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WO2021243979A1 - Implant composite de polyéther-éther-cétone, méthode de préparation associée et application associée - Google Patents

Implant composite de polyéther-éther-cétone, méthode de préparation associée et application associée Download PDF

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Publication number
WO2021243979A1
WO2021243979A1 PCT/CN2020/131209 CN2020131209W WO2021243979A1 WO 2021243979 A1 WO2021243979 A1 WO 2021243979A1 CN 2020131209 W CN2020131209 W CN 2020131209W WO 2021243979 A1 WO2021243979 A1 WO 2021243979A1
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regulating
function
substance
polymer coating
degradable polymer
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Chinese (zh)
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王怀雨
谢灵霞
童丽萍
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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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
    • A61L27/14—Macromolecular materials
    • A61L27/18—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222—Steroids, e.g. corticosteroids
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention belongs to the technical field of biomedical polymer materials, and relates to a polyetheretherketone composite implant with bone immune regulation function, and a preparation method and application thereof.
  • Bone defect is a common clinical disease, and implantation of filler materials is a common method for treating bone defects.
  • the performance requirements for traditional bone implant materials include: excellent physical and chemical properties, such as good corrosion resistance, non-wearing surfaces, and non-toxic effects of wear debris on the body; mechanical properties matching the bone tissue, and good biological properties Such as histocompatibility.
  • Poly-ether-ether-ketone is a semi-crystalline, thermoplastic linear aromatic polymer with light weight, good biological stability and non-toxicity, and its mechanical properties are close to that of human bones. FDA approved and used for clinical use. Compared with traditional metal materials, PEEK has a lower modulus of elasticity, which is close to that of human cortical bone. This similarity can reduce the stress shielding effect caused by elastic mismatch and avoid possible bone damage. In addition, PEEK has natural radiolucency, excellent mechanical properties and chemical resistance. However, the PEEK material itself is biologically inert, lacks immunological activity and osteogenic activity, and its osseointegration properties limit its clinical application.
  • PEEK Because of its unusually stable chemical inertness, the ability of chemical methods to modify its surface is very limited. It is often modified through physical methods such as blending, physical coating of functional coatings on the surface, and physical-mediated grafting.
  • Common modification methods of PEEK include blending with active material (hydroxyapatite) or constructing a hydroxyapatite coating on its surface [2] ; after sulfonating the surface of PEEK, plasma implantation of zinc ions [3] ; By wet chemical grafting, PEEK surface is coated with BMP-2 to improve the osteogenic performance [4] ; plasma immersion ion implantation is used to build a titanium dioxide or diamond-like coating on the surface of PEEK to increase the surface roughness, chemical modification, and other combinations.
  • Biologically active particles [5,6] . Modified by blending with active substances, its mechanical properties will often lead to mismatch with adjacent bone tissues, which affects the osteogenic effect; the PEEK surface is constructed with calcium phosphate or hydroxyapatite coating, which can improve its surface Biologically active, but the bonding strength between the prepared coating and the PEEK surface is limited, peeling may occur, the hydroxyapatite layer on the substrate is easily broken, and particle wear debris may be generated, which can change the immune response , Secrete inflammatory factors and cause pathological bone resorption.
  • Plasma immersion ion implantation builds titanium dioxide or diamond-like coating on the surface of PEEK, which can increase the surface roughness, chemical modification and combination with other biologically active particles; after sulfonating the PEEK surface, plasma implants zinc ions to increase the surface roughness
  • the performance of the above-mentioned coating or the factors attached to the surface is single, and the influence of inflammation on osteogenesis after implantation of the material is not considered, which may lead to inconsistent results in vivo and in vitro, and implant failure.
  • the invention of a PEEK composite implant with bone immunomodulatory function on the existing basis has important application value.
  • the purpose of the present invention is to provide a polyetheretherketone composite implant and its preparation method and application.
  • the polyetheretherketone composite implant of the present invention not only maintains the excellent mechanical properties of PEEK, but also increases the osteogenic activity on the surface, and can actively regulate bone immunity in the early stage of implantation to achieve better bone regeneration, and the preparation method is simple to operate convenient.
  • the present invention provides a polyether ether ketone composite implant, comprising: a polyether ether ketone substrate, wrapped on the polyether ether ketone substrate Functional substances supported and/or grafted on the surface of the degradable polymer coating and the degradable polymer coating;
  • the functional substance includes a substance that has a function of regulating immunity, and/or a substance that has a function of regulating osteogenesis; preferably, the functional substance includes a substance that has a function of regulating immunity and a substance that has a function of regulating osteogenesis;
  • the substance with regulating immune function includes a biological molecule with regulating immune function, and/or a drug with regulating immune function; said substance with regulating osteogenic function includes a biological molecule with regulating osteogenic function, and/or , A drug that regulates osteogenic function.
  • a polyether ether ketone substrate includes: a polyether ether ketone substrate, a degradable polymer coating wrapped on the surface of the polyether ether ketone substrate, and a functional substance supported and grafted on the degradable polymer coating;
  • the functional substance grafted by the degradable polymer coating includes a substance having a function of regulating immunity, and the substance having a function of regulating immunity includes a biological molecule with a function of regulating immunity, and/or, having a function of regulating immunity.
  • Functional medicine; the functional substance carried by the degradable polymer coating includes a substance with a function of regulating bone formation, and the substance with a function of regulating bone formation includes a biomolecule with a function of regulating bone formation, and/or, It is a medicine that regulates the function of bone formation.
  • the biomolecules with regulating immune function include one or a combination of at least two of the biomolecules with regulating inflammation function.
  • the biomolecules with regulating immune function include IL-4, IL- 6.
  • IL-10 a precursor of NO, one or a combination of at least two of IL-12 and TGF; more preferably, the biomolecule with immune function is the cytokine IL-10;
  • the drug with regulating immune function includes one or a combination of at least two immunosuppressive agents capable of inhibiting inflammatory response, inhibiting inflammatory cell proliferation and activating autophagy response.
  • the drug with regulating immune function includes One or a combination of at least two of glucocorticoids, tacrolimus, rapamycin, thalidomide, triptolide, infliximab, adalimumab, and mycophenolate mofetil.
  • the medicine with the function of regulating osteogenesis includes one or a combination of at least two medicines with anti-inflammatory, osteogenesis-promoting effect or osteoclast inhibitory effect.
  • the medicine with regulating osteogenesis includes One or a combination of at least two of dexamethasone, alendronate, fluoride, statins, teriparatide, and teronidine; more preferably, the osteogenesis-regulating drug is ground Semisone (DEX);
  • the biomolecules with the function of regulating bone formation include one or a combination of at least two of the biomolecules capable of promoting angiogenesis, or promoting the differentiation of stem cells into osteoblasts, or having the function of promoting the proliferation of osteoblasts.
  • the biomolecules capable of regulating osteogenesis include one or a combination of at least two of BMP-2, VEGF, OPG, PDGF, TGF, and insulin-like growth factor-1.
  • the degradable polymer coating includes one or a combination of at least two of the following polymers wrapped on the surface of a polyetheretherketone substrate, and the polymer includes polytrimethylene carbonate (PTMC), polylactic acid (PLA), polycaprolactone (PCL), polylactic acid and polyglycolic acid (PLGA), aliphatic polyester polymer, aromatic-aliphatic copolyester;
  • PTMC polytrimethylene carbonate
  • PLA polylactic acid
  • PCL polycaprolactone
  • PLGA polylactic acid and polyglycolic acid
  • aliphatic polyester polymer aromatic-aliphatic copolyester
  • the molecular weight of the polymer is 5,000 to 500,000 Daltons.
  • the present invention provides a method for preparing any one of the above-mentioned polyetheretherketone composite implants, including the following steps:
  • the functional substance includes a substance that has a function of regulating immunity, and/or a substance that has a function of regulating bone formation;
  • the substance with regulating immune function includes a biological molecule with regulating immune function, and/or a drug with regulating immune function; said substance with regulating osteogenic function includes a biological molecule with regulating osteogenic function, and/or , A drug that regulates osteogenic function.
  • the functional substance includes a substance that has a function of regulating immunity, and/or a substance that has a function of regulating bone formation;
  • the substance with regulating immune function includes a biological molecule with regulating immune function, and/or a drug with regulating immune function; said substance with regulating osteogenic function includes a biological molecule with regulating osteogenic function, and/or , A drug that regulates osteogenic function.
  • the functional substance includes a substance that has a function of regulating immunity, and/or a substance that has a function of regulating bone formation;
  • the substance with regulating immune function includes a biological molecule with regulating immune function, and/or a drug with regulating immune function; said substance with regulating osteogenic function includes a biological molecule with regulating osteogenic function, and/or , A drug that regulates osteogenic function.
  • the substance with regulating immune function includes a biological molecule with regulating immune function, and/or a drug with regulating immune function; said substance with regulating osteogenic function includes a biological molecule with regulating osteogenic function, and/or , A drug that regulates osteogenic function.
  • the method for constructing a degradable polymer coating loaded with a substance capable of regulating osteogenesis includes a solvent volatilization method, a pulling extraction method or an atomizing spraying method;
  • the mass ratio of the bone-regulating substance to the polymer in the degradable polymer coating constructed on the surface of the polyetheretherketone substrate and loaded with the substance that regulates bone formation is 1:1-30 .
  • the mass ratio of the bone-regulating substance to the polymer in the degradable polymer coating constructed on the surface of the polyetheretherketone substrate and loaded with the substance that regulates bone formation is 1:1-30 .
  • the method for introducing active groups on the surface of the biodegradable polymer coating loaded with substances capable of regulating osteogenesis is gas plasma immersion ion implantation;
  • the gas used for the gas plasma immersion ion implantation includes one or a combination of at least two of argon, nitrogen, ammonia, oxygen, hydrogen and other gases;
  • the background vacuum degree used for the gas plasma immersion ion implantation is 1 ⁇ 10 -3 to 9 ⁇ 10 -3 Pa;
  • the gas introduction flow rate used for the gas plasma immersion ion implantation is 20-100 SCCM;
  • the negative bias applied to the sample plate used for the gas plasma immersion ion implantation is 0-10kV;
  • the implantation pulse width used in the gas plasma immersion ion implantation is 20-200 microseconds;
  • the injection pulse frequency used for the gas plasma immersion ion implantation is 50 ⁇ 500 Hz;
  • the radio frequency power used for the gas plasma immersion ion implantation is 100 ⁇ 1000 W;
  • the implantation time used for the gas plasma immersion ion implantation is 10 to 120 minutes.
  • the method for grafting a substance with an immune function through an active group is to immerse the surface of a degradable polymer coating containing a substance with a function of regulating osteogenesis into a material containing a substance with a function of regulating immunity. Incubate in the solution for a certain period of time to covalently graft a substance that has an immune-regulating function.
  • the concentration of the solution containing the substance with the immune function is 10ng/mL-10 ⁇ g/mL;
  • the grafting time is 6 to 72 hours.
  • the present invention provides the application of any one of the above-mentioned polyetheretherketone composite implants in the preparation of implants for filling parts of bone defects.
  • the drug-loaded modified coating constructed on the PEEK surface of the present invention has the following advantages:
  • the drug-loaded modified coating constructed on the surface of PEEK has a time sequence for the controlled release of the drug, which simulates the self-repair process after a human fracture or bone defect occurs. It first regulates inflammation and then regulates osteogenesis, and regulates inflammation and regulation of formation. The double-layer effect of bone is superimposed to improve the immune activity and osteogenic activity of PEEK materials;
  • PEEK composite implants implanted in the body present the characteristics of sequential release of regulatory factors, that is, in the early inflammatory reaction stage, as the coating degrades, the most surface grafted immunomodulatory molecules are preferentially released in the bone immune environment for regulation Immune response, as the biodegradable polymer coating gradually degrades in the middle and late stages of osteogenesis, the internally loaded osteogenic drugs, such as dexamethasone, are continuously released to regulate osteogenesis, making the material possess both immunological activity and osteogenic activity , So as to better apply in the clinic;
  • the drug-loaded coating constructed on the surface of PEEK can control the long-term stable release of the drug, without cytotoxicity caused by excessive local drug concentration, and the concentration of the released drug can be adjusted by controlling the ratio of the drug to the polymer, and
  • the degradation cycle of the coating can be controlled by adjusting the thickness of the coating and the molecular weight of the polymer (for example, the higher the molecular weight of polytrimethylene carbonate, the faster the degradation speed); the content of grafted biomolecules can be adjusted by adjusting the solution of grafted biomolecules To control the concentration;
  • the polymer used in the drug-carrying coating constructed on the surface of PEEK is biodegradable, can be hydrolyzed or enzymatically in the body, and the degradation products are neutral, have little harm, have no toxic side effects to the body, and will not cause the body
  • this application does not change the properties of the PEEK material itself, maintains the excellent mechanical properties of the substrate PEEK, and the surface coating is tightly combined with the substrate;
  • biomolecules can be directly grafted after the surface of the drug-carrying polymer is treated by plasma immersion ion implantation, without the use of chemical cross-linking agents, which is safe and convenient.
  • the drug-loaded coating constructed on the surface of PEEK can greatly improve the physical and chemical properties of the surface, such as hydrophilicity and hydrophobicity, surface energy, surface chemical composition, and increase the surface biological activity without affecting the performance of the PEEK material matrix.
  • Figure 1a is a scanning electron micrograph of unmodified polyetheretherketone (PEEK) in Example 1 of the present invention
  • Figure 1b is a 5% DEX coating prepared on the surface of polyetheretherketone by solution volatilization in Example 1 of the present invention Scanning electron micrograph of the surface of the layer;
  • Example 2 is a scanning electron micrograph of a 5% DEX surface treated by nitrogen plasma immersion ion implantation in Example 2 of the present invention
  • Embodiment 3 is a scanning electron micrograph of the surface of 2KV-IL-10 with a concentration of 40ng/ml IL-10 after being implanted by nitrogen plasma immersion ion in Embodiment 3 of the present invention;
  • Figure 4a is the result of the static water contact angle of the surface before and after modification of the PEEK material in Example 4 of the present invention
  • Figure 4b is the result of the water contact angle of the sample after the plasma surface treatment of Example 2 in Example 4 of the present invention after being placed for one month Test result diagram;
  • Fig. 5 is a full spectrum diagram of surface elements measured by an X-ray electron spectrometer after modification of the PEEK material in Example 5 of the present invention
  • Fig. 6a is a graph showing the results of the proliferation of macrophages RAW264.7 on the surface of each sample in Example 6 of the present invention
  • Fig. 6b is a result of the use of Mouse TGF-beta1 Valukine in Example 6 of the present invention ELISA kit (R&D system) and Mouse TNF-A Valukine ELISA kit (R&D) detect the expression results of inflammation-related factors TNF- ⁇ and TGF- ⁇ 1
  • Figure 6c is the detection of M1 by real-time fluorescent quantitative PCR in Example 6 of the present invention The results of expression of genes related to M2;
  • Figure 7 is the result of real-time fluorescent quantitative PCR detecting the expression of osteogenic-related genes in the conditioned medium in Example 7 of the present invention; wherein RAW264.7 (+) represents the conditioned medium, and RAW264.7 (-) represents the non-conditioned medium;
  • Fig. 8a is a result of the proliferation of MC3T3-E1 cells on the surface of each sample in Example 8 of the present invention
  • Fig. 8b is the detection of bone formation related to MC3T3-E1 cells on the surface of the sample by real-time fluorescent quantitative PCR in Example 8 of the present invention
  • Figure 9 is a graph showing the immunofluorescence results of the macrophage phenotype of each sample implanted subcutaneously in rats in Example 9 of the present invention.
  • Figure 10a is the 3D model and 2D image obtained by Micro-CT after each sample implanted in the rat femur in Example 10 of the present invention. The result of tissue staining with VG.
  • the polyether ether ketone discs with a diameter of 15 mm and a thickness of 1 mm were polished with sand with meshes of 600, 800, 1000, 1200, and 2000 in turn.
  • the polished polyether ether ketone was successively polished with acetone, alcohol, and deionized water. Ultrasonic clean.
  • the sample after this pretreatment is labeled PEEK.
  • a drug-carrying coating was constructed on the surface of PEEK by solvent evaporation.
  • the selected polymer coating is polytrimethylene carbonate (PTMC), the solvent is dichloromethane, the drug is dexamethasone, and the mass ratio of drug to polymer is 1:5.
  • the sample after this pretreatment is labeled 5% DEX.
  • the specific preparation method is as follows: first add PTMC and dexamethasone in a dichloromethane solution at a mass ratio of 5:1 to form a uniform solution, and then pour the homogeneous solution containing PTMC and dexamethasone on the surface of the PEEK sample.
  • the solvent methylene chloride evaporates cleanly, forming a uniform coating on the surface of PEEK.
  • FIG. 1 The surface of the polyether ether ketone before and after the treatment was observed by scanning electron microscope, and the surface micro morphology as shown in FIG. 1 was obtained. It can be seen from Figure 1a that the surface of PEEK without coating can be traced by sandpaper. Figure 1b shows that the entire surface is smooth and flat after the drug-loaded coating is constructed on the surface, and no drug is concentrated on the surface.
  • the gas plasma immersion ion implantation technology was used to process the 5% DEX in Example 1.
  • the specific treatment process is as follows: background vacuum degree is 2 ⁇ 10 -3 Pa, gas introduction flow rate is 60 SCCM, negative bias voltage applied to the sample plate is 2 kV, injection pulse width is 50 microseconds, and injection pulse frequency is 50 Hz , The RF power is 1000 W. Among them, the injection time of nitrogen is 60 minutes, and the processed sample is called 2KV.
  • the 5% DEX surface after the nitrogen plasma immersion ion implantation treatment was observed by a scanning electron microscope, and the surface micro-topography picture shown in Fig. 2 was obtained. It can be seen from Fig. 2 that there is no obvious difference between the surface of 5% DEX and 2KV samples, indicating that the nitrogen plasma immersion ion implantation treatment does not significantly change the surface morphology of 5% DEX.
  • the modified 2KV sample in Example 2 was immersed in a phosphate buffer solution (PBS) containing IL-10, where the concentration of IL-10 was 40 ng/ml, and stored at 4 °C for 24 Hour. Then the sample was taken out of the IL-10 solution, and the sample was rinsed with PBS without IL-10 to remove the ungrafted IL-10, and the sample was labeled 2KV-IL-10.
  • PBS phosphate buffer solution
  • the microscopic morphology of the sample grafted with IL-10 was observed through a scanning electron microscope, and the result is shown in Figure 3. It can be seen from Figure 3 that there is no obvious change in the surface of the coating after grafting IL-10.
  • Example 4 Test of Hydrophilicity and Hydrophobicity of the Samples Obtained in Example 1, Example 2, and Example 3
  • Example 1 The samples obtained in Example 1, Example 2, and Example 3 were dried in a vacuum drying oven for 24 hours and then measured with a water contact angle meter to measure their surface hydrophilicity and hydrophobicity.
  • the results are shown in Figure 4a. It can be seen from Figure 4a that the water contact angle of PEEK is 95 degrees, which is a hydrophobic surface. After constructing 5% dexamethasone on its surface, the contact angle of 5% DEX surface is 85 degrees, which is hydrophilic.
  • Example 5 X-ray photoelectron spectroscopy test of the samples obtained in Example 1, Example 2, and Example 3
  • Example 1 The samples obtained in Example 1, Example 2, and Example 3 were analyzed by X-ray photoelectron spectroscopy (XPS) to analyze the changes of surface elements, and the full spectrum is shown in FIG. 5. It can be seen from Figure 5 that only the characteristic peaks of C1s (285.14 eV) and O1s (532.03 eV) appear in the polytrimethylene carbonate (PTMC) and 5% DEX spectra. After nitrogen plasma treatment, the 2KV sample newly appeared The characteristic peak of N1s (400.00 eV), after grafting IL-10, a new characteristic peak of Sp2 (164.02 eV) appeared, and the N signal in this sample was significantly enhanced. This is due to the grafting of IL-10 protein, IL-10 protein Contains a lot of N elements.
  • XPS X-ray photoelectron spectroscopy
  • Example 6 The samples obtained in Example 1, Example 2, and Example 3 were tested in vitro to regulate inflammatory response
  • Example 1 Culture the macrophages on the samples in Example 1, Example 2, and Example 3 for 1 to 3 days.
  • the culture medium was collected every day to obtain the culture supernatant, and the macrophage culture supernatant and DMEM high glucose were cultured.
  • Example 8 The samples obtained in Example 1, Example 2, and Example 3 were tested in vitro to regulate and control osteogenesis
  • Example 1 The samples in Example 1, Example 2, and Example 3 were subjected to the experiment of regulating osteogenesis in vitro.
  • MC3T3-E1 cells were inoculated on the surface of each sample. After 1, 3, and 7 days, the cells were detected on the surface by CCK-8 reagent. Proliferation effect; when the surface planted cells grow to 80%, replace the normal medium with osteoinductive liquid and re-culture for 7, 14, 21 days, and then use real-time fluorescence quantitative PCR to detect the expression of osteogenic related genes ALP, OCN, OPN, and pass Alizarin red staining detects the degree of cell mineralization on the sample surface, and the results are shown in Figure 8.
  • Figure 8a is a result of the proliferation of MC3T3-E1 cells on the surface of each sample;
  • Figure 8b is the detection of the expression of the osteogenic genes ALP, OCN, OPN of MC3T3-E1 cells on the surface of the sample and on the surface of the sample by real-time fluorescent quantitative PCR A result of mineralization. It can be seen from the proliferation results of MC3T3-E1 cells in Figure 8a that after 1 day, 3 days, and 7 days in culture, the cell proliferation of the 5% DEX group and the 2KV group was lower than that of PEEK due to the effect of the drug dexamethasone.
  • the 2KV-IL-10 group The proliferation of the cells was higher than that of the PEEK group, indicating that the modified coating 2KV-IL-10 on the surface of PEEK can promote the proliferation of MC3T3-E1 cells in vitro. From Figure 8b, the relative expression of the osteogenic genes ALP, OCN, and OPN can be It can be seen that the expression of 5% DEX, 2KV and 2KV-IL-10 is higher than that of PEEK group. Among them, the expression of 2KV-IL-10 group is the highest.
  • Example 9 explores whether the sample PEEK, 5% DEX, and 2KV-IL-10 in Example 1 and Example 3 can regulate inflammation in vivo
  • Example 1 The samples obtained in Example 1, Example 3, PEEK, 5% DEX, and 2KV-IL-10 were implanted into the subcutaneously of SD rats.
  • the specific process was as follows: 9 SD female rats about 12 weeks old were randomly divided For the three groups, 2% sodium pentobarbital (2.3ml/kg) was injected anesthetized before the operation. After the anesthesia was properly anesthetized, the rats were fixed on the operating table on their stomachs. Skin preparation, conventional iodophor, and ethanol disinfection, cut at symmetrical positions on both sides of the rat's back, implant each group of samples under the skin and suture, and iodophor disinfection. Rats were sacrificed 3 days after material implantation.
  • Example 10 explores the osteogenesis effect of the sample PEEK, 5% DEX, 2KV-IL-10 in Example 1 and Example 3 in vivo
  • Example 1 The samples in Example 1, Example 3, PEEK, 5% DEX, and 2KV-IL-10 were implanted into the femur of SD rats.
  • the specific operation is as follows: 9 SD female rats about 12 weeks old were randomly divided into three In the group, 2% sodium pentobarbital (2.3ml/kg) was injected anesthetized before the operation. After the anesthesia was proper, the rats were fixed in the supine position on the operating table. Skin preparation, conventional iodophor, and ethanol disinfection.
  • each rat had bilateral distal femoral defects. Suture the wound carefully. Postoperative iodophor disinfects the wound.
  • Figure 10a is the 3D model and 2D image obtained by Micro-CT.
  • the PEEK composite implant of the present application can simulate the human bone regeneration process, and promote the rapid regeneration of bone at the bone defect site by adjusting the bone immune system and bone healing growth factors.
  • cytokines can be used to regulate the phenotype of macrophages, making them polarized from the pro-inflammatory phenotype M1 to the anti-inflammatory M2, that is, regulating the immune system from inflammatory response to promoting Bone repair; and further promote osteogenic differentiation through subsequent drug release, thereby endowing the prepared PEEK composite implant with active bone immune regulation and achieving better bone regeneration.
  • the preparation method of the composite implant is simple to operate, safe and harmless.

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Abstract

La présente invention concerne un implant composite de polyéther-éther-cétone, sa méthode de préparation et son application. L'implant composite comprend : un substrat de polyéther-éther-cétone, un revêtement polymère dégradable enveloppé sur la surface du substrat de polyéther-éther-cétone, une substance fonctionnelle chargée et/ou greffée sur le revêtement polymère dégradable. La substance fonctionnelle comprend une substance ayant une fonction de régulation immunitaire, et/ou une substance ayant une fonction de régulation de l'ostéogenèse. La méthode de préparation comprend : la construction d'un revêtement polymère dégradable chargé d'une substance fonctionnelle sur la surface d'un substrat de polyéther-éther-cétone; la modification et l'activation de la surface du revêtement polymère dégradable chargé de la substance fonctionnelle, et l'introduction d'un groupe actif sur la surface du revêtement polymère dégradable chargé de la substance fonctionnelle; et le greffage de la substance fonctionnelle au moyen du groupe actif. L'invention concerne également une application de l'implant composite de polyéther-éther-cétone dans la préparation de médicaments pour le traitement de défauts osseux. L'implant composite de polyéther-éther-cétone préparé dans la présente invention non seulement maintient les excellentes propriétés mécaniques du substrat de polyéther-éther-cétone, mais ajoute également l'activité immunitaire et l'activité ostéogénique sur la surface.
PCT/CN2020/131209 2020-06-03 2020-11-24 Implant composite de polyéther-éther-cétone, méthode de préparation associée et application associée Ceased WO2021243979A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114668894A (zh) * 2022-04-07 2022-06-28 吉林大学 一种mof涂层修饰的聚醚醚酮基材植入材料的制备方法
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103865084A (zh) * 2014-04-09 2014-06-18 中国科学院上海硅酸盐研究所 一种聚醚醚酮材料及其表面改性的方法
CN106178104A (zh) * 2016-08-29 2016-12-07 上海交通大学 一种医用可载药多孔聚醚醚酮及其制造方法和应用
CN107189096A (zh) * 2017-04-28 2017-09-22 深圳先进技术研究院 一种高分子材料表面改性方法及其产品和用途
CN108310457A (zh) * 2018-03-15 2018-07-24 四川大学 聚醚醚酮骨缺损修复材料及制备方法
WO2019034207A2 (fr) * 2017-08-14 2019-02-21 Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) Procédé de réalisation d'une couche biocompatible sur une surface d'implant
CN109485896A (zh) * 2018-11-13 2019-03-19 山东凯旋美奥口腔门诊部有限公司 一种改性聚醚醚酮的制备方法和用途
CN110279890A (zh) * 2019-04-15 2019-09-27 首都医科大学附属北京世纪坛医院 基于脂质体的地塞米松/米诺环素在peek表面的修饰方法及应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1216984C (zh) * 2003-05-19 2005-08-31 浙江大学 在聚合物生物材料表面引入细胞生长因子的方法
US7875293B2 (en) * 2003-05-21 2011-01-25 Dexcom, Inc. Biointerface membranes incorporating bioactive agents
US9005648B2 (en) * 2010-07-06 2015-04-14 The Regents Of The University Of California Inorganically surface-modified polymers and methods for making and using them
CN102018996B (zh) * 2010-12-14 2013-03-06 中国医学科学院生物医学工程研究所 一种表面固定有抗体的药物血管支架的制备方法
CN104107459A (zh) * 2014-04-22 2014-10-22 吉林大学 具有时序响应功能的可降解高分子涂层支架及制造方法
CN106702341B (zh) * 2016-11-24 2019-10-29 深圳市中科摩方科技有限公司 聚醚醚酮材料及基于等离子体浸没注入的改性方法与应用
WO2020018947A1 (fr) * 2018-07-19 2020-01-23 CryoHeart Laboratories, Inc. Système et procédé pour fusionner des os

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103865084A (zh) * 2014-04-09 2014-06-18 中国科学院上海硅酸盐研究所 一种聚醚醚酮材料及其表面改性的方法
CN106178104A (zh) * 2016-08-29 2016-12-07 上海交通大学 一种医用可载药多孔聚醚醚酮及其制造方法和应用
CN107189096A (zh) * 2017-04-28 2017-09-22 深圳先进技术研究院 一种高分子材料表面改性方法及其产品和用途
WO2019034207A2 (fr) * 2017-08-14 2019-02-21 Verein zur Förderung von Innovationen durch Forschung, Entwicklung und Technologietransfer e.V. (Verein INNOVENT e.V.) Procédé de réalisation d'une couche biocompatible sur une surface d'implant
CN108310457A (zh) * 2018-03-15 2018-07-24 四川大学 聚醚醚酮骨缺损修复材料及制备方法
CN109485896A (zh) * 2018-11-13 2019-03-19 山东凯旋美奥口腔门诊部有限公司 一种改性聚醚醚酮的制备方法和用途
CN110279890A (zh) * 2019-04-15 2019-09-27 首都医科大学附属北京世纪坛医院 基于脂质体的地塞米松/米诺环素在peek表面的修饰方法及应用

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN114668894B (zh) * 2022-04-07 2022-10-14 吉林大学 一种mof涂层修饰的聚醚醚酮基材植入材料的制备方法
CN115382017A (zh) * 2022-08-16 2022-11-25 兰州大学 一种可载药的新型3d打印聚醚醚酮种植体及其制备方法
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CN118718099A (zh) * 2024-06-04 2024-10-01 大连理工大学 一种金属酚醛明胶涂层改性的聚芳醚骨植材在氧化应激下的骨修复应用
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