WO2019192116A1 - 具有细胞外基质电学拓扑特征的带电复合膜及其制备方法 - Google Patents

具有细胞外基质电学拓扑特征的带电复合膜及其制备方法 Download PDF

Info

Publication number
WO2019192116A1
WO2019192116A1 PCT/CN2018/099828 CN2018099828W WO2019192116A1 WO 2019192116 A1 WO2019192116 A1 WO 2019192116A1 CN 2018099828 W CN2018099828 W CN 2018099828W WO 2019192116 A1 WO2019192116 A1 WO 2019192116A1
Authority
WO
WIPO (PCT)
Prior art keywords
extracellular matrix
charged composite
polymer
composite membrane
barium titanate
Prior art date
Application number
PCT/CN2018/099828
Other languages
English (en)
French (fr)
Inventor
邓旭亮
白云洋
张学慧
Original Assignee
北京大学口腔医学院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京大学口腔医学院 filed Critical 北京大学口腔医学院
Priority to US16/348,099 priority Critical patent/US11141506B2/en
Publication of WO2019192116A1 publication Critical patent/WO2019192116A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L31/125—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L31/128—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix containing other specific inorganic fillers not covered by A61L31/126 or A61L31/127
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2/2875—Skull or cranium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • 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
    • A61L27/16—Macromolecular materials obtained 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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/28—Bones
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • 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 relates to the technical field of orthopedic and oral surgical repair materials, in particular to a charged composite membrane having electrical topological characteristics of an extracellular matrix and a preparation method thereof.
  • Implantation repair is currently the primary means of treating large-scale tissue defects. Artificial repair materials have received extensive attention in tissue repair materials due to their wide range of sources, controllable performance and low cost. According to the principle of bionics, there are damage potentials in skin wound healing, nerve repair, and bone defect repair. A large number of studies have confirmed that the damage potential plays an important role in tissue repair. Therefore, for tissue repair materials, charging the material will help promote tissue rapidity. healing and functional repair. In recent years, electroactive materials have become a research hotspot and trend, and also a new idea for the design of tissue repair materials.
  • the electroactive materials currently used do not have the network-like electrical topological characteristics of the natural extracellular matrix fibers, which makes the electrical properties of the materials poorly matched with the characteristics of the natural extracellular matrix, resulting in limited repair effects of the materials.
  • the invention provides a charged composite membrane with electrical topological characteristics of extracellular matrix and a preparation method thereof for the technical problem that the electrical characteristics of the material are poorly matched with the characteristics of the natural extracellular matrix and the repairing effect of the material is limited.
  • the present invention provides a charged composite membrane having electrical topological features of an extracellular matrix, the charged composite membrane having electrical topological features of the extracellular matrix being composed of a high molecular polymer and a piezoelectric fiber filler.
  • the material of the high molecular polymer is one of a ferroelectric polymer polyvinylidene fluoride (PVDF) or a polyvinylidene fluoride-trifluoroethylene (P(VDF-TrFE)) or a composite thereof;
  • PVDF ferroelectric polymer polyvinylidene fluoride
  • PVDF-TrFE polyvinylidene fluoride-trifluoroethylene
  • the piezoelectric fiber filler is a piezoelectric active fiber material
  • the piezoelectric active fiber material is one or more composites of barium titanate fiber, zinc oxide fiber, sodium potassium citrate fiber or the like.
  • the charged composite film is a film material, wherein the charged composite film has a thickness of 10 ⁇ m to 500 ⁇ m.
  • the charged composite membrane having the electrical topological characteristics of the extracellular matrix is a film-like material having a film thickness of 30-300 ⁇ m, and the barium titanate fiber has a volume content of 5-15 vol% in the charged composite membrane.
  • the method for preparing a charged composite film having the electrical topological characteristics of an extracellular matrix is completed by casting or casting. Specifically, the following steps are included:
  • the mixed solution obtained in the step (1) is injected into the syringe, and the barium titanate nanofiber having a diameter of 50 nm to 500 nm is obtained by electrospinning at a voltage of 10 kV to 16 kV; (3) the titanic acid obtained in the step (2) is obtained.
  • the nanofiber is added to a 0.01 to 0.1 mol/L dopamine aqueous solution to form a solution having a concentration ranging from 0.01 to 0.1 g/mL, stirred at 40 to 80 ° C for 6 to 12 hours, and then ultrasonically shaken for 1 to 15 minutes, and centrifuged. Washing 3 to 5 times, and then ultrasonicating for 1 to 10 minutes under the condition of 180 W, respectively, obtaining a barium titanate nanofiber filler having an aspect ratio of 8-20;
  • step (3) taking the barium titanate nanofiber filler obtained in step (3), adding to an organic solvent, ultrasonically shaking and stirring for 1 h to 3 h to obtain a fibrous filler dispersion;
  • the organic solvent is selected from nitrogen nitrogen dimethylformamide (DMF);
  • the mass percentage of the fibrous filler obtained in this step in the organic solvent ranges from 1.5% to 30%.
  • the film material obtained in the step (7) is subjected to polarization treatment, and the polarization parameters are: a polarization voltage of 1 kV to 30 kV, a polarization distance of 0 mm to 50 mm, a polarization temperature of 25 ° C to 150 ° C, and a polarization time of From 1 min to 60 min, a charged composite membrane with electrical topological characteristics of the extracellular matrix was obtained.
  • the volume mass ratio of glacial acetic acid to acetylacetone is 9: 1.34 ml/g.
  • the mass-to-volume ratio of the cerium acetate to the glacial acetic acid in the step (1) is 1.701:9 g/ml.
  • Ferroelectric polymers such as polyvinylidene fluoride (PVDF) and polyvinylidene fluoride-trifluoroethylene (P(VDF-TrFE)) are widely used because of their inherent spontaneous polarization properties and biocompatibility. Biomedical research, with good flexibility and processability, has good clinical operability and is the main source of current charged biomedical materials.
  • the present invention randomly incorporates piezoelectric ceramic barium titanate nanofibers to achieve electrical adaptation of the material to the cells/tissue.
  • the present invention provides a charged composite membrane having electrical topological characteristics of an extracellular matrix and a preparation method thereof.
  • the invention adopts ferroelectric polymer and piezoelectric active fiber filler as main components, and the formed film material has uniform structure, anisotropic distribution of fiber filler, stable performance, good flexibility, and strong clinical operability.
  • the film material prepared by the invention has a certain polarization charge on the surface of the film material due to the inherent spontaneous polarization property of the material, and can maintain a good electrical stability, and the fiber filler
  • the structural characteristics and potential distribution characteristics make the surface of the composite membrane have the electrical topological characteristics of the natural extracellular matrix. See Figure 3 and Figure 4 for details.
  • the charged composite membrane material prepared by the invention has good bone repairing performance after being implanted into the bone defect. See Figure 6 for details.
  • the preparation process adopted by the invention is simple, the yield is high, the operability is strong, and it can be used for industrial production.
  • the charged composite membrane having the electrical topological characteristics of the extracellular matrix has good performance in both macroscopic properties and microstructure, and can not only compensate for bone defects during bone repair. Electrical microenvironment, and can form a good electrical compatibility with host cells and tissues, promote new bone formation, without tissue adhesion, avoid material residue, and double in clinical adaptability and induced osteogenic adaptability improve.
  • Example 1 is a photograph of a photograph of a charged composite membrane having an electrical topological characteristic of an extracellular matrix as described in Example 1.
  • Example 2 is a scanning electron micrograph of the surface topography of the charged composite film having the electrical topological characteristics of the extracellular matrix described in Example 1.
  • Example 3 is a scanning electron micrograph of a cross-sectional morphology of the charged composite membrane having the electrical topological characteristics of the extracellular matrix described in Example 1.
  • Example 4 is a graph showing the electrical stability results of the charged composite membrane having the electrical topological characteristics of the extracellular matrix described in Example 1.
  • Fig. 5 is a simulation result of surface potential distribution analysis of the charged composite membrane having the electrical topological characteristics of the extracellular matrix described in Example 1.
  • Fig. 6 is a laser confocal micrograph of the adhesion and spreading of rat bone marrow mesenchymal stem cells after 12 hours of the charged composite membrane having the electrical topological characteristics of the extracellular matrix described in Example 1.
  • Fig. 7 is a Micro-CT photograph of a test group and a blank control group for repairing a rat skull defect by the charged composite membrane of Example 1.
  • the barium titanate nanofiber obtained in the step (2) is placed in a 0.01 mol/L aqueous solution of dopamine, heated and stirred in a 60-degree water bath for 12 hours, then ultrasonically shaken for 5 minutes, and centrifuged to obtain a titanic acid having an aspect ratio of 12. ⁇ nanofiber filler;
  • the dispersion obtained in the step (4) is added to the solution of the polymer P (VDF-TrFE) obtained in the step (5), so that the volume ratio of the barium titanate fiber filler to the polymer is 7 vol%, and the mixture is stirred for 10 hours to make titanic acid.
  • the ruthenium fiber filler is uniformly dispersed in the polymer P (VDF-TrFE) matrix to obtain a mixed liquid;
  • step (7) taking the mixture obtained in the step (6) is cast in a casting machine, the resulting cast film is dried at 55 ° C, the solvent is completely volatilized, to obtain a composite film material, the film thickness is 30 ⁇ m;
  • the film material obtained in the step (7) is subjected to polarization treatment, and the polarization parameters are: a polarization voltage of 20 kV, a polarization distance of 20 mm, a polarization temperature of 25 ° C, and a polarization time of 30 min.
  • the barium titanate fiber filler is in the charged composite film.
  • the volume content is 5 vol%.
  • the physical photograph of the product of this embodiment is shown in Fig. 1, the surface topography scanning electron micrograph is shown in Fig. 2, and the sectional topography scanning electron microscope photograph is shown in Fig. 3.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, and then cut into a circular membrane having a diameter of 8 mm, covered with a skull defect of 5 mm in diameter, and the defect was not covered with any material as a blank control group.
  • the animals were sacrificed 4 weeks after surgery, and the membrane material was separated and micro-CT scan was performed. The test results are shown in Figure 7.
  • the barium titanate nanofiber obtained in the step (2) is placed in a 0.05 mol/L dopamine aqueous solution, heated and stirred in a 60-degree water bath for 12 hours, and then ultrasonically shaken for 10 minutes, and centrifuged to obtain a barium titanate having an aspect ratio of 8.
  • Nanofiber filler
  • the dispersion obtained in the step (4) is added to the solution of the polymer P (VDF-TrFE) obtained in the step (5), so that the volume ratio of the barium titanate fiber filler to the polymer is 7 vol%, and the mixture is stirred for 10 hours to make titanic acid.
  • the ruthenium fiber filler is uniformly dispersed in the polymer P (VDF-TrFE) matrix to obtain a mixed liquid;
  • step (7) taking the mixture obtained in the step (6) is cast in a casting machine, the resulting cast film is dried at a temperature of 45 ° C, the solvent is completely volatilized, to obtain a composite film material, the film thickness is 50 ⁇ m;
  • the film material obtained in the step (7) is subjected to polarization treatment, and the polarization parameters are: a polarization voltage of 15 kV, a polarization distance of 20 mm, a polarization temperature of 50 ° C, and a polarization time of 60 min.
  • the barium titanate fiber filler is in the charged composite film.
  • the volume content is 7 vol%.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, the rat bone marrow mesenchymal stem cells having a density of 5 ⁇ 10 4 were seeded thereon, and the cells were fixed for 12 hours after the culture, and the adhesion was fixed. Staining was then observed using a laser confocal microscope.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, and then cut into a circular membrane having a diameter of 8 mm, covered with a skull defect of 5 mm in diameter, and the defect was not covered with any material as a blank control group.
  • the animals were sacrificed 4 weeks after surgery, and the membrane material was separated and micro-CT scan was performed.
  • the barium titanate nanofiber obtained in the step (2) is placed in a 0.08 mol/L dopamine aqueous solution, heated and stirred for 12 hours in a 60-degree water bath, and then ultrasonically shaken for 1 min, and centrifuged to obtain a barium titanate having an aspect ratio of 20.
  • step (7) taking the mixture obtained in the step (6) is cast in a casting machine, the resulting cast film is dried at 80 ° C, the solvent is completely volatilized, to obtain a composite film material, the film thickness is 100 ⁇ m;
  • the film material obtained in the step (7) is subjected to polarization treatment, and the polarization parameters are: a polarization voltage of 10 kV, a polarization distance of 15 mm, a polarization temperature of 100 ° C, and a polarization time of 40 min.
  • the volume content in the volume is 10 vol%.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, the rat bone marrow mesenchymal stem cells having a density of 5 ⁇ 10 4 were seeded thereon, and the cells were fixed for 12 hours after the culture, and the adhesion was fixed. Staining was then observed using a laser confocal microscope.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, and then cut into a circular membrane having a diameter of 8 mm, covered with a skull defect of 5 mm in diameter, and the defect was not covered with any material as a blank control group.
  • the animals were sacrificed 4 weeks after surgery, and the membrane material was separated and micro-CT scan was performed.
  • the barium titanate nanofiber obtained in the step (2) is placed in a 0.09 mol/L dopamine aqueous solution, heated and stirred for 12 hours in a 60-degree water bath, and then ultrasonically shaken for 1 min, and centrifuged to obtain a barium titanate having an aspect ratio of 20.
  • step (7) taking the mixture obtained in the step (6) is cast in a casting machine, the resulting cast film is dried at 80 ° C, the solvent is completely volatilized, to obtain a composite film material, the film thickness is 100 ⁇ m;
  • the film material obtained in the step (7) is subjected to polarization treatment, and the polarization parameters are: a polarization voltage of 10 kV, a polarization distance of 15 mm, a polarization temperature of 100 ° C, and a polarization time of 40 min.
  • the charged composite membrane with electrical topological characteristics of extracellular matrix, the main component of which is polymer PVDF and barium titanate nanofiber, is a film-like material with a film thickness of 120 ⁇ m, and the volume content of barium titanate fiber filler in the charged composite film is 10 vol. %.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, the rat bone marrow mesenchymal stem cells having a density of 5 ⁇ 10 4 were seeded thereon, and the cells were fixed for 12 hours after the culture, and the adhesion was fixed. Staining was then observed using a laser confocal microscope.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, and then cut into a circular membrane having a diameter of 8 mm, covered with a skull defect of 5 mm in diameter, and the defect was not covered with any material as a blank control group.
  • the animals were sacrificed 4 weeks after surgery, and the membrane material was separated and micro-CT scan was performed.
  • the barium titanate nanofiber obtained in the step (2) is placed in a 0.1 mol/L dopamine aqueous solution, heated and stirred in a 60-degree water bath for 12 hours, and then ultrasonically shaken for 15 minutes, and centrifuged to obtain a barium titanate having an aspect ratio of 8.
  • Nanofiber filler
  • the dispersion obtained in the step (4) is added to the solution of the polymer P (VDF-TrFE) obtained in the step (5) so that the volume ratio of the barium titanate fiber filler to the polymer is 15 vol%, and the mixture is stirred for 10 hours to make titanic acid.
  • the ruthenium fiber filler is uniformly dispersed in the polymer P (VDF-TrFE) matrix to obtain a mixed liquid;
  • step (7) taking the mixture obtained in the step (6) is cast in a casting machine, the resulting cast film is dried at a temperature of 100 ° C, the solvent is completely volatilized, to obtain a composite film material, the film thickness is 300 ⁇ m;
  • the film material obtained in the step (7) is subjected to polarization treatment, and the polarization parameters are: a polarization voltage of 30 kV, a polarization distance of 50 mm, a polarization temperature of 150 ° C, and a polarization time of 10 min.
  • the charged composite membrane with electrical topological characteristics of extracellular matrix is mainly composed of polymer P (VDF-TrFE) and barium titanate nanofiber. It is a film-like material with a film thickness of 300 ⁇ m.
  • the barium titanate fiber filler is in the charged composite film. The volume content is 15 vol%.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, the rat bone marrow mesenchymal stem cells having a density of 5 ⁇ 10 4 were seeded thereon, and the cells were fixed for 12 hours after the culture, and the adhesion was fixed. Staining was then observed using a laser confocal microscope.
  • the membrane material obtained in the step (8) was sterilized by cobalt 60, and then cut into a circular membrane having a diameter of 8 mm, covered with a skull defect of 5 mm in diameter, and the defect was not covered with any material as a blank control group.
  • the animals were sacrificed 4 weeks after surgery, and the membrane material was separated and micro-CT scan was performed.
  • Example 1 The product performance test results of Examples 2 to 5 are shown in Example 1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Materials Engineering (AREA)
  • Composite Materials (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nonwoven Fabrics (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Artificial Filaments (AREA)

Abstract

一种具有细胞外基质电学拓扑特征的带电复合膜及其制备方法，该具有细胞外基质电学拓扑特征的带电复合膜主要由铁电聚合物基体和压电活性纤维填料构成，其通过调节压电活性纤维的长径比、含量以及复合膜的厚度，可以实现膜材料的柔性和仿生细胞外基质电学拓扑特征，组织贴附性好，具有良好的电学适配性，临床可操作性强。

Description

具有细胞外基质电学拓扑特征的带电复合膜及其制备方法 技术领域
本发明涉及骨科及口腔外科修复材料技术领域，特别涉及一种具有细胞外基质电学拓扑特征的带电复合膜及其制备方法。
背景技术
植入修复是目前治疗大范围组织缺损的主要手段。人工修复材料由于来源广泛、性能可控及成本低，在组织修复材料中受到广泛关注。根据仿生原理，皮肤创伤愈合、神经修复、骨缺损修复等均存在损伤电位，大量研究证实损伤电位对组织修复具有重要作用，因此，对于组织修复材料而言，使得材料带电将有利于促进组织快速愈合和功能修复。近年来电活性材料成为研究热点和趋势，也是组织修复材料设计的新思路。
然而，目前所用的电活性材料不具备天然细胞外基质纤维网络样电学拓扑结构特征，使得材料的电学特征与天然细胞外基质特征的匹配性差，导致材料的修复效果受限。
发明内容
本发明针对材料的电学特征与天然细胞外基质特征的匹配性差、材料的修复效果受限的技术问题，提供一种具有细胞外基质电学拓扑特征的带电复合膜及其制备方法。
为此，本发明提供一种具有细胞外基质电学拓扑特征的带电复合膜，所述具有细胞外基质电学拓扑特征的带电复合膜由高分子聚合物和压电纤维填料构成。
优选的，高分子聚合物的材质为铁电高分子聚偏氟乙烯(Polyvinylidene fluoride，PVDF)或聚偏氟-三氟乙烯(P(VDF-TrFE))的一种或其复合物；
优选的，压电纤维填料为压电活性纤维材料，所述压电活性纤维材料为钛酸钡纤维、氧化锌纤维、铌酸钾钠纤维等的一种或多种复合物。
优选的，所述带电复合膜为薄膜材料，其中所述带电复合膜的厚度为10μm～500μm。
优选的，所述具有细胞外基质电学拓扑特征的带电复合膜是一种薄膜状材料，膜厚为30-300μm，所述钛酸钡纤维在带电复合膜中的体积含量为5-15vol％。
本发明所述具有细胞外基质电学拓扑特征的带电复合膜的制备方法，所述铁电聚合物基体与压电纤维填料的复合成膜过程通过浇铸或流延法完成。具体的说，包括以下步骤：
(1)取一定量的冰醋酸和乙酰丙酮混合均匀，搅拌5min，制备冰醋酸与乙酰丙酮的混合溶剂，将醋酸钡加入到冰醋酸与乙酰丙酮的混合溶剂中，搅拌1小时，加入与醋酸钡相同摩尔量的钛酸四丁酯，搅拌15min，然后加入与醋酸钡质量比为9∶32的聚乙烯吡咯烷酮(PVP)，搅拌3h。
(2)制备钛酸钡纳米纤维
将步骤(1)所得混合溶液注入注射器内，在电压10kV～16kV条件下，利用静电纺丝技术，获得直径为50nm～500nm的钛酸钡纳米纤维；(3)将步骤(2)所得钛酸钡纳米纤维加入到0.01～0.1mol/L的多巴胺水溶液中，形成浓度范围为0.01～0.1g/mL的溶液，在40℃～80℃下搅拌6h～12h，然后再超声震荡1min～15min，离心洗涤3～5次，然后在功率为180W的条件下超声1～10min，分别得到长径比为8～20的钛酸钡纳米纤维填料；
(4)取步骤(3)所得钛酸钡纳米纤维填料，加入有机溶剂中，超声振荡并搅拌1h～3h，得到纤维填料分散液；有机溶剂选自氮氮二甲基甲酰胺(DMF)；本步骤所得纤维填料在有机溶剂中的质量百分比范围为1.5％～30％。
(5)称取铁电高分子聚合物，加入到有机溶剂DMF中，搅拌3h～6h至完全溶解，得到聚合物溶液；所得溶液的浓度为0.14g/ml，所述铁电高分子聚合物为P(VDF-TrFE)或PVDF。
(6)将步骤(4)中所得分散液加入步骤(5)所得聚合物溶液中，使得钛酸钡纤维填料在聚合物基体中的体积含量范围为1～20vol％，搅 拌6h～12h使得纤维填料均匀分散在聚合物基体中，得到含有陶瓷纤维填料的聚合物混合液；
(7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于40℃～100℃温度下烘干，得到一种复合膜材料，膜厚为10μm～500μm；(8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为1kV～30kV，极化距离为0mm～50mm，极化温度为25℃～150℃，极化时间为1min～60min，得到一种具有细胞外基质电学拓扑特征的带电复合膜。
优选的，步骤(1)所述冰醋酸与乙酰丙酮的混合溶剂中，冰醋酸与乙酰丙酮的体积质量比为9∶1.34ml/g。
优选的，步骤(1)所述醋酸钡与冰醋酸的投料质量体积比为1.701∶9g/ml。
铁电聚合物如聚偏氟乙烯(Polyvinylidene fluoride，PVDF)、聚偏氟-三氟乙烯(P(VDF-TrFE))等因具有内在的自发极化性能和生物相容性，目前广泛用于生物医用研究领域，同时具有良好的柔韧性和可加工性，使其具备良好的临床可操作性，成为当前带电生物医用材料的主要来源。为使材料具有天然细胞外基质纤维网络样电学拓扑结构特征，本发明将压电陶瓷钛酸钡纳米纤维无规则掺入实现材料与细胞/组织的电学适配。
本发明的有益效果为：
针对现有技术不足，本发明提供了一种具有细胞外基质电学拓扑特征的带电复合膜及其制备方法。
(1)本发明采用铁电聚合物和压电活性纤维填料为主要成分，形成的膜材料结构均一、纤维填料分布各向异性、性能稳定，具有良好柔性，临床可操作性强，详见附图1和附图2。
(2)本发明所制得的膜材料由于材料内在的自发极化特性，经过极化处理后可使膜材料表面带有一定的极化电荷，并可保持良好电学稳定性，而且由于纤维填料的结构特性和电势分布特征，使得复合膜表面具备天然细胞外基质电学拓扑特征，详见附图3和附图4
(3)本发明所制得的带电复合膜材料植入骨缺损后具有良好的诱导骨修复性能。详见附图6。
(4)本发明所采用的制备工艺简单，产率较高，可操作性强，能用于工业化生产。
综上所述，本发明所提供的一种具有细胞外基质电学拓扑特征的带电复合膜在宏观性能和微观结构上均具有良好的性能，在骨修复过程中，不仅可为骨缺损补偿适宜的电学微环境，而且可与宿主细胞和组织形成良好的电学适配性，促进新骨生成，同时不会发生组织粘连，避免材料残留，在临床适应性和诱导成骨适配性两方面得到双重改善。
附图说明
图1是实施例1所述具有细胞外基质电学拓扑特征的带电复合膜的实物照片。
图2是实施例1所述具有细胞外基质电学拓扑特征的带电复合膜的表面形貌扫描电镜照片。
图3是实施例1所述具有细胞外基质电学拓扑特征的带电复合膜的断面形貌扫描电镜照片。
图4是实施例1所述具有细胞外基质电学拓扑特征的带电复合膜的电学稳定性结果。
图5是实施例1所述具有细胞外基质电学拓扑特征的带电复合膜的表面电势分布模拟分析结果。
图6是实施例1所述具有细胞外基质电学拓扑特征的带电复合膜作用大鼠骨髓间充质干细胞12小时后粘附和铺展情况的激光共聚焦显微镜照片。
图7是实施例1所述带电复合膜修复大鼠颅骨缺损试验试验组与空白对照组的Micro-CT照片。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，本领域的技术人 员容易理解，实施例所描述的内容仅用于说明本发明，而不应当也不会限制权力要求书中所描述的本发明。
实施例1
(1)取9ml冰醋酸和1.340g乙酰丙酮，混合搅拌5min后加入1.703g醋酸钡，搅拌1h，加入2.266g钛酸四丁酯，搅拌15min，然后加入0.45g聚乙烯吡咯烷酮(PVP)，搅拌3h；
(2)将步骤(1)所得混合溶液注入注射器内，在电压14kV条件下，利用静电纺丝技术，获得直径为200nm的钛酸钡纳米纤维；
(3)将步骤(2)所得钛酸钡纳米纤维放入0.01mol/L的多巴胺水溶液中，60度水浴加热搅拌12h，然后再超声震荡5min，离心干燥后得到长径比为12的钛酸钡纳米纤维填料；
(4)取适量步骤(3)所得钛酸钡纳米纤维填料超声振荡分散在3mL有机溶剂DMF中，采用超声振荡结合搅拌1.5h，得到纤维填料分散液；
(5)称取1g聚合物P(VDF-TrFE)，加入7mL有机溶剂DMF，搅拌5h使其完全溶解，得到聚合物P(VDF-TrFE)溶液；
(6)将步骤(4)中所得分散液加入步骤(5)所得聚合物P(VDF-TrFE)溶液中，使得钛酸钡纤维填料占聚合物的体积比为7vol％，搅拌10h使得钛酸钡纤维填料均匀分散在聚合物P(VDF-TrFE)基体中，得到混合液；
(7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于55℃温度下烘干，使溶剂完全挥发，得到一种复合膜材料，膜厚为30μm；
(8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为20kV，极化距离为20mm，极化温度为25℃，极化时间为30min，得到一种具有细胞外基质电学拓扑特征的带电复合膜，其主要成分为聚合物P(VDF-TrFE)和钛酸钡纳米纤维，为薄膜状材料，膜厚为30μm，钛酸钡纤维填料在带电复合膜中的体积含量为5vol％。本实施例产品实物照片见附图1，表面形貌扫描电镜照片见附图2，断面形貌扫描电镜照片见附图3。
产品性能检测：
(1)利用COMSOL软件对膜材料表面的电势分布特征进行模拟分 析。模拟分析结果见附图4。
(2)将步骤(8)所得膜材料放置于无血清培养基内，与37℃条件下分别孵育0、1、3、7、14和21天，每个时间点取出材料进行压电常数测试。测试结果见附图5。
(3)将步骤(8)所得膜材料经钴60灭菌后，在其上面接种密度为5×104的大鼠骨髓间充质干细胞，共培养12小时后对细胞进行固定、黏着斑免疫染色，然后利用激光共聚焦显微镜观察。测试结果见附图6。
(4)将步骤(8)所得膜材料经钴60灭菌后，剪成直径为8mm的圆形膜片，覆盖于直径为5mm的大鼠颅骨缺损处，缺损未覆盖任何材料作为空白对照组，术后4周处死动物，分离膜材料后进行micro-CT扫描观察。测试结果见附图7。
实施例2
(1)取9ml冰醋酸和1.340g乙酰丙酮，混合搅拌5min后加入1.703g醋酸钡，搅拌1h，加入2.266g钛酸四丁酯，搅拌15min，然后加入0.45g聚乙烯吡咯烷酮(PVP)，搅拌3h；
(2)将步骤(1)所得混合溶液注入注射器内，在电压16kV条件下，利用静电纺丝技术，获得直径为300nm的钛酸钡纳米纤维；
(3)将步骤(2)所得钛酸钡纳米纤维放入0.05mol/L多巴胺水溶液中，60度水浴加热搅拌12h，然后再超声震荡10min，离心干燥后得到长径比为8的钛酸钡纳米纤维填料；
(4)取适量步骤(3)所得钛酸钡纳米纤维填料超声振荡分散在3mL有机溶剂DMF中，采用超声振荡结合搅拌1.5h，得到纤维填料分散液；
(5)称取1g聚合物P(VDF-TrFE)，加入7mL有机溶剂DMF，搅拌3h使其完全溶解，得到聚合物P(VDF-TrFE)溶液；
(6)将步骤(4)中所得分散液加入步骤(5)所得聚合物P(VDF-TrFE)溶液中，使得钛酸钡纤维填料占聚合物的体积比为7vol％，搅拌10h使得钛酸钡纤维填料均匀分散在聚合物P(VDF-TrFE)基体中，得到混合液；
(7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于45℃温度下烘干，使溶剂完全挥发，得到一种复合膜材料，膜厚为50μm；
(8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为15kV，极化距离为20mm，极化温度为50℃，极化时间为60min，得到一种具有细胞外基质电学拓扑特征的带电复合膜，其主要成分为聚合物P(VDF-TrFE)和钛酸钡纳米纤维，为薄膜状材料，膜厚为50μm，钛酸钡纤维填料在带电复合膜中的体积含量为7vol％。
产品性能检测：
(1)利用COMSOL软件对膜材料表面的电势分布特征进行模拟分析。
(2)将步骤(8)所得膜材料放置于无血清培养基内，与37℃条件下分别孵育0、1、3、7、14和21天，每个时间点取出材料进行压电常数测试。
(3)将步骤(8)所得膜材料经钴60灭菌后，在其上面接种密度为5×10 4的大鼠骨髓间充质干细胞，共培养12小时后对细胞进行固定、黏着斑免疫染色，然后利用激光共聚焦显微镜观察。
(4)将步骤(8)所得膜材料经钴60灭菌后，剪成直径为8mm的圆形膜片，覆盖于直径为5mm的大鼠颅骨缺损处，缺损未覆盖任何材料作为空白对照组，术后4周处死动物，分离膜材料后进行micro-CT扫描观察。
实施例3
(1)取9ml冰醋酸和1.340g乙酰丙酮，混合搅拌5min后加入1.703g醋酸钡，搅拌1h，加入2.266g钛酸四丁酯，搅拌15min，然后加入0.45g聚乙烯吡咯烷酮(PVP)，搅拌3h；
(2)将步骤(1)所得混合溶液注入注射器内，在电压12kV条件下，利用静电纺丝技术，获得直径为400nm的钛酸钡纳米纤维；
(3)将步骤(2)所得钛酸钡纳米纤维放入0.08mol/L多巴胺水溶液中，60度水浴加热搅拌12h，然后再超声震荡1min，离心干燥后得到长径比为20的钛酸钡纳米纤维填料；
(4)取适量步骤(3)所得钛酸钡纳米纤维填料超声振荡分散在3mL有机溶剂DMF中，采用超声振荡结合搅拌1.5h，得到纤维填料分散液；
(5)称取1g聚合物P(VDF-TrFE)，加入7mL有机溶剂DMF，搅拌5h使其完全溶解，得到聚合物P(VDF-TrFE)溶液；
(6)将步骤(4)中所得分散液加入步骤(5)所得聚合物P(VDF-TrFE)溶液中，使得钛酸钡纤维填料占聚合物的体积比为10vol％，搅拌10h使得纤维填料(如钛酸钡)均匀分散在聚合物P(VDF-TrFE)基体中，得到混合液；
(7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于80℃温度下烘干，使溶剂完全挥发，得到一种复合膜材料，膜厚为100μm；
(8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为10kV，极化距离为15mm，极化温度为100℃，极化时间为40min，得到一种具有细胞外基质电学拓扑特征的带电复合膜，其主要成分为聚合物P(VDF-TrFE)和钛酸钡纳米纤维，其为薄膜状材料，膜厚为100μm，钛酸钡纤维填料在带电复合膜中的体积含量为10vol％。
产品性能检测：
(1)利用COMSOL软件对膜材料表面的电势分布特征进行模拟分析。
(2)将步骤(8)所得膜材料放置于无血清培养基内，与37℃条件下分别孵育0、1、3、7、14和21天，每个时间点取出材料进行压电常数测试。
(3)将步骤(8)所得膜材料经钴60灭菌后，在其上面接种密度为5×10 4的大鼠骨髓间充质干细胞，共培养12小时后对细胞进行固定、黏着斑免疫染色，然后利用激光共聚焦显微镜观察。
(4)将步骤(8)所得膜材料经钴60灭菌后，剪成直径为8mm的圆形膜片，覆盖于直径为5mm的大鼠颅骨缺损处，缺损未覆盖任何材料作为空白对照组，术后4周处死动物，分离膜材料后进行micro-CT扫描观察。
实施例4
(1)取9ml冰醋酸和1.340g乙酰丙酮，混合搅拌5min后加入1.703g醋酸钡，搅拌1h，加入2.266g钛酸四丁酯，搅拌15min，然后加入0.45g 聚乙烯吡咯烷酮(PVP)，搅拌3h；
(2)将步骤(1)所得混合溶液注入注射器内，在电压12kV条件下，利用静电纺丝技术，获得直径为400nm的钛酸钡纳米纤维；
(3)将步骤(2)所得钛酸钡纳米纤维放入0.09mol/L多巴胺水溶液中，60度水浴加热搅拌12h，然后再超声震荡1min，离心干燥后得到长径比为20的钛酸钡纳米纤维填料；
(4)取适量步骤(3)所得钛酸钡纳米纤维填料超声振荡分散在3mL有机溶剂DMF中，采用超声振荡结合搅拌1.5h，得到纤维填料分散液；
(5)称取1g聚合物PVDF，加入7mL有机溶剂DMF，搅拌5h使其完全溶解，得到聚合物PVDF溶液；
(6)将步骤(4)中所得分散液加入步骤(5)所得聚合物PVDF溶液中，使得钛酸钡纤维填料占聚合物的体积比为10vol％，搅拌10h使得纤维填料(如钛酸钡)均匀分散在聚合物PVDF基体中，得到混合液；
(7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于80℃温度下烘干，使溶剂完全挥发，得到一种复合膜材料，膜厚为100μm；
(8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为10kV，极化距离为15mm，极化温度为100℃，极化时间为40min，得到一种具有细胞外基质电学拓扑特征的带电复合膜，其主要成分为聚合物PVDF和钛酸钡纳米纤维，为薄膜状材料，膜厚为120μm，钛酸钡纤维填料在带电复合膜中的体积含量为10vol％。
产品性能检测：
(1)利用COMSOL软件对膜材料表面的电势分布特征进行模拟分析。
(2)将步骤(8)所得膜材料放置于无血清培养基内，与37℃条件下分别孵育0、1、3、7、14和21天，每个时间点取出材料进行压电常数测试。
(3)将步骤(8)所得膜材料经钴60灭菌后，在其上面接种密度为5×10 4的大鼠骨髓间充质干细胞，共培养12小时后对细胞进行固定、黏着斑免疫染色，然后利用激光共聚焦显微镜观察。
(4)将步骤(8)所得膜材料经钴60灭菌后，剪成直径为8mm的圆形膜片，覆盖于直径为5mm的大鼠颅骨缺损处，缺损未覆盖任何材料作为空白对照组，术后4周处死动物，分离膜材料后进行micro-CT扫描观察。
实施例5
(1)取9ml冰醋酸和1.340g乙酰丙酮，混合搅拌5min后加入1.703g醋酸钡，搅拌1h，加入2.266g钛酸四丁酯，搅拌15min，然后加入0.45g聚乙烯吡咯烷酮(PVP)，搅拌3h；
(2)将步骤(1)所得混合溶液注入注射器内，在电压10kV条件下，利用静电纺丝技术，获得直径为500nm的钛酸钡纳米纤维；
(3)将步骤(2)所得钛酸钡纳米纤维放入0.1mol/L多巴胺水溶液中，60度水浴加热搅拌12h，然后再超声震荡15min，离心干燥后得到长径比为8的钛酸钡纳米纤维填料；
(4)取适量步骤(3)所得钛酸钡纳米纤维填料超声振荡分散在3mL有机溶剂DMF中，采用超声振荡结合搅拌1.5h，得到纤维填料分散液；
(5)称取1g聚合物P(VDF-TrFE)，加入7mL有机溶剂DMF，搅拌5h使其完全溶解，得到聚合物P(VDF-TrFE)溶液；
(6)将步骤(4)中所得分散液加入步骤(5)所得聚合物P(VDF-TrFE)溶液中，使得钛酸钡纤维填料占聚合物的体积比为15vol％，搅拌10h使得钛酸钡纤维填料均匀分散在聚合物P(VDF-TrFE)基体中，得到混合液；
(7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于100℃温度下烘干，使溶剂完全挥发，得到一种复合膜材料，膜厚为300μm；
(8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为30kV，极化距离为50mm，极化温度为150℃，极化时间为10min，得到一种具有细胞外基质电学拓扑特征的带电复合膜，其主要成分为聚合物P(VDF-TrFE)和钛酸钡纳米纤维，为薄膜状材料，膜厚为300μm，钛酸钡纤维填料在带电复合膜中的体积含量为15vol％。
产品性能检测：
(1)利用COMSOL软件对膜材料表面的电势分布特征进行模拟分析。
(2)将步骤(8)所得膜材料放置于无血清培养基内，与37℃条件下分别孵育0、1、3、7、14和21天，每个时间点取出材料进行压电常数测试。
(3)将步骤(8)所得膜材料经钴60灭菌后，在其上面接种密度为5×10 4的大鼠骨髓间充质干细胞，共培养12小时后对细胞进行固定、黏着斑免疫染色，然后利用激光共聚焦显微镜观察。
(4)将步骤(8)所得膜材料经钴60灭菌后，剪成直径为8mm的圆形膜片，覆盖于直径为5mm的大鼠颅骨缺损处，缺损未覆盖任何材料作为空白对照组，术后4周处死动物，分离膜材料后进行micro-CT扫描观察。
实施例2～5的产品性能检测结果参见实施例1。

Claims (9)

  1. 一种具有细胞外基质电学拓扑特征的带电复合膜，其特征是，所述具有细胞外基质电学拓扑特征的带电复合膜由高分子聚合物和压电纤维填料构成。
  2. 根据权利要求1所述的一种具有细胞外基质电学拓扑特征的带电复合膜，其特征是，所述高分子聚合物的材质为铁电高分子聚偏氟乙烯或聚偏氟-三氟乙烯的一种或其复合物。
  3. 根据权利要求2所述的一种具有细胞外基质电学拓扑特征的带电复合膜，其特征是，所述压电纤维填料为压电活性纤维材料，所述压电活性纤维材料为钛酸钡纤维、氧化锌纤维、铌酸钾钠纤维等的一种或多种复合物。
  4. 根据权利要求1所述的一种具有细胞外基质电学拓扑特征的带电复合膜，其特征是，所述带电复合膜为薄膜材料，其中所述带电复合膜的厚度为10μm～500μm。
  5. 根据权利要求3所述的一种具有细胞外基质电学拓扑特征的带电复合膜，其特征是，所述具有细胞外基质电学拓扑特征的带电复合膜是一种薄膜状材料，膜厚为30-300μm，所述钛酸钡纤维在带电复合膜中的体积含量为5-15vol％。
  6. 权利要求1～5任意一项权利要求所述具有细胞外基质电学拓扑特征的带电复合膜的制备方法，其特征是，所述带电复合膜制备过程通过有机溶剂分散、溶解以及流延法完成，包括以下步骤：
    (1)取冰醋酸和乙酰丙酮混合均匀，搅拌5min，制备冰醋酸与乙酰丙酮的混合溶剂，将醋酸钡加入到冰醋酸与乙酰丙酮的混合溶剂中，搅拌1小时，加入与醋酸钡相同摩尔量的钛酸四丁酯，搅拌15min，然后加入与醋酸钡质量比为9∶32的聚乙烯吡咯烷酮，搅拌3h；
    (2)将步骤(1)所得混合溶液注入注射器内，在电压10kV～16kV条件下，利用静电纺丝技术，获得直径为50nm～500nm的钛酸钡纳米纤维；
    (3)将步骤(2)所得钛酸钡纳米纤维加入到0.01～0.1mol/L的多巴胺水溶液中，形成浓度范围为0.01～0.1g/mL的溶液，在40℃～80℃ 下搅拌6h～12h，然后再超声震荡1min～15min，离心洗涤3～5次，然后在功率为180W的条件下超声1～10min，分别得到长径比为8～20的钛酸钡纳米纤维填料；
    (4)取步骤(3)所得钛酸钡纳米纤维填料，加入有机溶剂氮氮二甲基甲酰胺中，超声振荡并搅拌1h～3h，得到纤维填料分散液；
    (5)称取铁电高分子聚合物，加入到有机溶剂DMF中，搅拌3h～6h至完全溶解，得到聚合物溶液；所得溶液的浓度为0.14g/ml；所述铁电高分子聚合物为聚偏氟乙烯或聚偏氟-三氟乙烯；
    (6)将步骤(4)中所得分散液加入步骤(5)所得聚合物溶液中，使得钛酸钡纤维填料在聚合物基体中的体积含量范围为1～20vol％，搅拌6h～12h使得纤维填料均匀分散在聚合物基体中，得到含有陶瓷纤维填料的聚合物混合液；
    (7)取步骤(6)所得混合液于流延机中流延，将所得流延膜置于40℃～100℃温度下烘干，得到一种复合膜材料，膜厚为10μm～500μm；
    (8)将步骤(7)所得膜材料经过极化处理，极化参数为：极化电压为1kV～30kV，极化距离为0mm～50mm，极化温度为25℃～150℃，极化时间为1min～60min，得到一种具有细胞外基质电学拓扑特征的带电复合膜。
  7. 按照权利要求6所述具有细胞外基质电学拓扑特征的带电复合膜的制备方法，其特征是，步骤(1)所述冰醋酸与乙酰丙酮的混合溶剂中，冰醋酸与乙酰丙酮的体积质量比为9∶1.34ml/g。
  8. 按照权利要求6所述具有细胞外基质电学拓扑特征的带电复合膜的制备方法，其特征是，步骤(1)醋酸钡与冰醋酸的投料质量体积比为1.703∶9g/ml。
  9. 按照权利要求6所述具有细胞外基质电学拓扑特征的带电复合膜的制备方法，其特征是：步骤(4)所得纤维填料在有机溶剂中的质量百分比范围为1.5％～30％。
PCT/CN2018/099828 2018-04-03 2018-08-10 具有细胞外基质电学拓扑特征的带电复合膜及其制备方法 WO2019192116A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/348,099 US11141506B2 (en) 2018-04-03 2018-08-10 Electrified composite membrane with extracellular matrix electrical topology characteristics, and preparation method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810288369.5A CN108498868B (zh) 2018-04-03 2018-04-03 具有细胞外基质电学拓扑特征的带电复合膜及其制备方法
CN201810288369.5 2018-04-03

Publications (1)

Publication Number Publication Date
WO2019192116A1 true WO2019192116A1 (zh) 2019-10-10

Family

ID=63379897

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/099828 WO2019192116A1 (zh) 2018-04-03 2018-08-10 具有细胞外基质电学拓扑特征的带电复合膜及其制备方法

Country Status (3)

Country Link
US (1) US11141506B2 (zh)
CN (1) CN108498868B (zh)
WO (1) WO2019192116A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115976741A (zh) * 2023-01-01 2023-04-18 长春理工大学 基于芴酮光开关型发光各向异性导电膜及其制备技术
CN116835980A (zh) * 2023-05-17 2023-10-03 合肥工业大学 铌酸钾钠纳米粉的制备方法、压电支架及其制备方法
CN116835980B (zh) * 2023-05-17 2024-05-31 合肥工业大学 铌酸钾钠纳米粉的制备方法、压电支架及其制备方法

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109453431B (zh) * 2018-10-23 2022-08-26 北京大学口腔医学院 一种表面电势可控的带电修复膜材料及其制备方法
CN110314250A (zh) * 2019-07-15 2019-10-11 江西理工大学 一种pvdf/dbt复合骨支架的制备方法
CN110882420A (zh) * 2019-08-23 2020-03-17 上海交通大学 一种可自发电刺激的压电支架组合物及其制备方法与应用
CN114181428B (zh) * 2021-12-09 2022-12-23 四川大学 一种具有压电性能的高分子复合膜及其制备和应用
CN114411334B (zh) * 2022-01-17 2022-11-29 清华大学 一种电容器薄膜及其制备方法和应用
CN114775171B (zh) * 2022-03-15 2024-01-12 四川大学 一种基于P(VDF-TrFE)复合压电纤维膜及其制备方法
CN115554471B (zh) * 2022-07-18 2023-08-01 北京大学口腔医学院 一种具有高成骨活性和防止组织粘连的带电复合膜材料及其制备方法
CN115725501B (zh) * 2022-09-27 2023-11-14 北京大学口腔医学院 专用于增强t淋巴细胞功能的培养基材、方法及用途
CN115286883A (zh) * 2022-09-30 2022-11-04 北京大学口腔医学院 调控抗菌活性的方法及用途
CN115252872A (zh) * 2022-09-30 2022-11-01 北京大学口腔医学院 基于铁电材料的抗菌敷料及其制备方法和用途
CN116350844A (zh) * 2023-04-07 2023-06-30 北京大学口腔医学院 一种表面电势可控的内部多孔带电修复膜材料及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045461A1 (de) * 2001-11-23 2003-06-05 Feg Textiltechnik Forschungs- Und Entwicklungsgesellschaft Mbh Textiles erzeugnis mit oberflächenmodifikation und entsprechendes verfahren zur oberflächenmodifikation
CN104208754A (zh) * 2014-09-19 2014-12-17 北京大学口腔医院 一种压电活性骨修复复合材料及其制备方法
CN106751250A (zh) * 2017-01-12 2017-05-31 上海交通大学医学院附属新华医院 一种高分子压电复合材料及其制备方法和应用
CN107233625A (zh) * 2017-06-13 2017-10-10 北京大学口腔医学院 一种用于颅骨修补的防粘连带电复合膜及其制备方法
CN107261205A (zh) * 2017-06-13 2017-10-20 北京大学口腔医学院 一种带电防粘连组织修复膜及其制备方法

Family Cites Families (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040018226A1 (en) * 1999-02-25 2004-01-29 Wnek Gary E. Electroprocessing of materials useful in drug delivery and cell encapsulation
US20030215624A1 (en) * 2002-04-05 2003-11-20 Layman John M. Electrospinning of vinyl alcohol polymer and copolymer fibers
DE10255418A1 (de) * 2002-11-28 2004-06-17 Stockhausen Gmbh & Co. Kg Gezogene absorbierende Polymerfasern
TW200600092A (en) * 2004-05-31 2006-01-01 Showa Denko Kk Topical slimming preparation and a cosmetic containing a carnitine derivative
US20060204539A1 (en) * 2005-03-11 2006-09-14 Anthony Atala Electrospun cell matrices
EP1896088A2 (en) * 2005-06-14 2008-03-12 Cartificial A/S Medical device for insertion into a joint
DE102005040422A1 (de) * 2005-08-25 2007-03-01 TransMIT Gesellschaft für Technologietransfer mbH Herstellung von Metall-Nano- und -Mesofasern
JP2008002011A (ja) * 2006-06-22 2008-01-10 Toyobo Co Ltd ポリイミド不織布およびその製造方法
US8512741B2 (en) * 2006-09-01 2013-08-20 Cornell Research Foundations, Inc. Electrospun calcium phosphate nanofibers
CN101631813A (zh) * 2007-01-12 2010-01-20 陶氏康宁公司 含硅氧烷的组合物
US8784893B2 (en) * 2007-02-05 2014-07-22 Carbylan Therapeutics, Inc. Polymer formulations for delivery of bioactive agents
TW200843802A (en) * 2007-02-09 2008-11-16 Drugtech Corp Compositions for improving gastrointestinal nutrient and drug absorption
US20080199698A1 (en) * 2007-02-16 2008-08-21 Sumitomo Chemical Company, Limited Method for producing liquid crystalline polyester fiber
US8088323B2 (en) * 2007-02-27 2012-01-03 Ppg Industries Ohio, Inc. Process of electrospinning organic-inorganic fibers
JP2008274512A (ja) * 2007-04-03 2008-11-13 Nisshinbo Ind Inc 抗菌性ナノファイバー
US20100099640A1 (en) * 2007-05-04 2010-04-22 Joannes Geuns Tissue degeneration protection
JP4299365B2 (ja) * 2007-05-07 2009-07-22 三菱樹脂株式会社 積層多孔性フィルム及び電池用セパレータ
US20090326128A1 (en) * 2007-05-08 2009-12-31 Javier Macossay-Torres Fibers and methods relating thereto
US20080294089A1 (en) * 2007-06-06 2008-11-27 Biovaluation & Analysis, Inc. Dendritic Polymers for Use in Acoustically Mediated Intracellular Drug Delivery in vivo
WO2008157594A2 (en) * 2007-06-18 2008-12-24 New Jersey Institute Of Technology Electrospun ceramic-polymer composite as a scaffold for tissue repair
JP5274345B2 (ja) * 2008-04-08 2013-08-28 日本バイリーン株式会社 無機含有有機繊維の製造方法及びこの繊維を含む不織布
CZ2008277A3 (cs) * 2008-05-06 2009-11-18 Elmarco S.R.O. Zpusob výroby anorganických nanovláken elektrostatickým zvláknováním
KR101009281B1 (ko) * 2008-07-23 2011-01-18 한국과학기술연구원 탄소 재료 제조 방법, 이에 따라 제조된 탄소 재료, 이를이용하는 전지 재료 및 장치
US8946974B2 (en) * 2008-08-19 2015-02-03 The Johns Hopkins University Piezoelectric polymer fibers
KR101265093B1 (ko) * 2008-12-26 2013-05-16 한국과학기술연구원 나노 분말, 나노 잉크 및 마이크로 로드와 그 제조 방법
PE20110991A1 (es) * 2009-02-05 2012-02-06 Takeda Pharmaceutical Compuestos de fenil-piridazinona-pirazol-fenilo como inhibidores de pde
US9192655B2 (en) * 2009-03-12 2015-11-24 New Jersey Institute Of Technology System and method for a hydrogel and hydrogel composite for cartilage repair applications
US8765238B2 (en) * 2009-03-18 2014-07-01 Boston Scientific Scimed, Inc. Polymeric/inorganic composite materials for use in medical devices
US20120045487A1 (en) * 2009-04-29 2012-02-23 The Regents Of The University Of Michigan Multiphasic microfibers for spatially guided cell growth
US8211352B2 (en) * 2009-07-22 2012-07-03 Corning Incorporated Electrospinning process for aligned fiber production
US8257639B2 (en) * 2009-09-22 2012-09-04 Kent State University Method of making stimuli responsive liquid crystal-polymer composite fibers
US20120178332A1 (en) * 2009-10-29 2012-07-12 Nippon Kayaku Kabushiki Kaisha Fiber Comprising Heat Curable Polyamide Resin Composition, Nonwoven Fabric And Producing Method Thereof
US9180166B2 (en) * 2010-03-12 2015-11-10 New Jersey Institute Of Technology Cartilage repair systems and applications utilizing a glycosaminoglycan mimic
US9428847B2 (en) * 2010-05-29 2016-08-30 Nanostatics Corporation Apparatus, methods, and fluid compositions for electrostatically-driven solvent ejection or particle formation
US10292808B2 (en) * 2010-06-07 2019-05-21 Q3 Medical Devices Limited Device and method for management of aneurism, perforation and other vascular abnormalities
NZ603705A (en) * 2010-06-09 2014-10-31 Semprus Biosciences Corp Non-fouling, anti-microbial, anti-thrombogenic graft-from compositions
US20110305898A1 (en) * 2010-06-09 2011-12-15 Zheng Zhang Non-fouling, anti-microbial, anti-thrombogenic graft compositions
US10016354B2 (en) * 2011-03-23 2018-07-10 Basf Se Compositions containing polymeric, ionic compounds comprising imidazolium groups
US9102570B2 (en) * 2011-04-22 2015-08-11 Cornell University Process of making metal and ceramic nanofibers
US20140332733A1 (en) * 2011-08-30 2014-11-13 Cornell University Pure metal and ceramic nanofibers
CN102504449B (zh) * 2011-11-01 2014-04-23 清华大学 一种高储能密度的聚合物基复合膜及其制备方法
WO2013083698A1 (en) * 2011-12-08 2013-06-13 Basf Se Process for producing water-absorbing polymer fibres
WO2013123137A1 (en) * 2012-02-16 2013-08-22 Cornell University Ordered porous nanofibers, methods, and applications
US9879363B2 (en) * 2012-03-19 2018-01-30 Cornell University Method for preparing a nanofiber or non-woven mat
US10117962B2 (en) * 2012-04-03 2018-11-06 Servico Group Oy Antipathogenic compositions
WO2014004746A2 (en) * 2012-06-26 2014-01-03 Harvard Bioscience, Inc. Methods and compositions for promoting the structural integrity of scaffolds for tissue engineering
WO2014043612A1 (en) * 2012-09-17 2014-03-20 Cornell University Carbonaceous metal/ceramic nanofibers
JP5948370B2 (ja) * 2013-08-08 2016-07-06 花王株式会社 ナノファイバ製造装置、ナノファイバの製造方法及びナノファイバ成型体
EP3031799B1 (en) * 2013-08-09 2018-04-04 Takeda Pharmaceutical Company Limited Aromatic compound
CN104056306B (zh) * 2014-06-09 2016-12-07 南京师范大学 具有拓扑结构的cnt/导电聚合物复合涂层修饰的神经导管材料及其制备方法
CN104225685B (zh) * 2014-09-18 2016-09-07 东华大学 一种导电缓释型神经组织工程支架的制备方法
KR102541705B1 (ko) * 2015-03-31 2023-06-12 신에쓰 가가꾸 고교 가부시끼가이샤 실리콘 변성 폴리유레테인계 섬유 및 그 제조 방법
US10131653B2 (en) * 2015-04-24 2018-11-20 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10632230B2 (en) * 2015-07-10 2020-04-28 Warsaw Orthopedic, Inc. Implants having a high drug load of an oxysterol and methods of use
JP6701896B2 (ja) * 2016-04-04 2020-05-27 信越化学工業株式会社 シリコーン変性ポリウレタン系繊維及びその製造方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003045461A1 (de) * 2001-11-23 2003-06-05 Feg Textiltechnik Forschungs- Und Entwicklungsgesellschaft Mbh Textiles erzeugnis mit oberflächenmodifikation und entsprechendes verfahren zur oberflächenmodifikation
CN104208754A (zh) * 2014-09-19 2014-12-17 北京大学口腔医院 一种压电活性骨修复复合材料及其制备方法
CN106751250A (zh) * 2017-01-12 2017-05-31 上海交通大学医学院附属新华医院 一种高分子压电复合材料及其制备方法和应用
CN107233625A (zh) * 2017-06-13 2017-10-10 北京大学口腔医学院 一种用于颅骨修补的防粘连带电复合膜及其制备方法
CN107261205A (zh) * 2017-06-13 2017-10-20 北京大学口腔医学院 一种带电防粘连组织修复膜及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115976741A (zh) * 2023-01-01 2023-04-18 长春理工大学 基于芴酮光开关型发光各向异性导电膜及其制备技术
CN116835980A (zh) * 2023-05-17 2023-10-03 合肥工业大学 铌酸钾钠纳米粉的制备方法、压电支架及其制备方法
CN116835980B (zh) * 2023-05-17 2024-05-31 合肥工业大学 铌酸钾钠纳米粉的制备方法、压电支架及其制备方法

Also Published As

Publication number Publication date
US20200261621A1 (en) 2020-08-20
US11141506B2 (en) 2021-10-12
CN108498868A (zh) 2018-09-07
CN108498868B (zh) 2020-09-15

Similar Documents

Publication Publication Date Title
WO2019192116A1 (zh) 具有细胞外基质电学拓扑特征的带电复合膜及其制备方法
CN106729980B (zh) 一种用于外周神经修复的仿生神经移植物及其制备方法
Nseir et al. Biodegradable scaffold fabricated of electrospun albumin fibers: mechanical and biological characterization
Hotaling et al. Nanofiber scaffold-based tissue-engineered retinal pigment epithelium to treat degenerative eye diseases
WO2018228018A1 (zh) 一种带电防粘连组织修复膜及其制备方法
US20060095137A1 (en) Nanofibrous nonwoven membrane of silk fibroin for guided bone tissue regeneration and manufacturing method thereof
Li et al. Culturing primary human osteoblasts on electrospun poly (lactic-co-glycolic acid) and poly (lactic-co-glycolic acid)/nanohydroxyapatite scaffolds for bone tissue engineering
CN112553785B (zh) 一种双层引导组织再生膜及其制备方法
CN109876186B (zh) 一种用于神经修复的生物医用可降解双层支架及其制备方法
WO2018228019A1 (zh) 一种用于颅骨修补的防粘连带电复合膜及其制备方法
CN106540327A (zh) 一种仿自然血管的三层人造血管支架及其制备方法
CN101507843A (zh) 多用途外科生物补片材料
Alamein et al. Mass production of nanofibrous extracellular matrix with controlled 3D morphology for large-scale soft tissue regeneration
CN110453378A (zh) 一种磺酸基量子点/丝素蛋白复合纳米纤维膜及其制备方法和应用
WO2019020039A1 (zh) 一种静电纺纤维改性复合膜及其制备方法
Huang et al. Tissue performance of bladder following stretched electrospun silk fibroin matrix and bladder acellular matrix implantation in a rabbit model
Flanagan et al. Development of a sutureless dural substitute from Bombyx mori silk fibroin
CN106390196A (zh) 一种纳米纤维神经组织工程支架的制备方法
Zhang et al. Electrospun piezoelectric scaffold with external mechanical stimulation for promoting regeneration of peripheral nerve injury
CN111823569A (zh) 一种基于丝素蛋白3d打印的生物支架及其制备方法和应用
CN109125782A (zh) 一种多孔纤维/无机生物材料颗粒复合型皮肤创面敷料及其制备方法
Dong et al. Electrospun nanofibrous membranes of recombinant human collagen type III promote cutaneous wound healing
CN110624133B (zh) 一种用于神经修复的神经基质导管及其制备方法
CN110975013A (zh) 一种复合神经导管及制备方法
Mohammadzadehmoghadam et al. Electrospinning of silk fibroin-based nanofibers and their applications in tissue engineering

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18913359

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18913359

Country of ref document: EP

Kind code of ref document: A1