WO2016013594A1 - Élément biorésorbable pour utilisation médicale et son procédé de fabrication - Google Patents

Élément biorésorbable pour utilisation médicale et son procédé de fabrication Download PDF

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WO2016013594A1
WO2016013594A1 PCT/JP2015/070888 JP2015070888W WO2016013594A1 WO 2016013594 A1 WO2016013594 A1 WO 2016013594A1 JP 2015070888 W JP2015070888 W JP 2015070888W WO 2016013594 A1 WO2016013594 A1 WO 2016013594A1
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polymer
disk
medical
layer
bioabsorbable member
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PCT/JP2015/070888
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English (en)
Japanese (ja)
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廣本　祥子
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国立研究開発法人物質・材料研究機構
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Priority to JP2016535960A priority Critical patent/JP6338666B2/ja
Publication of WO2016013594A1 publication Critical patent/WO2016013594A1/fr

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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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • 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

Definitions

  • the present invention relates to a medical bioabsorbable member and a method for producing the same.
  • the present invention relates to a medical bioabsorbable member using a biological magnesium alloy.
  • a special property is required that dissolves at an appropriate dissolution rate while holding, and assimilates and disappears from a living tissue or bone.
  • a member exhibiting such characteristics is called a medical bioabsorbable member.
  • a medical or bioabsorbable member generally requires strength, and therefore, a metal or an alloy is used as a main material.
  • a metal or an alloy is used as a main material.
  • magnesium and its alloys have been researched and developed as main materials.
  • various alloy compositions and processing processes have been researched and developed in response to the above requirements for characteristics.
  • Non-patent Document 1 an AZ91 magnesium alloy chitosan-calcium phosphate composite coating is disclosed (Non-patent Document 1).
  • hydroxyapatite (HAp) nanopowder and chitosan are simultaneously deposited by electrophoretic deposition.
  • a method for producing a composite film by a method combining anodization, electrophoretic deposition and alkali treatment is disclosed.
  • Chitosan is an ionic polymer.
  • grains is not pointed out.
  • Patent Document 1 relates to a phosphate coating material, an apatite coating material, and a production method thereof, and discloses a coating of a base material (stainless steel, titanium alloy, cobalt chromium alloy) having high corrosion resistance. .
  • a base material stainless steel, titanium alloy, cobalt chromium alloy
  • various kinds of composite coatings including calcium phosphate and a polymer are included.
  • the film is made.
  • the polymer insoluble polymers such as polyethylene terephthalate and polyethylene are used.
  • Patent Document 2 relates to a bone implant and a set for manufacturing a bone implant, and in a hole made of a porous metal material (existing biomaterial such as titanium alloy, magnesium alloy, zinc alloy, etc.),
  • a bone implant containing a polymer such as collagen and gelatin and a composite material such as phosphate is disclosed.
  • the composite material is used to impart osteoconductivity, osteoinductivity, and osteogenesis within the pores of the porous metal material.
  • the polymer include hydrophilic and ionic biological collagen and polysaccharides.
  • Non-Patent Document 2 reports a hydrophobic biodegradable polymer (polylactic acid, polycaprolactone) as a corrosion-resistant coating of a bioabsorbable Mg alloy. However, it has low adhesion to the surface of a metal or alloy covered with a hydroxide and / or oxide that is hydrophilic due to hydrophobicity. There is concern about the influence of the surrounding pH drop on the surrounding living tissue due to the monomer (hydroxy acid) released with the degradation of these biodegradable polymers.
  • Patent Document 3 relates to a medical bioabsorbable member and a method for producing the same, and a medical material in which a surface of a base material made of magnesium or a magnesium alloy is covered with a corrosion-resistant film that adjusts the dissolution time in a living body.
  • a method for producing an absorbent member comprising immersing a magnesium or magnesium alloy base material molded into a predetermined shape in an aqueous solution in which phosphate ions and non-chlorinated calcium ions are dissolved in a supersaturated state,
  • Patent Document 4 relates to a biodegradable magnesium material for medical use, forming a film containing magnesium hydroxide on the surface of magnesium or a magnesium alloy, and a simulated body fluid containing the magnesium material containing phosphate ions and calcium ions. It is described that calcium phosphate is deposited on the surface of the film by dipping in the film.
  • Patent Document 5 relates to a transplant material and a method for producing the same, and a transplant material base material made of pure magnesium or a magnesium alloy is coated with an apatite layer through an intermediate layer made of magnesium hydroxide. The materials are listed.
  • JP 2012-95735 A Japanese translation of PCT publication 2010-510817 Japanese Patent No. 5339347 International Publication No. 2007/108450 JP 2010-63534 A
  • the present invention relates to a bioabsorbable member for medical use having a surface layer with high biosafety and biocompatibility, which exhibits various corrosion resistances in order to suppress corrosion dissolution of a base material and suppress it to an arbitrary corrosion dissolution rate. It is an object to provide a manufacturing method.
  • the period of time required to suppress the corrosion and dissolution required for medical devices made of bioabsorbable members is the type of device and the condition of the affected area. And depending on the initial strength of the base alloy, it spans a very wide range of lengths. For example, in the case of a fracture fixing material, it is desired that the device supports the load for a period of 3 months to 1 year until the fracture is healed, and then the disassembly of the entire device is almost completed in a period of 8 months to 5 years.
  • a magnesium alloy that can suppress corrosion and dissolution in a living body for 3 months or more has not been developed.
  • metal or alloy substrates can be coated by a wet film-forming method in which the substrate is simply immersed in an aqueous polymer solution without any special pretreatment such as anodization or thin coating of insoluble magnesium fluoride on the substrate. There were no literature reports on what to do.
  • the present inventor conducted various experiments and examined the literature, and if the aqueous solution of a hydrophilic and nonionic polymer was used, the metal or alloy substrate was not corroded without corroding the surface of the metal or alloy substrate. I came to think that the material could be polymer coated. Therefore, only by polishing the surface of the magnesium alloy disk, and applying a hydrophilic and nonionic polymer by dipping method, the surface of the metal or alloy substrate is not corroded, and the metallic luster is maintained and the hydrophilicity is maintained. And nonionic polymer thin films could be formed. Further, it was found that the elution of metal ions from the base material can be effectively prevented by the immersion corrosion test.
  • a thin hydroxide and / or oxide layer is formed on the surface of the metal or alloy substrate, and a hydrophilic and nonionic polymer is formed so as to cover the hydroxide and / or oxide layer.
  • a layer was formed.
  • the O atom of the OH group of the hydrophilic and nonionic polymer is coordinated to a metal atom in the hydroxide and / or oxide layer, for example, an Mg atom, the polymer layer (2)
  • a metal atom in the hydroxide and / or oxide layer for example, an Mg atom
  • the polymer layer By having at least these two layers, even if the film thickness is thin, the elution of the metal ions of the base material can be highly prevented, and (3)
  • the biocompatibility is enhanced by covering the surface with a hydrophilic and nonionic polymer, and (4) the hydrophilic and nonionic polymer is formed on the hydroxide and / or oxide layer due to bending / straining of the substrate.
  • the hydrophilic and nonionic polymer As the hydrophilic and nonionic polymer is decomposed and disappears in the living body, the base material begins to corrode and dissolve, and then the metal or alloy base material becomes a living tissue or bone. May be lost It
  • the present invention is the first to demonstrate the usefulness of hydrophilic and nonionic polymers as constituent materials for medical bioabsorbable members, and is applicable to a wide range of polymers in view of their mechanism of action. It is shown.
  • the present invention has the following configuration.
  • a medical bioabsorbable member comprising a metal or alloy base, a hydroxide and / or oxide layer, and a polymer layer.
  • the metal or alloy base material contains any one metal selected from the group consisting of Mg, Ca, Mn, Fe, Zn, Cu, La or Al (1) to (4) The bioabsorbable member for medical use according to any one of the above.
  • the hydroxide and / or oxide layer is Mg (OH) 2 , Ca (OH) 2 , Mn (OH) 2 , Fe (OH) 2 [iron hydroxide (II)] or Fe (OH) [Iron (III) hydroxide], Zn (OH) 2 , Cu (OH) 2 , La (OH) 3, or any one or more hydroxides selected from the group of Al (OH) 3 and / or Alternatively, it is characterized by comprising one or two or more oxides selected from the group consisting of MgO, CaO, MnO, FeO, Fe 2 O 3 , ZnO, CuO, La 2 O 3 and Al 2 O 3 ( The medical bioabsorbable member according to any one of 1) to (4).
  • the polymer having an electron donating group is one or more polymers selected from the group consisting of polyethylene glycol (PEG), polyvinyl alcohol (PVA), and poly-2-hydroxyethyl methacrylate (PHEMA).
  • PEG polyethylene glycol
  • PVA polyvinyl alcohol
  • PHEMA poly-2-hydroxyethyl methacrylate
  • the polymer electrolyte is any one or more anions selected from the group consisting of polyacrylic acid, polyaspartic acid, polystyrene sulfonic acid, polyanetol sulfonic acid, polyvinyl sulfate, polyvinyl phosphate, and salts thereof
  • the polyelectrolyte is any one or two or more cationic polymers selected from the group consisting of polyamine, polydiallyldimethylammonium, polyethyleneimine, poly-L-lysine, and salts thereof.
  • the ceramic layer includes any one or more ceramics selected from the group consisting of calcium phosphate, magnesium phosphate, magnesium hydroxide, bioactive glass, and biological ceramics (1) to ( The bioabsorbable member for medical use according to any one of 4). (15) The bioabsorbable member for medical use according to (14), wherein the ceramic layer has a thickness of 500 nm to 10,000 nm.
  • a method for producing a medical bioabsorbable member comprising forming a hydrophilic and nonionic polymer layer on a surface of a material.
  • the ceramic layer forming solution is heated to a temperature range of 40 ° C. or higher and 100 ° C. or lower, the ceramic layer forming substrate is immersed for 0.1 hour or longer on the surface of the ceramic layer forming substrate.
  • the medical bioabsorbable member of the present invention has a metal or alloy base, a hydroxide and / or oxide layer, and a polymer layer, the hydroxide and / or oxide layer at the boundary. It adheres firmly to the metal or alloy substrate due to the composition gradient.
  • the OH group at the end or side chain of the hydrophilic and nonionic polymer is attached to the metal atom on the outermost surface of the hydroxide and / or oxide layer.
  • hydrogen bonding is performed between OH groups, and the hydroxide and / or oxide layer and the hydrophilic and nonionic polymer layer can be firmly bonded.
  • corrosion of the metal substrate Mg occurs locally such as defects in the Mg (OH) 2 film.
  • a hydrophilic and nonionic polymer such as PEG having high hydrophilicity causes water Molecules are constrained by the polymer layer, and contact of water molecules with the Mg (OH) 2 film is suppressed, so that the magnesium alloy can be prevented from being rapidly corroded and dissolved in the living environment.
  • biosafety and biocompatibility can be improved by making the outermost layer a highly safe polymer (for example, a hydrophilic and nonionic polymer).
  • the medical bioabsorbable member of the present invention has a structure in which a ceramic layer is formed so as to cover the polymer layer, for example, PEG and PVA which are hydrophilic and nonionic polymers, and HAp as a material of the ceramic layer It can be bonded at the molecular / atomic level with calcium phosphate such as calcium phosphate (hereinafter also referred to as “Ca-P”) and can be firmly bonded.
  • a ceramic layer is formed so as to cover the polymer layer, for example, PEG and PVA which are hydrophilic and nonionic polymers, and HAp as a material of the ceramic layer It can be bonded at the molecular / atomic level with calcium phosphate such as calcium phosphate (hereinafter also referred to as “Ca-P”) and can be firmly bonded.
  • Ca-P calcium phosphate
  • the medical bioabsorbable member of the present invention has a structure in which a ceramic layer is formed between the hydroxide and / or oxide layer and the polymer layer.
  • a ceramic layer is formed between the hydroxide and / or oxide layer and the polymer layer.
  • a hydrophilic and nonionic polymer PEG or PVA and Ca—P such as HAp as the material of the ceramic layer can be bonded at the molecular / atomic level and can be firmly bonded.
  • a hydrophilic and nonionic polymer aqueous solution is heated to a temperature range of 30 ° C. or higher and 100 ° C. or lower, and then the polymer layer forming substrate is heated for 0.1 hour. Since it is so constructed that the hydrophilic and nonionic polymer is bonded to the surface of the base material for forming the polymer layer, the surface of the base material can be easily and in a short time with a small number of steps and at a low cost. A hydrophilic and nonionic polymer layer having a desired thickness can be formed. Thereby, the bioabsorbable member for medical use having high biosafety and biocompatibility, which exhibits various corrosion resistances in order to suppress the corrosion dissolution of the base material and suppress it to an arbitrary corrosion dissolution rate, can be manufactured.
  • FIG. 6 is a manufacturing process diagram of the disk of Example 1-1.
  • 2 is an optical microscopic image of the surface of a disk (5PEG600-coat) of Example 1-1.
  • 4 shows Fourier transform infrared spectroscopy (FT-IR) spectra of the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as polished).
  • 2 is an atomic force microscope (AFM) image of the disk of Example 1-1.
  • 4 is an atomic force microscope (AFM) image of the disk of Example 1-3.
  • 4 is an atomic force microscope (AFM) image of the disk of Comparative Example 1.
  • 6 is a graph showing changes over time in the elution amount of Mg ions into the cell culture medium of the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as polished).
  • 2 is a graph showing Mg ion elution rates after the first day of immersion of the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as polished) into the cell culture medium.
  • 6 is a graph showing corrosion resistance in Hanks liquids of the disks of Examples 1-1, 1-2, 1-5, and 1-6 (each PEG-coat) and Comparative Example 1 (as polished).
  • Example 2-1 It is a SEM image of the disk (PEG600 ⁇ Ca—P) surface of Example 2-1. It is a SEM image of the disk (PVA ⁇ Ca—P) surface of Example 2-5.
  • 6 is a graph showing changes over time in the amount of Mg ions eluted into the cell culture medium of the disks of Examples 2-1 to 2-4 and the disk of Comparative Example 1.
  • 7 is a graph showing the amount of Mg ions eluted on the 7th and 10th days of immersion of the disks of Examples 2-1, 2-5 and 2-7 and the disks of Comparative Examples 1 and 2 in physiological saline. In the graph of each disk, the left side is the 7th day of immersion, and the right side is the 10th day.
  • 4 is an optical microscopic image of the disk of Example 3-3 (Ca—P ⁇ 25PEG600). It is a SEM image of the disk (Ca-P ⁇ 25PEG600) of Example 3-3. 4 is an FT-IR spectrum of the disks of Examples 3-1 to 3-3 and the disk of Comparative Example 2. 4 is a graph showing Mg ion elution amounts on the 7th and 10th days of immersion of the disks of Examples 3-1 to 3-3 and the disk of Comparative Example 2 in physiological saline. In the graph of each disk, the left side is the 7th day of immersion, and the right side is the 10th day.
  • Example 3 is a stereomicroscopic image of a surface having no indentation after the disk of Example 3-1 (Ca—P ⁇ 5PEG600) was immersed in physiological saline for 10 days.
  • 6 is a graph showing Mg ion elution amounts on the first and fourth days of immersion of the disks of Examples 4-1 to 4-9 and the disk of Comparative Example 1 in a cell culture solution. In the graph of each disk, the left side is the first day of immersion, and the right side is the fourth day. 6 is a graph showing the amount of Mg ions eluted on the fourth day of immersion in the cell culture solution of the disks of Examples 5-1 to 5-9 and the disk of Comparative Example 3.
  • FIG. 6 is an SEM image of scratched portions on the surface of the disks of Examples 7-5 and 7-6 and the disk of Comparative Example 2 that were scratched with a cutter knife after 3 days of immersion in Hanks liquid. It is a graph which shows the composition analysis result of the deposit of the flaw part of the surface obtained by the energy dispersive X-ray analysis (EDS) after the Hanks liquid immersion of the disk of Examples 7-5 and 7-6. In the graph of each atom, the left side is Example 7-6 and the right side is Example 7-5.
  • EDS energy dispersive X-ray analysis
  • 6 is a graph showing the amount of Mg ions eluted into the Hanks solution of the disks of Examples 8-1 to 8-4 and Comparative Example 1.
  • 6 is a graph showing the amount of Mg ions eluted into the Hanks solution of the disks of Examples 8-1 to 8-8 and Comparative Example 3.
  • Examples 8-1 to 8-4 have no flaws on the left side and Examples 8-5 to 8-8 have flaws on the right side.
  • 4 is a graph showing the amount of Mg ions eluted into the cell culture fluid of the disks of Examples 8-1 to 8-4 and Comparative Example 1.
  • FIG. 1 is a view for explaining an example of a medical bioabsorbable member according to an embodiment of the present invention, and is a plan view (a), a sectional view taken along line AA ′, and a B-part view (c). It is.
  • FIG. 2 is a schematic view of the B part chemical structure.
  • a medical bioabsorbable member 11 according to an embodiment of the present invention has a substantially disk shape.
  • the shape is not limited to this, and various shapes such as a cubic shape, a spherical shape, and a conical shape may be used. What is necessary is just to set it as the shape suitable for using for preparation of a fracture fixing material, a stent, an artificial bone, etc.
  • the bioabsorbable member 11 for medical use which is embodiment of this invention is the metal or alloy base material 12, the hydroxide and / or oxide layer 13, the polymer layer 14, and Have.
  • the metal or alloy substrate 12 is covered with a hydroxide and / or oxide layer 13, and the hydroxide and / or oxide layer 13 is covered with a polymer layer 14.
  • FIG. 2 shows a case where the polymer layer 14 is a hydrophilic and nonionic polymer layer described later.
  • the metal or alloy base 12 preferably contains any one metal selected from the group consisting of Mg, Ca, Mn, Fe, Zn, Cu, La, and Al.
  • Mg is preferable. This is because Mg is an abundant element on the surface of the earth, can be applied to engineering, is light, has high toughness per unit mass, has high vibration absorption, is non-toxic, and has good castability. From the viewpoint of biomaterials, Mg is one of the essential elements of living organisms, so it has low harm, and Young's modulus (elastic modulus) is close to the bone value, so even if it is used for a member that receives load instead of bone, This is because it is not shielded.
  • the metal or alloy substrate 12 is preferably covered with a hydroxide and / or oxide layer 13. Thereby, it can suppress that the metal ion of a metal or the alloy base material 12 elutes in living body environment.
  • the hydroxide and / or oxide layer 13 is Mg (OH) 2 , Ca (OH) 2 , Mn (OH) 2 , Fe (OH) 2 [iron (II) hydroxide] or Fe (OH) [water Iron (III) oxide], Zn (OH) 2 , Cu (OH) 2 , La (OH) 3 or Al (OH) 3 , MgO, CaO, MnO, FeO [iron (II) oxide] or Fe 2 O 3 ) [iron oxide (III)], ZnO, CuO , La 2 O 3 or any one or more hydroxides and / or MgO is selected from the group of Al 2 O 3, CaO, MnO , FeO or Fe It is preferably made of any one or two or more oxides selected from the group consisting of 2 O 3 , ZnO, CuO, La 2 O 3 or Al 2 O 3 . Thereby, while being able to adhere
  • the hydroxide and / or oxide layer 13 may be a hydroxide and / or oxide of an alloy element that is naturally formed by exposing a metal or alloy material to room temperature atmosphere. Since the hydroxide and / or oxide layer naturally formed in the room temperature atmosphere is firmly attached to the substrate, the polymer layer 14 can be firmly adhered.
  • the thickness of the hydroxide and / or oxide layer 13 is preferably 5,000 nm or less, more preferably 2,000 nm or less, and even more preferably 1,000 nm or less. Thereby, the metal or alloy base material 12 and the polymer layer 14 can be firmly bonded. If it exceeds 5,000 nm, cracks may occur due to the peeling of the hydroxide and / or oxide layer.
  • the polymer layer 14 is preferably a hydrophilic and nonionic polymer layer.
  • the hydrophilic and nonionic polymer layer preferably has a polymer having an electron donating group such as OH group or NH 2 group. Thereby, it can suppress more that the metal ion of the metal or alloy base material 12 elutes in living body environment. Moreover, the influence of the crack etc. by bending can be suppressed.
  • polymer having an OH group examples include polyethylene glycol (PEG), polyvinyl alcohol (PVA), and poly-2-hydroxyethyl methacrylate (PHEMA).
  • PEG polyethylene glycol
  • PVA polyvinyl alcohol
  • PHEMA poly-2-hydroxyethyl methacrylate
  • hydrophilic and electron-donating groups (OH groups) of the nonionic polymer are coordinated to the metal ions of the hydroxide and / or oxide layer, and OH Hydrogen bonding is performed between groups, and the hydroxide and / or oxide layer and the hydrophilic and nonionic polymer layer can be firmly bonded.
  • the polymer film of PEG and PVA is transparent, it can maintain the metallic luster of the surface, and if different medical devices are made using different metals or alloys, they can be easily discriminated visually.
  • Examples of the polymer having an NH 2 group include PEG or poly (N, N-dimethylacrylamide (PDMAA)) having a terminal modified with NH 2 .
  • PEG poly (N, N-dimethylacrylamide (PDMAA)) having a terminal modified with NH 2 .
  • the one terminal of these polymers may be modified by arbitrary substituents (for example, arbitrary alkyl groups).
  • a polymer having an OH group capable of forming a polymer layer by being coordinated to a hydroxide and / or a metal ion of the oxide layer can be used.
  • examples of such a polymer include DL-3- (3,4-dihydroxyphenyl) alanine (DL-DOPA) shown below, and polymers of DL-DOPA and other polymers.
  • a layer having a polymer electrolyte having a dissociating group (charged group) in the polymer molecule can be used.
  • the polymer electrolyte include an anionic polymer and a cationic polymer.
  • the anionic polymer include polyacrylic acid, polyaspartic acid, polystyrene sulfonic acid, polyanetol sulfonic acid, polyvinyl sulfuric acid, polyvinyl phosphoric acid, and salts thereof.
  • the cationic polymer include polyamine (eg, allylamine polymer, diallylamine polymer), polydiallyldimethylammonium, polyethyleneimine, poly-L-lysine, and salts thereof.
  • Such polyelectrolytes include those known as functional polymers such as superabsorbent polymers and stimulus-responsive polymers.
  • functional polymers such as superabsorbent polymers and stimulus-responsive polymers.
  • polymer electrolyte which can be used as a material of the polymer layer 14 is shown.
  • polyacrylic acid and salts thereof include compounds represented by the following structural formula (A-1). Note that in the structural formula (A-1), M represents a hydrogen atom or an alkali metal atom.
  • polystyrene sulfonic acid and salts thereof include compounds represented by the following structural formula (A-2). Note that in the structural formula (A-2), M represents a hydrogen atom or an alkali metal atom.
  • polyvinyl sulfate and salts thereof include compounds represented by the following structural formula (A-3). Note that in the structural formula (A-3), M represents a hydrogen atom or an alkali metal atom.
  • polyvinyl phosphoric acid and salts thereof include compounds represented by the following structural formula (A-4). Note that in the structural formula (A-4), M represents a hydrogen atom or an alkali metal atom.
  • Examples of polyanetol sulfonic acid and salts thereof include compounds represented by the following structural formula (A-5). Note that in the structural formula (A-5), M represents a hydrogen atom or an alkali metal atom.
  • polydiallyldimethylammonium and salts thereof include compounds represented by the following structural formula (B-1). Note that in the structural formula (B-1), X represents a halogen.
  • allylamine polymer examples include compounds represented by the following structural formula (B-2).
  • polyethyleneimine examples include compounds represented by the following structural formula (B-3).
  • poly-L-lysine examples include compounds represented by the following structural formula (B-4).
  • diallylamine polymers examples include compounds represented by the following structural formula (B-5).
  • the thickness of the polymer layer 14 is preferably 0.2 nm or more and 10,000 nm or less, more preferably 0.2 nm or more and 5,000 nm or less, and further preferably 0.2 nm or more and 500 nm or less. Thereby, elution of the metal ion from the metal or alloy base material 12 can be suppressed for a certain time, and can be eliminated by the environment in the living body after a certain time. If the thickness is less than 0.2 nm, these effects may not be sufficient. If it exceeds 10,000 nm, the stability of the polymer layer 14 cannot be maintained, and the layer may be displaced or peeled off.
  • the hydroxide and / or the oxide layer 13 can be prevented from cracking, and Mg ions from the cracked portion can be prevented. Elution can be suppressed. Furthermore, biocompatibility can be improved. By adopting a two-layer structure of hydroxide and / or oxide layer 13 and polymer layer 14, the effect is enhanced.
  • Drawing 3 is a flowchart explaining an example of a manufacturing method of a medical bioabsorbable member which is an embodiment of the present invention.
  • a metal or alloy substrate is prepared, and the metal or alloy substrate is polished.
  • An oxide film can be formed instantaneously (in milliseconds) during polishing.
  • a method of storing the metal that has just been polished there is a method of storing it in an air atmosphere of 0 ° C. or more and 40 ° C. or less and a relative humidity of 5% or more and 100% or less, in a vacuum, or in water. Thereby, the hydroxide and / or oxide layer formed on the surface of the metal or alloy substrate can be retained.
  • an aqueous solution of a hydrophilic and nonionic polymer was prepared, and the aqueous solution was heated to a temperature range of 30 ° C. or higher and 100 ° C. or lower, and this aqueous solution was coated with a hydroxide and / or an oxide layer.
  • the polymer layer forming substrate 19 made of a metal or alloy substrate is immersed for 0.1 hour or more. Thereby, the polymer layer 14 (hydrophilic and nonionic polymer layer) is formed on the surface of the base material 19 for polymer layer formation.
  • conditions such as the density
  • the temperature of the polymer aqueous solution can be set to room temperature (25 ° C.).
  • FIG. 4 is a view showing another example of the medical bioabsorbable member according to the embodiment of the present invention, and is a plan view (a), a sectional view taken along the line CC ′ (b), and a D section view (c). ).
  • the medical bioabsorbable member 31 according to the embodiment of the present invention has the same configuration as that of the first embodiment of the present invention except that the ceramic layer 32 is formed so as to cover the polymer layer 14. .
  • the thickness of the ceramic layer 32 is preferably 500 nm or more and 10,000 nm or less, more preferably 500 nm or more and 5,000 nm or less, and further preferably 1,000 nm or more and 5,000 nm or less. Thereby, not only can corrosion resistance be improved, but biocompatibility to bone can be further improved. If it is less than 500 nm, the corrosion resistance cannot be sufficiently improved. If it exceeds 10,000 nm, the ceramic layer 32 tends to peel off.
  • the ceramic layer 32 preferably contains any one or more ceramics selected from the group consisting of calcium phosphate, magnesium phosphate, magnesium hydroxide, bioactive glass, and bioceramics. Thereby, the biocompatibility with respect to a bone can be improved and it can utilize by making biocompatibility higher as a fracture fixing material or a material of artificial bone.
  • FIG. 5 is a flowchart explaining an example of the manufacturing method of the medical absorptive member which is an embodiment of the present invention.
  • a medical biological body having a metal or alloy base material 12, a hydroxide and / or oxide layer 13, and a polymer layer 14.
  • a ceramic layer forming substrate 21 made of the absorbent member 11 is prepared.
  • a ceramic forming solution is prepared.
  • As the ceramic forming solution a mixed solution of Ca-EDTA, KH 2 PO 4 and NaOH can be used.
  • the ceramic layer forming substrate 21 is immersed for 0.1 hour or longer. Thereby, the ceramic layer 32 is formed on the surface.
  • FIG. 6 is a view showing another example of the medical bioabsorbable member according to the embodiment of the present invention, and is a plan view (a), a cross-sectional view taken along line EE ′, and a F-part view (c). ).
  • the medical bioabsorbable member 41 according to the embodiment of the present invention is the first of the present invention except that the ceramic layer 32 is formed between the hydroxide and / or the oxide layer 13 and the polymer layer 14.
  • the configuration is the same as that of the embodiment.
  • the corrosion resistance of the polymer layer 14 can be complemented in the in vivo environment. Further, a layer having high biocompatibility to bone is exposed from the gap of the submicron diameter of the polymer layer 14, and the base material can be used so that the base material can be dissolved and lost while being biocompatible with bone. it can. It can be used as a fracture fixing material or artificial bone material adapted to a special part.
  • FIG. 7 is a flowchart explaining an example of the manufacturing method of the medical absorptive member which is an embodiment of the present invention.
  • a ceramic layer forming substrate 22 made of a metal or alloy substrate on which a hydroxide and / or oxide layer is formed is prepared.
  • a ceramic forming solution is prepared, and the ceramic forming solution is heated to a temperature range of 40 ° C. or higher and 100 ° C. or lower.
  • the substrate 22 is immersed for 0.1 hour or longer. Thereby, the ceramic layer 32 is formed on the surface. This is designated as polymer layer forming substrate 20.
  • an aqueous polymer solution is prepared, and the aqueous solution is heated to a temperature range of 30 ° C. or higher and 100 ° C. or lower. Soak for more than 1 hour. Thereby, the polymer layer 14 is formed on the surface. Thereby, the medical bioabsorbable member 41 is manufactured.
  • the medical bioabsorbable member 11, 31, 41 has a metal or alloy base material 12, a hydroxide and / or oxide layer 13, and a polymer layer 14.
  • the oxide and / or oxide layer is strongly bonded to the metal or alloy substrate by the composition gradient at the boundary, for example, the end of the hydrophilic and nonionic polymer, the side chain OH group, NH 2 group, etc.
  • the electron-donating group is coordinated to the metal atom on the outermost surface of the hydroxide and / or oxide layer, and is hydrogen-bonded between the OH groups, thereby strengthening the hydroxide and / or the oxide layer and the polymer layer. Can be glued to.
  • corrosion of the metal substrate Mg occurs locally from a defect of Mg (OH) 2 coating, although progress while breaking the Mg (OH) 2 coating, for example, hydrophilic than Mg (OH) 2
  • hydrophilic and nonionic polymers such as high PEG
  • the polymer layer binds water molecules that cause corrosion and suppresses contact with the Mg (OH) 2 film. Sudden corrosion and dissolution in a living environment can be suppressed.
  • biosafety and biocompatibility can be improved by making the outermost layer a highly safe polymer (for example, a hydrophilic and nonionic polymer).
  • the Young's modulus of the surface layer of the medical bioabsorbable member can be lowered, and when plastic deformation according to the shape of the affected part is applied during surgery, Even if deformation of the base material occurs due to repeated loading in the hydrophilic and non-ionic polymer layer following the deformation, the hydrophilic and non-ionic polymer layer will not crack. it can.
  • the hydrophilic polymer layer since the hydrophilic polymer layer is included, the polymer layer restrains water molecules that cause corrosion and suppresses contact with the Mg (OH) 2 film. Even when cracks or peeling occurs in the metal, the corrosion of the metal or alloy substrate can be suppressed.
  • a medical bioabsorbable member 11 includes a metal or alloy substrate 12, a hydroxide and / or oxide layer 13 covering the substrate, and the hydroxide and / or oxide. And a polymer layer 14 covering the layer, the outermost layer has a highly safe polymer (for example, a hydrophilic and nonionic polymer), and can improve biosafety and biocompatibility. .
  • the medical bioabsorbable member 31 has a structure in which the ceramic layer 32 is formed so as to cover the polymer layer 14, for example, a hydrophilic and nonionic polymer and a hydrophilic ceramic (calcium phosphate).
  • a hydrophilic and nonionic polymer and a hydrophilic ceramic calcium phosphate
  • a metal or alloy substrate By laminating, adhesion with a metal or alloy substrate can be enhanced.
  • a ceramic layer made of Ca—P such as HAp is formed on the surface of PEG or PVA
  • the OH group of the polymer chain of PEG or PVA becomes a nucleation site of Ca—P such as HAp, and OH The group promotes the precipitation of phosphate ceramics.
  • PEG, PVA, and Ca—P such as HAp can be bonded at the molecular / atomic level, and the ceramic layer can be firmly bonded to the surface of the hydrophilic and nonionic polymer layer.
  • the tolerance with respect to the deformation crack of a metal or an alloy base material can be improved. Thereby, it can be used for an orthopedic device used in or around the bone.
  • the medical bioabsorbable member 41 has a structure in which the ceramic layer 32 is formed between the hydroxide and / or the oxide layer 13 and the polymer layer 14. It is possible to form a multilayer film in which the OH group of the polymer is coordinately bonded to the metal atoms and firmly bonded, and the Young's modulus can be reduced as compared with the ceramic layer single-layer film. Thereby, even if a metal or alloy base material deform
  • a layer with high biocompatibility to bone is exposed from the submicron gap of the polymer layer, and it is used so that the base material is corroded and dissolved / disappeared while being biocompatible with bone. be able to. It can be used as a fracture fixing material or artificial bone material adapted to a special part.
  • the medical bioabsorbable members 11, 31, 41 which are embodiments of the present invention are any one in which the metal or alloy base 12 is selected from the group of Mg, Ca, Mn, Fe, Zn, Cu, La or Al. Since it includes one metal, a hydroxide and / or oxide layer that is firmly bonded to the surface of the metal or alloy in room temperature air or water is formed.
  • the medical bioabsorbable members 11, 31, 41 have a hydroxide and / or oxide layer 13 of Mg (OH) 2 , Ca (OH) 2 , Mn (OH) 2 , Fe (OH) 2 [iron (II) hydroxide] or Fe (OH) [iron (III) hydroxide], Zn (OH) 2 , Cu (OH) 2 , La (OH) 3 or Al (OH) 3
  • Any one or more hydroxides selected from the group and / or selected from the group of MgO, CaO, MnO, FeO or Fe 2 O 3 , ZnO, CuO, La 2 O 3 or Al 2 O 3 Since it is composed of any one or more oxides, the dissolution / disappearance rate of the bioabsorbable member for medical use is formed by forming a hydroxide and / or oxide layer firmly bonded to the metal or alloy surface.
  • a structure that can suppress Door can be.
  • the medical bioabsorbable members 11, 31, and 41 according to the embodiment of the present invention have a structure in which the thickness of the hydroxide and / or the oxide layer 13 is 5000 nm or less, so that the medical bioabsorbable member is dissolved / disappeared. Speed can be suppressed.
  • the medical bioabsorbable members 11, 31, 41 according to the embodiment of the present invention are hydrophilic and nonionic since the polymer layer 14 is a hydrophilic and nonionic polymer layer having a polymer having an electron donating group.
  • the hydrophilic and electron donating group (OH group or NH 2 group) of the ionic polymer is coordinated and bonded to the metal ion of the hydroxide and / or oxide layer, and hydrogen bonds between the OH groups, The oxide and / or the oxide layer and the hydrophilic and nonionic polymer layer can be firmly bonded.
  • the polymer having the electron donating group is polyethylene glycol (PEG), polyvinyl alcohol (PVA), or poly-2-hydroxyethyl methacrylate (PHEMA).
  • the structure is one or two or more polymers selected from the group of PEG or poly (N, N-dimethylacrylamide (PDMAA) modified with NH 2 at the end, so that the hydrophilicity of the hydrophilic and nonionic polymer And an electron donating group (OH group or NH 2 group) is coordinated to a hydroxide and / or a metal ion of the oxide layer, and is hydrogen-bonded between OH groups to form a hydroxide and / or an oxide.
  • the physical layer and the hydrophilic and nonionic polymer layer can be firmly bonded.
  • the polymer film of PEG and PVA is transparent, it can maintain the metallic luster of the surface, and if different medical devices are made using different metals or alloys, they can be easily discriminated visually.
  • the medical bioabsorbable members 11, 31, and 41 that are the embodiments of the present invention form a polymer layer by coordination bonding of the polymer layer 14 to metal ions of the hydroxide and / or oxide layer. It is also possible to form a polymer layer formed using a polymer having an OH group that can be formed, or a polymer electrolyte having a dissociating group (charged group) in the polymer molecule.
  • the polymer layer 14 has a polymer electrolyte, so the hydrophilic and electron donating group (OH group or NH 2 group) of the hydrophilic polymer is water. While coordinating and bonding to the metal ions of the oxide and / or oxide layer, the OH groups can be hydrogen bonded to each other, and the hydroxide and / or oxide layer and the polymer layer can be firmly bonded.
  • the medical bioabsorbable members 11, 31, and 41 that are embodiments of the present invention have a configuration in which the thickness of the polymer layer 14 is 0.2 nm or more and 2500 nm or less, and thus, for example, included in the hydrophilic and nonionic polymer layer
  • the OH group or NH 2 group of the polymer can be coordinated to the metal atom on the outermost surface of the hydroxide and / or oxide layer, and the hydroxide and / or oxide layer and the polymer layer can be firmly bonded .
  • the dissolution / disappearance rate of the medical bioabsorbable member can be controlled by decomposing the polymer layer according to the in vivo environment.
  • the ceramic layer 32 is any one or two selected from the group consisting of calcium phosphate, magnesium phosphate, magnesium hydroxide, bioactive glass, and bioceramics. Since it is a structure containing the above ceramics, it can be utilized in such a manner that the base material undergoes corrosion dissolution / disappearance while being biocompatible with bone. In particular, when the ceramic layer contains calcium phosphate, there is good bonding with the surrounding bone and promotion of bone formation, and healing of the surrounding bone can be promoted.
  • the bioabsorbable members 31 and 41 for medical use which are embodiments of the present invention have a structure in which the thickness of the ceramic layer 32 is 500 nm or more and 10,000 nm or less, by dissolving the ceramic layer according to the in vivo environment, The dissolution / disappearance rate of the medical bioabsorbable member can be controlled.
  • a hydrophilic and nonionic polymer aqueous solution 30 is used. After heating to a temperature range of not lower than 100 ° C. and lower than 100 ° C., the polymer layer forming base materials 19 and 20 are immersed for not less than 0.1 hour, and the surface of the polymer layer forming base material is hydrophilic and nonionic polymer. Since the layer is formed, the hydrophilic and nonionic polymer layer having a desired thickness can be formed on the surface of the substrate easily, in a short time, with a small number of steps, and at a low cost. Moreover, since it is aqueous solution immersion treatment, it is possible to effectively coat not only the Mg alloy but also the Fe alloy, Ca alloy, and Zn alloy regardless of the shape of the base material and the composition.
  • the manufacturing method of the medical bioabsorbable members 31 and 41 according to the embodiment of the present invention includes heating the ceramic layer forming solution to a temperature range of 40 ° C. to 100 ° C. 22 is immersed for 0.1 hour or longer to form a ceramic layer on the surface of the ceramic layer forming base material. Therefore, the number of steps can be reduced easily and in a short time at a low cost.
  • a ceramic layer having a desired thickness can be formed on the surface. If a polymer layer is formed after forming a ceramic layer made of hydrophilic calcium phosphate, the adhesiveness can be increased due to the high affinity between the hydrophilic properties.
  • the medical bioabsorbable member and the manufacturing method thereof according to the embodiment of the present invention are not limited to the above embodiment, and can be implemented with various modifications within the scope of the technical idea of the present invention. . Specific examples of this embodiment are shown in the following examples. However, the present invention is not limited to these examples.
  • FIG. 8 is a manufacturing process diagram of the disk of Example 1-1.
  • an Mg-3 mass% Al-1 mass% Zn (hereinafter abbreviated as AZ31) disk was prepared, and the surface was finished with # 1200 water-resistant abrasive paper.
  • AZ31 Mg-3 mass% Al-1 mass% Zn
  • PEG 600 polyethylene glycol having a molecular weight of 600
  • Example 1-1 5PEG600-coat
  • the edges of the disc were coated with epoxy resin or Teflon tape for corrosion testing.
  • Example 1-2 A disk (5PEG6k-coat) of Example 1-2 was produced in the same manner as Example 1-1 except that polyethylene glycol having a molecular weight of 6,000 (hereinafter abbreviated as PEG6k) was used.
  • PEG6k polyethylene glycol having a molecular weight of 6,000
  • Example 1-3 A disc (5PEG20k-coat) of Example 1-3 was produced in the same manner as Example 1-1 except that polyethylene glycol having a molecular weight of 20,000 (hereinafter abbreviated as PEG20k) was used.
  • PEG20k polyethylene glycol having a molecular weight of 20,000
  • Example 1-4 The disk of Example 1-4 (1PEG500k-coat) was prepared in the same manner as Example 1-1 except that polyethylene glycol having a molecular weight of 500,000 (hereinafter abbreviated as PEG500k) was used and the concentration was 1 wt%. Produced.
  • PEG500k polyethylene glycol having a molecular weight of 500,000
  • Example 1-5 A disc (5PEG200-coat) of Example 1-5 was produced in the same manner as Example 1-1 except that polyethylene glycol having a molecular weight of 200 (hereinafter abbreviated as PEG200) was used.
  • PEG200 polyethylene glycol having a molecular weight of 200
  • Example 1-6 The disc of Example 1-6 (5CPEG400) was used in the same manner as Example 1-1 except that polyethylene glycol having a molecular weight of 400 having a methyl group (CH 3 group) at one end (hereinafter abbreviated as CPEG400) was used. -Coat).
  • Example 1--7 A disk (5PVA-coat) of Example 1-7 was produced in the same manner as Example 1-1 except that polyvinyl alcohol (hereinafter abbreviated as PVA) having an average degree of polymerization of 1,500 was used.
  • PVA polyvinyl alcohol
  • Comparative Example 1 a disk of Comparative Example 1 was manufactured with the AZ31 disk polished with # 1200 water-resistant abrasive paper (hereinafter abbreviated as “as polished”). Table 1 summarizes the production conditions.
  • FIG. 9 is an optical microscopic image showing the surface of the disk of Example 1-1 (5PEG600-coat) whose edge was coated with an epoxy resin.
  • the polymer dip coated surface maintained a metallic luster.
  • the disks of Examples 1-2 to 1-7 also had the same appearance. That is, a surface having a metallic luster was obtained regardless of the type of polymer and the molecular weight of the polymer.
  • FT-IR measurement Fourier transform infrared spectroscopy (FT-IR) measurements were performed on the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as polished).
  • FIG. 10 shows Fourier transform infrared (FT-IR) spectra of the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as polished).
  • FT-IR Fourier transform infrared
  • FIG. 11 to 13 are atomic force microscope (AFM) images of the disks of Examples 1-1, 1-3, and Comparative Example 1, respectively.
  • FIG. 14 is a cross-sectional profile obtained from FIGS. In the as-polished disc of Comparative Example 1, due to polishing traces of # 1200 abrasive paper and abrasive debris and abrasive particles that were not cleaned, the cross-sectional profile of FIG. Observed.
  • Example 1-1 In the PEG 600-coat of Example 1-1, rounded irregularities of about 5 nm were observed in the ridges and valleys of the ridge having a height difference of about 100 nm that were obtained by polishing. This confirmed that PEG having a molecular weight of 600 was applied with a thickness of one molecule. The thickness of the PEG molecule was about 0.2 nm and the length was about 2.5 nm, suggesting that the thickness of the thin part of the PEG layer was about 0.2 nm. PEG formed a monomolecular adsorption layer. For this reason, there are gaps between molecules at the nano level.
  • Example 1-3 In the PEG20k-coat of Example 1-3, rounded irregularities of 10 to 20 nm were observed in the ridges and valleys of the sandstone with a difference in height of about 100 nm.
  • the PEG molecule having a molecular weight of 20,000 has a thickness of about 0.2 nm and a length of about 90 nm. Since such a long-chain polymer is usually rounded in a string shape, it is rounded by 10 to 20 nm.
  • the unevenness is considered to correspond to PEG20k. Since the unevenness due to the PEG molecule is larger than that in the case of the molecular weight of 600, it was shown that the thickness of the PEG layer can be increased by increasing the molecular weight of PEG.
  • the thickness of the PEG layer having a molecular weight of 600 in Example 1-1 is expected to be about 2.5 nm which is the length of the PEG molecule.
  • the thickness of the PEG layer having a molecular weight of 500,000 in Example 1-4 is expected to be about 2,500 nm, which is the length of the PEG molecule.
  • the thickness of the polymer layer was estimated from the size of PEG and PVA molecules. 0.2 nm was the thickness of one molecular layer estimated from the diameter of the PEG chain, and 2500 nm was calculated from the length of the PEG chain having a molecular weight of 500,000. Although the film thickness was estimated from the change in surface morphology with AFM, one molecule of PEG could not be observed with AFM yet because one molecule of PEG was small.
  • FIG. 15 is a graph showing changes over time in the elution amount of Mg ions into the cell culture medium of the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as-polished). .
  • the cell culture solution contains 3 mg / 150 mL of Mg ions.
  • FIG. 16 shows Mg ion elution rates after the first day of immersion of the disks of Examples 1-1 to 1-4 (each PEG-coat) and the disk of Comparative Example 1 (as polished) into the cell culture solution. It is a graph.
  • the Mg ion elution rate after the first day of immersion of the disks of Examples 1-1 to 1-3 (5PEG600-coat, 5PEG6k-coat, 5PEG20k-coat) is 1 day of immersion of the disk of Comparative Example 1 (as polished) It was about 50% or less of the Mg ion elution rate after the first. From this, it became clear that the corrosion resistance of the Mg alloy can be improved by adopting the PEG-coat configuration.
  • FIG. 17 is a graph showing the corrosion resistance of the disks of Examples 1-1, 1-2, 1-5, and 1-6 (each PEG-coat) and Comparative Example 1 (as polished) in Hanks solution. .
  • the corrosion resistance of the disk of Comparative Example 1 was 1200 ⁇ ⁇ cm 2 , whereas the disks of the examples coated with the polymer all showed corrosion resistance higher than 3000 ⁇ ⁇ cm 2 . This indicates that the corrosion rate is reduced to 1/2 or less by polymer application. From this, it became clear that even when the molecular weight of PEG is 200, the corrosion resistance of the Mg alloy can be improved by adopting the PEG-coat configuration. It was also found that the corrosion resistance of the Mg alloy can be improved by adopting a CPEG-coat structure even when one end of PEG is modified with a substituent.
  • FIG. 18 shows the surface obtained by energy dispersive X-ray analysis (EDS) after immersion in Hanks solution of the disks of Examples 1-1 and 1-6 (each PEG-coat) and Comparative Example 1 (as polished). It is a graph which shows Ca and P density
  • Example 2-1 First, 5 wt% of PEG having a molecular weight of 600 was dissolved in ultrapure water to prepare an aqueous polymer solution. Next, after the polymer aqueous solution was heated to 40 ° C., an AZ31 disk whose surface was finished with # 1200 water-resistant abrasive paper was immersed in it for 1 hour to apply PEG600.
  • an AZ31 disk coated with PEG 600 was placed in a solution of 250 mM ethylenediaminetetraacetate calcium (Ca-EDTA), potassium dihydrogen phosphate (KH 2 PO 4 ), and sodium hydroxide (NaOH) at 60 ° C., 1
  • the disk of Example 2-1 (5PEG600 ⁇ Ca—P) was produced by dipping for a period of time to coat calcium phosphate (Ca—P) on the PEG600 coated surface.
  • the edges of the disc were coated with epoxy resin or Teflon tape for corrosion testing.
  • Example 2-2 A disk (5PEG6k ⁇ Ca-P) of Example 2-2 was produced in the same manner as Example 2-1, except that PEG6k was used.
  • Example 2-3 A disk (5PEG20k ⁇ Ca-P) of Example 2-3 was produced in the same manner as Example 2-1, except that PEG20k was used.
  • Example 2-4 A disk of Example 2-4 (1PEG500k ⁇ Ca—P) was produced in the same manner as in Example 2-1, except that PEG500k was used and the concentration was 1 wt%.
  • Example 2-5 A disk (25PEG200 ⁇ Ca—P) of Example 2-5 was produced in the same manner as in Example 2-1, except that PEG200 was used and the concentration was 25 wt%.
  • Example 2-6 A disk (5PVA ⁇ Ca—P) of Example 2-6 was produced in the same manner as in Example 2-1, except that PVA was used.
  • Example 2--7 A disk (10PVA ⁇ Ca—P) of Example 2-7 was produced in the same manner as in Example 2-1, except that PVA was used and the concentration was 10 wt%.
  • Comparative Example 2 For comparison, the disk of Comparative Example 2 in which the surface of the AZ31 disk polished with # 1200 water-resistant abrasive paper was coated with a Ca—P film in the same manner as in Example 2-1 (as-polished ⁇ Ca—P ) was produced. Table 2 summarizes the production conditions.
  • FIG. 19 shows XRD patterns of the surfaces of the disks of Examples 2-1 to 2-4 and the disk of Comparative Example 2. In all XRD patterns, diffraction peaks derived from HAp and / or OCP (octa calcium phosphate) were observed.
  • FIG. 20 shows the FT-IR spectrum of each disk.
  • the disc of Comparative Example 1 no PO 4 peak derived from HAp and / or OCP was observed, whereas in the discs of Examples 2-1 to 2-4 and the disc of Comparative Example 2, which FT Even in the -IR spectrum, a PO 4 peak derived from HAp and / or OCP was observed.
  • the surfaces of the disks of Examples 2-1 to 2-4 and the disk of Comparative Example 2 were coated with Ca—P.
  • FIG. 21 is an optical microscopic image of the surface of the disk (5PEG600 ⁇ Ca—P) of Example 2-1 with the edge covered with an epoxy resin.
  • the surface of the Ca—P coating was uniform.
  • the disks of Examples 2-2 to 2-7 also had the same appearance. That is, a uniform surface was obtained regardless of the type of polymer and the molecular weight of the polymer.
  • FIG. 22 is an SEM image of the surface of the disk of Example 2-1 (5PEG600 ⁇ Ca—P). HAp and / or OCP dome-shaped crystals densely covered the surface.
  • the disks of Examples 2-2 to 2-5 also had the same appearance. That is, regardless of the molecular weight of the polymer, the dome-shaped crystal densely covered the surface.
  • FIG. 23 is an SEM image of the surface of the disk (5PVA ⁇ Ca—P) of Example 2-6. Even after PVA dip coating, the HAp and / or OCP dome-shaped crystals densely covered the surface.
  • the disk of Example 2-7 also had the same appearance. That is, regardless of the type of polymer, the dome-shaped crystal densely covered the surface.
  • FIG. 24 is a graph showing changes over time in the elution amount of Mg ions into the cell culture medium of the disks of Examples 2-1 to 2-4 and the disk of Comparative Example 1.
  • the cell culture solution contains 3 mg / 150 mL of Mg ions.
  • FIG. 25 is a graph showing Mg ion elution amounts on the 7th and 10th days of immersion of the disks of Examples 2-1, 2-5 and 2-7 and the disks of Comparative Examples 1 and 2 in physiological saline. is there. In the graph of each disk, the left side is the 7th day of immersion, and the right side is the 10th day.
  • Example 3-1 First, an AZ31 disk was prepared, and this surface was finished with # 1200 water-resistant abrasive paper. Next, disodium calcium ethylenediaminetetraacetate (Ca-EDTA) at a concentration of 250 mM, potassium dihydrogen phosphate (KH 2 PO 4 ), and sodium hydroxide (NaOH) were mixed to prepare a mixed solution. Next, after the mixed solution was heated to 60 ° C., the polished disc was immersed for 1 hour, and the surface was coated with a calcium phosphate (Ca—P) film. Next, PEG600 was prepared and dissolved in ultrapure water by 5 wt% to prepare a polymer aqueous solution.
  • Ca-EDTA disodium calcium ethylenediaminetetraacetate
  • KH 2 PO 4 potassium dihydrogen phosphate
  • NaOH sodium hydroxide
  • PEG600 was prepared and dissolved in ultrapure water by 5 wt% to prepare a polymer aqueous solution.
  • the disk coated with Ca—P on the surface was dipped for 1 hour, and the polymer was dipped on the surface to obtain the disk of Example 3-1 (Ca—P ⁇ 5PEG600).
  • the edges of the disc were coated with epoxy resin or Teflon tape for corrosion testing.
  • Example 3-2 A disk (Ca-P ⁇ 10PEG600) of Example 3-2 was produced in the same manner as in Example 3-1, except that the polymer dissolution concentration was 10 wt%.
  • Example 3-3 A disk (Ca—P ⁇ 25PEG600) of Example 3-3 was produced in the same manner as in Example 3-1, except that the polymer concentration was 25 wt%.
  • Example 3-4 A disk (Ca—P ⁇ 50 PEG 600) of Example 3-4 was produced in the same manner as in Example 3-1, except that the polymer concentration was 50 wt%.
  • Example 3-5 A disk (Ca-P ⁇ 5PVA) of Example 3-5 was produced in the same manner as in Example 3-1, except that PVA was used. Table 3 summarizes the production conditions.
  • FIG. 26 is an optical microscopic image of the disk of Example 3-3 (Ca—P ⁇ 25 PEG600). There was no change in the appearance of the Ca—P coated surface by PEG coating, and the surface was uniform.
  • FIG. 27 is an SEM image of the disk of Example 3-3 (Ca-P ⁇ 25PEG600). There was no change in the surface morphology of the SEM image of the Ca—P coated surface by PEG coating, and the dome-shaped crystals covered the surface densely.
  • FIG. 28 shows the FT-IR spectrum of each disk.
  • a PO 4 peak derived from HAp and / or OCP was observed in any FT-IR spectrum.
  • the shoulder peak near 1050 cm ⁇ 1 which was hardly seen in the disc of Comparative Example 2, was more clearly seen in the discs of Examples 3-1 to 3-3, so that it became a PO 4 peak around 1050 cm ⁇ 1. It can be seen that the peaks derived from PEG overlapped.
  • FIG. 29 is a graph showing Mg ion elution amounts on the 7th and 10th days of immersion of the disks of Examples 3-1 to 3-3 and the disk of Comparative Example 2 in physiological saline. In the graph of each disk, the left side is the 7th day of immersion, and the right side is the 10th day.
  • FIG. 30 shows the immersion of the discs of Examples 2-1, 2-6, 3-1 and 3-5 and the discs of Comparative Examples 1 and 2 with indentations in physiological saline on the 7th and 10th days. It is a graph which shows Mg ion elution amount. In the graph of each disk, the left side is the 7th day of immersion, and the right side is the 10th day.
  • FIG. 31 (a) is a stereomicroscopic image of the indented surface after the disk of Example 3-1 (Ca—P ⁇ 5PEG600) was immersed in physiological saline for 10 days, and FIG. It is an enlarged image of the indentation part in 31 (a).
  • FIG. 32 is a stereomicroscopic image of the surface without indentation after the disk of Example 3-1 (Ca—P ⁇ 5PEG600) was immersed in physiological saline for 10 days.
  • Example 3-1 (Ca-P ⁇ 5 PEG 600) is more than the disc of Comparative Example 1 (as-polished) and Comparative Example 2 (as-polished ⁇ Ca-P) on both the 7th and 10th days of immersion. A small Mg ion elution amount was shown. On the other hand, in the disks of Examples C-1, C-3, and C-4, the amount of Mg ions eluted on the 7th day of immersion was the disks of Comparative Example 1 (as polished) and Comparative Example 2 (polished ⁇ Ca-P).
  • the Mg ion elution amount was smaller than that of the disks of Comparative Example 1 (as polished) and Comparative Example 2 (polished ⁇ Ca—P). Further, as shown in FIGS. 31 to 32, the corrosion from the indented portion did not proceed, and the corrosion that occurred from the portion other than the indented portion was observed. It has been clarified that a film in which Ca—P and a polymer such as PEG or PVA are combined does not necessarily cause corrosion even if there is a defect due to deformation. For this reason, it was clarified that the corrosion resistance of the Mg alloy can be improved by combining Ca—P and PEG even when deformation is applied.
  • Example 4-1 to Example 4-9 First, a PEG having a molecular weight of 600, a PEG having a molecular weight of 400 having a methyl group (CH 3 group) at one end, and a PEG having a molecular weight of 400 are dissolved in ultrapure water at 5 wt%, 50 wt%, or 75 wt%, respectively. Was prepared. Next, after heating the aqueous polymer solution to 40 ° C., an AZ31 disk whose surface was finished with # 1200 water-resistant abrasive paper was immersed for 1 hour to dip-apply the polymer on the surface. Examples 4-1 to 4- 9 disks were produced. The edges of the disk were then covered with Teflon tape for corrosion testing. Table 4 summarizes the production conditions. The disks of Example 4-1 and Example 4-4 have the same configuration as that of Example 1-1 and Example 1-6, respectively.
  • Example 4 was observed with an optical microscope.
  • the polymer dip coated surface maintained a metallic luster.
  • the disks of Examples 4-2 to 4-9 had the same appearance. That is, a surface having a metallic luster was obtained regardless of the type, molecular weight and concentration of the polymer.
  • FIG. 33 is a graph showing Mg ion elution amounts on the first and fourth days of immersion in the cell culture medium of the disks of Examples 4-1 to 4-9 and the disk of Comparative Example 1. In the graph of each disk, the left side is the first day of immersion, and the right side is the fourth day. Originally, the cell culture solution contains 3 mg / 150 mL of Mg ions.
  • Examples 5-1 to 5-9 First, a PEG having a molecular weight of 600, a CPEG having a molecular weight of 400 having a methyl group (CH 3 group) at one end, and a PEG having a molecular weight of 400 are dissolved in ultrapure water at 5 wt%, 50 wt%, or 75 wt%, respectively. Was prepared. Next, the aqueous polymer solution was heated to 40 ° C., and then the AZ31 disk whose surface was finished with # 1200 water-resistant abrasive paper was immersed for 1 hour, and the polymer was immersed on the surface. Examples 5-1 to 5- 9 disks were produced. Next, for the corrosion test, the edge of the disk was covered with Teflon (registered trademark) tape, and one side was scratched with a cutter knife.
  • Teflon registered trademark
  • Example 3 For comparison, the edge of the disc of Comparative Example 1 with AZ31 disc polished with # 1200 water-resistant abrasive paper was covered with Teflon (registered trademark) tape, and one side of the disc was marked with an X mark with a cutter knife. The disk of Example 3 was produced. Table 5 summarizes the production conditions.
  • the disks of Examples 5-1 to 5-9 have the same configuration as that of Examples 4-1 to 4-9, respectively, except that there are scratches marked with a cross on one side.
  • FIG. 34 is a graph showing the amount of Mg ions eluted on the fourth day of immersion in the cell culture medium of the disks of Examples 5-1 to 5-9 and the disk of Comparative Example 3.
  • the cell culture solution contains 3 mg / 150 mL of Mg ions.
  • FIG. 34 for comparison based on the presence or absence of scratches on the disk surface, the cell culture shown in FIG. The elution amount of Mg ions on the fourth day of immersion in the liquid was shown.
  • Comparative Example 1 (as-polished) and Comparative Example 3 disc (polished_X)
  • Comparative Example 3 with scratches had a larger amount of elution of Mg ions and corrosion from the scratches occurred.
  • Examples 5-1 to 5-9 (each PEG-coat_X) and Examples 4-1 to 4-9 (each PEG-coat)
  • the Mg ion elution amount was the same regardless of the presence or absence.
  • the tendency for the Mg ion elution amount to be smaller was observed when there was a scratch. From this, it was found that the surface to which PEG600, CPEG400 and PEG400 were applied exhibited self-healing ability against the scratches on the film.
  • Example 6-1 an aqueous polymer solution is prepared by dissolving 10 wt% of tetrapolyethylene glycol (hereinafter abbreviated as PTE200) represented by the following structural formula and having a terminal modified with an amino group in ultrapure water. did.
  • PTE200 tetrapolyethylene glycol
  • Example 6-1 (10PTE200-coat) was then applied. Produced. The edges of the disk were then covered with Teflon tape for corrosion testing.
  • Example 6-2 The disk of Example 6-2, which has the same configuration as that of Example 6-1 except that the edge and the back surface of the disk were coated with Teflon (registered trademark) tape and then the surface was scratched with a cutter knife. (10PTE200-coat_X) was produced. Table 6 summarizes the production conditions.
  • Example 6-1 (10 PTE200-coat), Comparative Example 1 (as-polished), Example 6-2 (10PTE200-coat_X), and Comparative Example 3 (with the edges and back surface covered with Teflon (registered trademark) tape and Comparative Example 3 ( Polishing_X) discs were each immersed in 75 mL of Hanks solution, and the Mg ion elution amount on the first day of immersion was measured.
  • FIG. 35 (a) is a graph showing the amount of Mg ions eluted into the Hanks solution of the disks of Example 6-1 and Comparative Example 1.
  • FIG. Hanks solution 75 mL originally contains 1.5 mg of Mg ions.
  • FIG. 35B is a graph showing the amount of Mg ions eluted into the Hanks solution of the disks of Examples 6-1 and 6-2 and Comparative Example 3.
  • the amount of Mg ions eluted from the disk of Example 6-2 was smaller than that of the disk of Example 6-1 and smaller than that of the disk of Comparative Example 3. From this, since the PTE200 coating film exhibits a self-repairing ability with respect to the scratch on the coating film, it is considered that the amount of elution of Mg ions is smaller than that in the case where there is no scratch.
  • Example 6-1 (10 PTE200-coat), Comparative Example 1 (as-polished), Example 6-2 (10PTE200-coat_X), and Comparative Example 3 (with the edges and back surface covered with Teflon (registered trademark) tape and Comparative Example 3 ( Polishing_X) discs were each immersed in 75 mL of cell culture solution, and the amount of Mg ions eluted on the fourth day of immersion was measured.
  • FIG. 36 (a) is a graph showing the amount of Mg ions eluted into the cell culture medium of the disks of Example 6-1 and Comparative Example 1.
  • FIG. The cell culture solution 75 mL originally contains 1.5 mg of Mg ions.
  • FIG. 36 (b) is a graph showing the amount of Mg ions eluted into the cell culture medium of the disks of Examples 6-1 and 6-2 and Comparative Example 3.
  • the amount of Mg ions eluted from the disk of Example 6-2 was the same as that of the disk of Example 6-1. From this, it is considered that the PTE200 coating exhibited a self-healing ability with respect to the wound of the coating even in the cell culture solution, and therefore showed an elution amount equivalent to that without the scratch.
  • Example 7-1 First, an AZ31 disk was prepared, and this surface was finished with # 1200 water-resistant abrasive paper. Next, disodium calcium ethylenediaminetetraacetate (Ca-EDTA) at a concentration of 250 mM, potassium dihydrogen phosphate (KH 2 PO 4 ), and sodium hydroxide (NaOH) were mixed to prepare a mixed solution. Next, after the mixed solution was heated to 60 ° C., the polished disk was immersed for 1 hour, and the surface was coated with a calcium phosphate (Ca—P) film. Next, sodium polyacrylate (hereinafter abbreviated as SAP) was prepared, and a 15% SAP-phosphate buffer solution (polymer aqueous solution) was prepared.
  • SAP sodium polyacrylate
  • Example 7-1 (Ca-P ⁇ 15SAP) was made.
  • Example 7-2 sodium polyacrylate (SAP) was prepared, and a 15% SAP-phosphate buffer solution (polymer aqueous solution) was prepared. Next, an AZ31 disk whose surface was finished with # 1200 water-resistant abrasive paper at room temperature was immersed in an aqueous polymer solution for 10 seconds or more, then air-dried, and SAP was applied to form the disk (15SAP-coat) of Example 7-2. Produced.
  • SAP sodium polyacrylate
  • SAP-phosphate buffer solution polymer aqueous solution
  • Example 7-3 The disk of Example 7-3 (Ca-P ⁇ 15 PDDA) was prepared in the same manner as Example 7-1 except that poly diallyldimethylammonium chloride (hereinafter abbreviated as PDDA) was used instead of SAP. ) was produced.
  • PDDA poly diallyldimethylammonium chloride
  • Example 7-4 A disk (15PDDA-coat) of Example 7-4 was produced in the same manner as in Example 7-2 except that polydiallyldimethylammonium chloride (PDDA) was used instead of SAP.
  • PDDA polydiallyldimethylammonium chloride
  • Example 7-5 A disk (Ca-P ⁇ 10SAP) of Example 7-5 was produced in the same manner as Example 7-1 except that the concentration of the SAP-phosphate buffer solution (polymer aqueous solution) was 10%.
  • Example 7-6 A disk (10SAP-coat) of Example 7-6 was produced in the same manner as in Example 7-2 except that the concentration of the SAP-phosphate buffer (aqueous polymer solution) was 10%. Table 7 summarizes each production condition.
  • the Mg ion concentration on the third day of immersion was hardly changed from the Mg ion concentration (2.0 mg / dL) originally contained in the Hanks solution. From this, it became clear that a stimulus-responsive polymer such as SAP and PDDA that greatly changes the microstructure with respect to the pH and cation concentration of the solution can be used for the corrosion resistant coating of the Mg alloy.
  • a stimulus-responsive polymer such as SAP and PDDA that greatly changes the microstructure with respect to the pH and cation concentration of the solution can be used for the corrosion resistant coating of the Mg alloy.
  • FIG. 37 is an SEM image of scratches on the surface 3 days after immersion of the disks of Examples 7-5 and 7-6 and the disk of Comparative Example 2 in Hanks solution.
  • the precipitates inside the scratches on the surfaces of the disks of Examples 7-5 and 7-6 were mainly composed of carbon, oxygen, calcium and phosphorus. From this, it was found that the precipitate was a composite of calcium phosphate precipitated from the SAP and Hanks solutions.
  • the SAP coating has been found to exhibit a self-healing function that creates a precipitate in the scratched area and physically isolates the solution from the metal surface exposed inside the wound.
  • Example 8-1 sodium polyacrylate (SAP) was prepared and 10 wt% was dissolved in ultrapure water to prepare a polymer aqueous solution. Next, 100 ⁇ L of an aqueous polymer solution was dropped onto the surface of an AZ31 disk whose surface was finished with # 1200 water-resistant abrasive paper, and the polymer was applied by allowing to stand for 1 hour, and the disk of Example 8-1 (10 SAP-coat) was applied. Produced. Next, the edges and back of the disk were coated with Teflon tape for corrosion testing.
  • SAP sodium polyacrylate
  • Example 8-2 The disc of Example 8-2 (10 PSS) was used in the same manner as Example 8-1, except that poly sodium 4-styrenesulfonate (hereinafter abbreviated as PSS) was used instead of SAP. -Coat).
  • PSS poly sodium 4-styrenesulfonate
  • Example 8-3 The disk of Example 8-3 (5PVS) was used in the same manner as Example 8-1 except that potassium polyvinyl sulfate (hereinafter abbreviated as PVS) was used instead of SAP and the concentration was 5 wt%. -Coat).
  • PVS potassium polyvinyl sulfate
  • Example 8-4 A disk (10PDDA-coat) of Example 8-4 was produced in the same manner as in Example 8-1, except that polydiallyldimethylammonium chloride (PDDA) was used instead of SAP.
  • PDDA polydiallyldimethylammonium chloride
  • Example 8-5 Similar to Example 8-1, except that the edges and back of the disk were coated with Teflon (registered trademark) tape, and then the surface not coated with Teflon (registered trademark) tape was scratched with a cutter knife.
  • a disk (10SAP-coat_X) of Example 8-5 having the structure was manufactured.
  • Example 8-6 The same as in Example 8-2, except that the edges and back of the disk were covered with Teflon (registered trademark) tape, and then the surface not covered with Teflon (registered trademark) tape was scratched with a cutter knife.
  • a disk (10PSS-coat_X) of Example 8-6 having the structure was manufactured.
  • Example 8-7 The same as in Example 8-3, except that the edge and the back surface of the disk were coated with Teflon (registered trademark) tape, and then the surface not coated with Teflon (registered trademark) tape was scratched with a cutter knife.
  • a disk (5PVS-coat_X) of Example 8-7 having the structure was manufactured.
  • Example 8-8 The same as in Example 8-4, except that the edges and back of the disk were covered with Teflon (registered trademark) tape, and then the surface not covered with Teflon (registered trademark) tape was scratched with a cutter knife.
  • a disk (10PDDA-coat_X) of Example 8-8 having the structure was manufactured.
  • Table 9 is a table summarizing each production condition.
  • FIG. 39 is a graph showing the amount of Mg ions eluted into the Hanks solution of the disks of Examples 8-1 to 8-4 and Comparative Example 1.
  • Hanks solution 75 mL originally contains 1.5 mg of Mg ions.
  • the amount of Mg ions eluted from the disks of Examples 8-1 to 8-4 was equal to or less than that of the disk of Comparative Example 1. This suggested that the anionic and cationic polymer coatings exhibit corrosion resistance.
  • FIG. 40 is a graph showing the amount of Mg ions eluted into the Hanks solution of the disks of Examples 8-1 to 8-8 and Comparative Example 3.
  • Examples 8-1 to 8-4 have no flaws on the left side and Examples 8-5 to 8-8 have flaws on the right side.
  • the surface of the disks of Examples 8-5 to 8-8 having scratches showed the same or lower Mg ion elution amount as the surface of the disks of Examples 8-1 to 8-4 without scratches. From this, it is considered that the surface to which the anionic and cationic polymers were applied exhibited a self-healing ability with respect to the scratches on the film, and thus the Mg ion elution amount was equal to or less than that without the scratches.
  • each of the disks of Examples 8-1 to 8-4 (anionic / cationic polymer-coat) and Comparative Example 1 (as-polished) coated with Teflon (registered trademark) tape on the edges and the back surface was 75 mL.
  • the sample was immersed in the cell culture medium, and the elution amount of Mg ions on the fourth day of immersion was measured.
  • FIG. 41 is a graph showing the amount of Mg ions eluted into the cell culture fluid of the disks of Examples 8-1 to 8-4 and Comparative Example 1.
  • the cell culture solution 75 mL originally contains 1.5 mg of Mg ions.
  • the amount of Mg ions eluted from the disks of Examples 8-1 to 8-4 was equal to or less than that of the disk of Comparative Example 1. This suggests that the anionic and cationic polymer coatings show corrosion resistance even in the cell culture medium.
  • the medical bioabsorbable member and the method for producing the same according to the present invention relate to a medical bioabsorbable member in which elution of metal ions from a substrate is suppressed even when the film thickness is thin, and a method for producing the same.
  • the objective of corrosion rate control and biocompatibility improvement of biocompatible metals or alloys can be achieved, corrosion resistance can be demonstrated not only in biomaterials but also in places where stress is applied in corrosive environments, and in vivo devices and
  • the affinity with the surrounding tissue can be changed according to differences in a site where strong adhesion with the surrounding tissue is required or a site where adhesion of the surrounding tissue to the device surface is not required. Thereby, it may be used not only in the medical member manufacturing industry such as fracture fixing materials, stents and artificial bones but also in the industrial member manufacturing industry not limited to biomaterials.
  • SYMBOLS 11 Medical bioabsorbable member, 12 ... Metal or alloy base material, 13 ... Hydroxide and / or oxide layer, 14 ... Polymer layer, 19, 20 ... Base material for polymer layer formation, 21, 22 ... Ceramics Layer forming substrate, 31 ... medical bioabsorbable member, 32 ... ceramic layer, 41 ... medical bioabsorbable member.

Abstract

La présente invention résout le problème de fourniture de : un élément biorésorbable pour utilisation médicale, qui a une couche de surface ayant une sécurité biologique élevée et une biocompatibilité élevée, tout en présentant différentes résistances à la corrosion pour supprimer le taux de corrosion-dissolution d'une base à une valeur arbitraire en supprimant la corrosion et la dissolution de la base ; et un procédé de fabrication de cet élément biorésorbable pour utilisation médicale. Le problème mentionné ci-dessus peut être résolu par un élément biorésorbable pour utilisation médicale (11), qui comprend une base de métal ou d'alliage (12), une couche d'hydroxyde et/ou d'oxyde (13) et une couche de polymère (14).
PCT/JP2015/070888 2014-07-24 2015-07-22 Élément biorésorbable pour utilisation médicale et son procédé de fabrication WO2016013594A1 (fr)

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JP2018030278A (ja) * 2016-08-23 2018-03-01 キヤノン株式会社 三次元造形装置および三次元造形物の製造方法
CN112826981A (zh) * 2021-01-04 2021-05-25 西南交通大学 在可降解金属表面制备促骨修复和再生功能涂层的方法

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CN112826981A (zh) * 2021-01-04 2021-05-25 西南交通大学 在可降解金属表面制备促骨修复和再生功能涂层的方法

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