后铁基合金可溶性腐蚀产物中可溶性铁的质量百分比为35wt.％。
实施例4
将铸态纯铁坯料热轧成盘条，冷拔成空心铁丝，在铁丝内腔中填充络合剂葡萄糖酸钠和抗氧化剂三聚磷酸钠；以熔融聚合方式得到的重均分子量为50万、多分散系数为5的乳酸-磷酸酯共聚物坯料并拉拔成丝，将共聚物和铁丝一起多股绞合形成丝径更大的绞线，向其中加入环糊精并紧压成型，制成可吸收缝线。缝线中铁丝与乳酸-磷酸酯共聚物的质量比为50:50。
本实施例制备的缝线的初始抗拉强度为400MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为25wt.％。
实施例5
将含碳量为0.3wt.％的中碳钢通过铸造获得坯料并进一步热处理；并将中碳钢与重均分子量为260万、多分散系数为2的分散有抗坏血酸钠的聚乳酸(PLA)坯料共同挤压制成横截面如图3所示的多层复合棒材，其中51为中碳钢层，52为聚合物层，向中碳钢层51和聚合物层52之间加入了聚酯热熔胶，再通过机械加工方式将棒材制成实心骨钉，其中，中碳钢和聚乳酸的质量比为50:50。
本实施例制备的骨钉的材料初始弯曲强度为450MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为15wt.％。
实施例6
将合金含量<6wt.％的低合金高强度钢通过铸造获得坯料，然后热轧成盘条，冷拔成空心钢丝，在钢丝内腔中填充络合剂葡萄糖酸钠；将重均分子量为300万、多分散系数为1.2的乳酸(PLA)-马来酸酐共聚物拉拔成丝，共聚物中还分散有抗氧化剂丁基羟基茴香醚；将所述钢丝和共聚物丝一起绞合成复合绞线，绞线制作过程中在钢丝和共聚物丝之间加入了聚酰胺热熔胶；最后将绞线机加工成加压钉，该加压钉中钢丝与共聚物丝的质量比为65:35。
本实施例制备的加压钉的初始弯曲强度为500MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为15wt.％。
实施例7
通过粉末冶金将含碳量为0.1wt.％的低碳低合金钢制成坯料并进一步热处理；将重均分子量为200万、多分散系数为1.8的聚乳酸和重均分子量为15万的聚马来酸酐-甘氨酸共聚物制成共混物；将低碳低合金钢坯料挤压成型后机加工成空心骨钉，并将聚乳酸与聚马来酸酐-蛋氨酸共聚物的共混物和抗氧化剂谷胱甘肽及络合剂六偏磷酸钠填充在骨钉内腔中，其中，低碳低合金钢与共混物的质量比为80:20。
本实施例制备的骨钉的材料初始弯曲强度为600MPa，体外加速腐蚀四周后铁基合金腐蚀产物中可溶性铁的质量百分比为10wt.％。
对比例1
将铸态的纯铁坯料热轧成盘条，冷拔成铁丝，将铁丝多股绞合制成缝线。
该缝合线的初始抗拉强度为600MPa。体外加速腐蚀四周后铁基合金腐蚀产物中可溶性铁的质量百分比为0。
对比例2
通过粉末冶金将含碳量为0.1wt.％的低碳低合金钢制成坯料并进一步热处理；将重均分子量为200万、多分散系数为1.8的聚乳酸和重均分子量为15万的聚马来酸酐-甘氨酸共聚 物制成共混物；将低碳低合金钢坯料挤压成型后机加工成空心骨钉，并将聚乳酸与聚马来酸酐-蛋氨酸共聚物的共混物填充在骨钉内腔中，其中，低碳低合金钢与共混物的质量比为95:5。
该骨钉的材料初始弯曲强度为650MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为2wt.％。。
对比例3
将合金含量<6wt.％的低合金高强度钢铸造形成坯料，将坯料冷拔成直径为0.2mm的超细钢丝并进行热处理。
将重均分子量为10万、多分散系数为15的聚乳酸乙醇酸(PLGA)坯料加热到熔融状态；将上述步骤制备的直径0.2mm的钢丝剪成长度不等的小段并定向排列加入到熔融的PLGA坯料中作为增强相，冷凝固化后挤压成棒材，再机加工成如图1所示的骨钉10。其中钢丝增强相11与聚乳酸乙醇酸相12质量比为20:80。
该骨钉的材料初始弯曲强度为60MPa，体外加速腐蚀三周后铁基合金腐蚀产物中可溶性铁的质量百分比为10wt.％。
由实施例1～7和对比例1～3可以看出，各实施例制备的可吸收内固定植入医疗器械初始抗弯曲强度不低于350Mpa或抗拉强度不低于400MPa，均具有优良的初始力学性能，适用于承重部位的固定；通过设置铁基合金与可降解聚合物的质量比和组合方式，减少了铁基合金腐蚀产物中难溶性腐蚀产物的比例，抗氧化剂和络合剂的加入进一步降低了铁基合金腐蚀产物中难溶性腐蚀产物的比例，减轻了组织对腐蚀产物代谢的负担。
以上实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种可吸收铁基合金内固定植入医疗器械，其基体包括铁基合金和可降解聚合物，其特征在于，所述铁基合金与可降解聚合物的质量比在[1:4，4:1]之间，所述可降解聚合物的重均分子量在[15，300]万之间，多分散系数在[1，6]之间。
  2. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述铁基合金与可降解聚合物的质量比在[1:4，1:1]之间。
  3. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述器械还包括抗氧化剂，所述抗氧化剂选自丁基羟基茴香醚、二丁基羟基甲苯、叔丁基对苯二酚、没食子酸丙酯、维生素A、类胡萝卜素、泛醌、谷胱甘肽、水溶性多酚、生育酚、三聚磷酸钠、抗坏血酸钠、硫辛酸盐、抗坏血酸棕榈酸酯中的至少一种。
  4. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述铁基合金与所述可降解聚合物的组合方式选自以下至少一种：所述铁基合金以实心或中空须状、丝状、棒状、不规则支架或网状的形式分布在所述可降解聚合物中；或
    所述铁基合金与所述可降解聚合物分别形成层状物且铁基合金层与聚合物层相互交替；或
    所述铁基合金以丝状绞合在所述可降解聚合物丝上；或
    所述铁基合金具有凹槽、孔隙、缝隙或中空内腔，所述可降解聚合物填充在所述凹槽、孔隙、缝隙或中空内腔中。
  5. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述可降解聚合物包括可降解聚酯，或所述可降解聚酯与可降解聚酸酐、可降解聚氨基酸、可降解聚磷酸酯中至少一种的混合物，或至少一种形成所述可降解聚酯的单体与至少一种形成所述可降解聚酸酐、可降解聚氨基酸或可降解聚磷酸酯的单体的共聚物。
  6. 根据权利要求5所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚已内酯、聚羟基脂肪酸酯、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至少一种，或者选自形成前述可降解聚酯的单体中的至少两种单体的共聚物；所述可降解聚酸酐选自交联聚酸酐、芳香族聚酸酐、脂肪族聚酸酐、杂环聚酸酐、聚酰酸酐、聚酰胺酸酐、含磷聚酸酐中的至少一种；所述可降解聚氨基酸选自聚甘氨酸、聚蛋氨酸、聚硫代氨酸、聚天冬氨酸中的至少一种。
  7. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述器械还包括络合剂，所述络合剂选自单齿配体和/或多齿配体，所述单齿配体含有单个配位基 团，所述多齿配体含有至少两个配位基团，所述配位基团选自稠环芳烃上的羟基、巯基、胺基、芳杂环基团、亚硝基、羰基、磺基，磷酸基团或有机膦基团。
  8. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述器械还包括粘结剂，所述可降解粘结剂选自聚酯热熔胶、聚酰胺热熔胶、淀粉、环糊精、木质素中的至少一种；或选自由形成聚酯热熔胶、聚酰胺热熔胶、淀粉、环糊精、木质素单体中的至少两种共聚物。
  9. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述铁基合金为含碳质量百分比不高于2.11wt.％的纯铁或铁基合金。
  10. 根据权利要求1所述的可吸收铁基合金内固定植入医疗器械，其特征在于，所述器械为骨钉或缝线。
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