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WO2023138593A1 - Endoprothèse antibactérienne ayant une structure à micro-nano-double couche, son procédé de préparation et son utilisation - Google Patents

Endoprothèse antibactérienne ayant une structure à micro-nano-double couche, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023138593A1
WO2023138593A1 PCT/CN2023/072758 CN2023072758W WO2023138593A1 WO 2023138593 A1 WO2023138593 A1 WO 2023138593A1 CN 2023072758 W CN2023072758 W CN 2023072758W WO 2023138593 A1 WO2023138593 A1 WO 2023138593A1
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nano
micro
antibacterial
polyhydroxyalkanoate
stent
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English (en)
Chinese (zh)
Inventor
孙玉春
陈国强
张旭
周永胜
王勇
陈凡凡
赵梓帆
翟文茹
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Peking University School of Stomatology
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Peking University School of Stomatology
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/045—Cobalt or cobalt alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • 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
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
    • 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
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • 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
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the invention relates to the technical field of oral medical products, in particular to a micro-nano double-layer structure antibacterial bracket and its preparation method and application.
  • Soft tissue augmentation is a standard procedure prior to implant surgery and prosthetic restorations, and was achieved by Friedman in 1957 in the membranous gingival procedure. This procedure maintains sufficient keratinized or attached gingival tissue to prevent further loss of gingival attachment.
  • Autologous tissue is the gold standard for traditional soft tissue augmentation procedures in terms of gingival width, thickness, aesthetics, and long-term stability.
  • the use of autologous tissue requires the opening of a second surgical site.
  • the amount of soft tissue available in the donor site is relatively limited.
  • the graft valve is prone to contraction and does not match the recipient site, and the incidence of complications (such as pain, bleeding, swelling, etc.) is high. Therefore, one of the biggest challenges of soft tissue augmentation technology is still the development of gingival tissue substitutes.
  • An ideal gingival tissue substitute should have good biocompatibility, antibacterial properties, mechanical stability, ease of operation, and synchronous biodegradation to achieve tissue regeneration.
  • biofilm products such as collagen matrix have high biocompatibility, their mechanical strength is low, the degradation rate is difficult to control, and the structure is easy to collapse, which has the risk of causing severe immunogenicity and inflammation.
  • nutrients for oral bacteria its components may also cause wound infection.
  • Synthetic polymer membranes have better mechanical properties, but have lower biocompatibility. The membrane often causes rejection in the body, affects the speed of soft tissue regeneration, and the repair effect is not ideal.
  • Polyhydroxyalkanoates (Polyhydroxyalkanoates, PHA) is a biological material synthesized by microorganisms. It mainly exists as a carbon source and energy storage substance in the organism. It has physical and chemical properties similar to synthetic polymer materials and excellent properties such as biodegradability and biocompatibility that synthetic polymer materials do not have.
  • PHA polylactic acid
  • PLGA poly(lactic-co-glycolic acid)
  • tissue engineering scaffolds prepared by PHA have achieved good results in the repair of bone, cartilage, heart valves, blood vessels, nerves and other tissues or organs.
  • polyhydroxyalkanoate as a biological material synthesized by microorganisms, is easily mixed with endotoxins of the special structure of the cell wall of PHA-producing Gram-negative bacteria, which has toxic effects on human cells.
  • endotoxins of the special structure of the cell wall of PHA-producing Gram-negative bacteria which has toxic effects on human cells.
  • antibacterial drugs such as drug resistance, low stability, low oral bioavailability and poor drug targeting, etc. Therefore, it is still a great challenge to prepare a functional and unique scaffold material for gingival tissue regeneration.
  • the invention provides a micro-nano double-layer structure antibacterial stent and its preparation method and application, which solves the technical problems in the existing soft tissue regeneration technology that the biological product film is prone to bacterial infection, low mechanical strength, low biocompatibility of the polymer film, easy to cause body rejection, poor stability of traditional antibacterial drugs, low oral bioavailability, and poor drug targeting.
  • the present invention provides the following technical solutions:
  • the invention provides a method for preparing an antimicrobial bracket with a micro-nano double-layer structure, comprising the following steps:
  • polyhydroxyalkanoate material is mixed with nanometer antibacterial drug, add organic solvent to dissolve, obtain polyhydroxyalkanoate solution;
  • the polyhydroxyalkanoate material is a detoxified and purified material; the polyhydroxyalkanoate material includes one or more of poly- ⁇ -hydroxybutyrate, poly(3-hydroxybutyrate-co-4-hydroxybutyrate), polyhydroxybutyrate valeric acid copolyester, polyhydroxybutyrate caproic acid copolyester, polyhydroxybutyrate undecanoic acid copolyester and polyhydroxydecanoic acid copolyester.
  • the nano-antibacterial drug includes one or more of nano-silver, nano-silicon dioxide, nano-zinc oxide, nano-cobalt, nano-selenium and nano-cadmium.
  • the organic solvent includes one or more of chloroform, dichloromethane and tetrahydrofuran.
  • the poor solvent for the polyhydroxyalkanoate material includes one or more of absolute ethanol, absolute methanol and acetone.
  • the mass ratio of the polyhydroxyalkanoate material to the nano antibacterial drug is 10:0.25-2.
  • the solution replacement time in step (2) is 5-8 hours.
  • the present invention also provides a micro-nano double-layer structure antibacterial support obtained by the above-mentioned preparation method.
  • the micro-nano double-layer structure antibacterial scaffold includes a micro-pore structure layer and a nano-pore structure layer; the nano-antibacterial drug is modified in the micro-pore structure layer.
  • the pore diameter of the micropores in the microporous structure layer is 1-10 ⁇ m; the pore diameter of the nanopores in the nanoporous structure layer is 200-800 nm; the thickness ratio of the microporous structure layer to the nanoporous structure layer is 6-8:1-3.
  • the present invention also provides an application of the antimicrobial bracket with micro-nano double-layer structure as preparation of oral soft tissue repair materials or medicines.
  • the present invention also provides a method for repairing the oral soft tissue of a subject, the method comprising embedding or exposing the antimicrobial scaffold with a micro-nano double-layer structure in the wound of the soft oral tissue of the subject.
  • the present invention also provides a method for promoting the adhesion and/or proliferation of gingival fibroblasts, the method comprising making gingival fibroblasts
  • the fiber cells are in contact with the antimicrobial scaffold with micro-nano double-layer structure.
  • the present invention also provides a method for inhibiting oral soft tissue bacterial infection of a subject, the method comprising embedding or exposing the antimicrobial stent with a micro-nano double-layer structure in the wound of the subject's oral soft tissue.
  • the antimicrobial bracket with a micro-nano double-layer structure is composed of a micro-pore structure layer and a nano-pore structure layer modified with nano-antibacterial drugs.
  • the microporous structure layer is a three-dimensional penetrating "large" pore structure with a pore size between 1 and 10 ⁇ m and a porosity of 60% to 90%. It is decorated with nanoparticles of antibacterial drugs and evenly distributed on its surface. It is used to guide soft tissue regeneration and resist the invasion of various bacteria on the wound in a complex oral environment.
  • the nanoporous structure layer is a relatively dense "small" pore structure with a pore size between 200 and 800nm, which acts as a mechanical barrier to prevent soft tissue from growing into hard tissue (bone tissue), while allowing the exchange and circulation of nutrients.
  • the micro-nano double-layer structure antibacterial scaffold provided by the present invention has good cytocompatibility and antibacterial property, can effectively promote the adhesion and proliferation of gingival fibroblasts and reduce wound bacterial infection, showing its great potential in oral soft tissue regeneration engineering.
  • the micro-nano double-layer structure antibacterial bracket provided by the invention can be used for rapid repair of large-area soft tissue defects, while protecting the soft tissue defect surface and allowing exposed use, which greatly increases the scope of use.
  • it can be used in the closure of extraction sockets for delayed implantation (after extracting teeth that meet the extraction indications and need for implantation, fill the extraction sockets with bone meal, and use the antibacterial scaffold of the present invention to seal the extraction sockets), and to widen the attached gingiva before complex restorations (long-term dentition defects tend to cause muscle fibers and ligaments to grow in, and the attached gingiva narrows.
  • Fig. 1 is the scanning electron microscope structural diagram of the microporous structure layer of the P34HB+0.5%ZnO antibacterial support of embodiment 1, scale bar 5 ⁇ m, magnification 5000 times;
  • Fig. 2 is the scanning electron microscope structural diagram of the nanoporous structure layer of the P34HB+0.5%ZnO antibacterial support of embodiment 1, scale bar 5 ⁇ m, magnification 5000 times;
  • Figures 3a-d are X-ray energy spectrum analysis diagrams of the P34HB+0.5%ZnO antibacterial stent of Example 1, with a scale of 2.5 ⁇ m, wherein Figure 3a is a microscopic distribution diagram of carbon, oxygen, and zinc on the antibacterial scaffold, Figure 3b is a microscopic distribution diagram of carbon elements on the antibacterial material, Figure 3c is a microscopic distribution diagram of oxygen elements on the antibacterial material, and Figure 3d is a microscopic distribution diagram of the zinc element on the antibacterial material;
  • Fig. 4 is the cell proliferation of human gingival fibroblasts in Example 2 cultured on different antibacterial supports for 1d, 4d, and 7d; in the results of each time, each group is Heal All collagen film, P34HB support, P34HB+0.5%ZnO antibacterial support, P34HB+1%ZnO antibacterial support;
  • Fig. 5 is the cell morphology diagram of human gingival fibroblasts cultured on different antibacterial supports for 24 hours in Example 2, Among them, the nucleus was stained blue by DAPI, and the cytoskeleton was stained red by rhodamine-phalloidin;
  • Fig. 6 is the morphological observation of the antibacterial stent implanted in the soft tissue defect of the palate of the rat in Example 3 for 1 week.
  • the invention provides a method for preparing an antimicrobial bracket with a micro-nano double-layer structure, comprising the following steps:
  • polyhydroxyalkanoate material is mixed with nanometer antibacterial drug, add organic solvent to dissolve, obtain polyhydroxyalkanoate solution;
  • the polyhydroxyalkanoate material is detoxified and purified before preparing the antimicrobial bracket with a micro-nano double-layer structure.
  • the detoxification preferably uses a Soxhlet extractor to extract and remove endotoxins in polyhydroxyalkanoate raw materials.
  • the loss rate of polyhydroxyalkanoate material was 40%. That is, 100 parts of detoxified polyhydroxyalkanoate material can obtain 60 parts of detoxified polyhydroxyalkanoate material.
  • the organic solvent used for extraction preferably includes one or more of chloroform, dichloromethane and tetrahydrofuran, more preferably chloroform.
  • the purification is preferably carried out by the following method:
  • the mass volume ratio of the detoxified polyhydroxyalkanoate material to chloroform is preferably 1g:5-15ml, more preferably 1g:8-12ml, even more preferably 1g:10ml.
  • the amount of absolute ethanol added is preferably added according to the volume ratio of chloroform to absolute ethanol of 1:6-10, more preferably added according to the volume ratio of 1:8.
  • the purification time is preferably 20-40 minutes, more preferably 30 minutes.
  • the method for separating the precipitated solid is preferably centrifugal separation.
  • the rotational speed of the centrifugal separation is preferably 5000-10000 rpm, more preferably 6000-9000 rpm, and even more preferably 8000 rpm.
  • the centrifugation time is preferably 10-15 minutes, more preferably 12 minutes.
  • the present invention mixes the polyhydroxyalkanoate material with nano antibacterial drugs, dissolves them with an organic solvent, and obtains a polyhydroxyalkanoate solution.
  • the polyhydroxyalkanoate material preferably includes one or more of poly- ⁇ -hydroxybutyrate (PHB), poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB), polyhydroxybutyrate valerate copolyester (PHBV), polyhydroxybutyrate hexanoate copolyester (PHBHHx), polyhydroxybutyrate undecanoate copolyester and polyhydroxydecanoate dodecanoate copolyester, more preferably poly(3-hydroxybutyrate-co-4-hydroxybutyrate) ( P34HB).
  • P34HB poly(3-hydroxybutyrate-co-4-hydroxybutyrate)
  • P34HB poly(3-hydroxybutyrate-co-4-hydroxybutyrate)
  • the nano-antibacterial drug preferably includes one or more of nano-silver, nano-silicon dioxide, nano-zinc oxide, nano-cobalt, nano-selenium and nano-cadmium, more preferably nano-zinc oxide.
  • the mass ratio of the polyhydroxyalkanoate material to the nano antibacterial drug is preferably 10:0.25-2, more preferably 10:0.5-1.5, and even more preferably 10:1.
  • the mass volume ratio of the nano antibacterial drug in the organic solvent is preferably 0.1%-1%, more preferably 0.5%.
  • the organic solvent preferably includes one or more of chloroform, dichloromethane and tetrahydrofuran, more preferably chloroform.
  • the polyhydroxyalkanoate material and the nano-antibacterial drug after adding the polyhydroxyalkanoate material and the nano-antibacterial drug into the organic solvent, it is preferably placed in an ultrasonic cleaner for ultrasonic mixing, so that the nano-antibacterial drug can be evenly distributed in the organic solvent.
  • the power of the ultrasonic cleaner is 30-50 kHz, more preferably 40 kHz.
  • the ultrasonic time is preferably 5-15 minutes, more preferably 10 minutes.
  • the polyhydroxyalkanoate solution is poured into a mold, and the mold filled with the polyhydroxyalkanoate solution is immersed in a poor solvent of the polyhydroxyalkanoate material for solution replacement to obtain a semi-solid stent.
  • the polyhydroxyalkanoate solution when the polyhydroxyalkanoate solution is poured into the mold, the polyhydroxyalkanoate solution is filled with the mold.
  • the mold is preferably a Corning cuvette.
  • the poor solvent of the polyhydroxyalkanoate material preferably includes one or more of absolute ethanol, absolute methanol and acetone, more preferably absolute ethanol.
  • the poor solvent described in the present invention is relative to the good solvent, and the so-called good solvent refers to a solvent with good solubility to a certain substance. Therefore, the poor solvent in the present invention refers to a solvent with poor solubility to polyhydroxyalkanoate materials.
  • the poor solvent when the polyhydroxyalkanoate solution is infiltrated with a poor solvent, the poor solvent needs to be poured into a larger container, preferably a glass dish (125mm ⁇ 65mm) of 500ml, so that the mold containing the polyhydroxyalkanoate solution is completely submerged by the poor solvent. It should be noted that it is best to completely immerse the mold containing the polyhydroxyalkanoate solution in the poor solvent during infiltration, and when putting it into the mold, it needs to be put in slowly to avoid disturbing the polyhydroxyalkanoate solution in the mold and destroying its solution composition and structure. The solution replacement starts immediately after putting it in.
  • the chloroform solution is slowly displaced by ethanol, leaving behind the polyhydroxyalkanoate material, which forms a porous structure.
  • the mold is the shape of the Corning small glass dish, the lower part is sealed and the upper part is open, so in the solution replacement During the process, a micro-nano double-layer structure with different micro-porous structures will be formed, the micro-porous structure layer is formed at the upper opening of the mold, and the nano-porous structure layer is formed as the lower sealing part.
  • the microporous structure layer is positioned at the opening of the upper part when the solution is replaced, because the speed of chloroform replacement is fast and the replacement amount is large, resulting in larger micropores after replacement, the microporous structure layer is formed, the pore diameter of the micropores is 1-10 ⁇ m, and the porosity can reach 60-90%.
  • the solution replacement time is preferably 5-8 hours, more preferably 6 hours. As the solution replacement proceeded, it could be observed with the naked eye that the clear and transparent polyhydroxyalkanoate solution gradually turned into a white semi-solid scaffold.
  • the solution when the solution is replaced, it is preferable to cover a layer of aluminum foil on the surface of the poor solvent container to avoid the solution from being polluted and excessively evaporated.
  • the semi-solid support is freeze-dried to obtain an antibacterial support with a micro-nano double-layer structure.
  • pre-freezing is performed before freeze-drying.
  • the pre-freezing temperature is preferably -120°C to -60°C, more preferably -100°C to -70°C, and even more preferably -80°C.
  • the pre-freezing time is preferably 15-45 minutes, more preferably 20-40 minutes, and even more preferably 30 minutes.
  • the freeze-drying is preferably carried out in a freeze dryer.
  • the temperature of the sample is set at 20-25°C, preferably 23°C or 25°C; the temperature of cold hydrazine is preferably -60°C--40°C, more preferably -50°C; the degree of vacuum is preferably 50-1000Pa, more preferably 50-100Pa, 100-200Pa or 200-800Pa, and still more preferably 100Pa or 600Pa; the time for freeze-drying is preferably 8-16h , more preferably 10 to 14h, still more preferably 12h.
  • the pre-cooling and freeze-drying treatment can remove ethanol in the scaffold through sublimation on the one hand, eliminate the toxic effect of ethanol on soft tissue cells, and on the other hand help to stabilize the structure of micropores and nanopores.
  • the present invention also provides an antimicrobial bracket with a micro-nano double-layer structure prepared by the above-mentioned preparation method.
  • the antimicrobial scaffold with micro-nano double-layer structure preferably includes a micro-pore structure layer and a nano-pore structure layer.
  • the nano antibacterial drug is preferably modified in the microporous structure layer.
  • the porous structure on the microporous structure layer increases the release surface and regulates the release rate of the nano-antibacterial drug.
  • the nano-antibacterial drug will be released continuously with the degradation of the membrane body, which is beneficial to resist bacterial invasion of the wound in a complex oral environment.
  • the pore size range of the micropores in the microporous structure layer is preferably between 1-10 ⁇ m; the pore size range of the nanopores in the nanoporous structure layer is preferably between 200-800 nm.
  • the thickness ratio of the microporous structure layer to the nanoporous structure layer is preferably 6-8:1-3, more preferably 7:3.
  • the present invention also provides a kind of antimicrobial support with micro-nano double-layer structure as the oral soft tissue repair material or pharmaceutical applications.
  • the medicament is preferably used to inhibit bacterial infections in the oral cavity, including but not limited to Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum.
  • the present invention also provides a method for repairing the oral soft tissue of a subject, the method comprising implanting the antimicrobial scaffold with a micro-nano double-layer structure into the wound of the soft oral tissue of the subject.
  • the method includes: cutting the antimicrobial scaffold with a micro-nano double-layer structure into a suitable size and shape, and implanting it into the wound of the oral soft tissue of the subject.
  • the nanoporous structure layer of the scaffold when implanting, is made to be close to the bottom layer of the defect, and sticks to the bone tissue below the wound to isolate the defective soft tissue from the underlying bone tissue, so that the microporous structure layer of the scaffold is in contact with the defective soft tissue, and the surface is exposed in the oral cavity without drawing and suturing.
  • the present invention also provides a method for promoting the adhesion and/or proliferation of gingival fibroblasts, the method comprising contacting the gingival fibroblasts with the micro-nano bilayer structure antibacterial scaffold.
  • the methods can be performed in vivo or in vitro in a subject, and can be used for therapeutic or non-therapeutic purposes (eg, research purposes).
  • the gingival fibroblasts are cells in a subject.
  • the gingival fibroblasts are cells that exist in vitro, eg, cells derived from a subject.
  • the present invention also provides a method for inhibiting oral soft tissue bacterial infection of a subject, the method comprising implanting the micro-nano bilayer structure antibacterial scaffold into or placing on the soft oral tissue of the subject.
  • the bacteria include but not limited to Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum.
  • the subject is preferably mammals, such as bovines, equines, porcines, canines, felines, rodents, primates, such as humans.
  • the PHA material used in this example is poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB), which was purchased from Beijing Weimogongchang Biotechnology Co., Ltd.
  • the nano-antibacterial drug used is nano-zinc oxide particles (diameter between 40nm and 100nm), purchased from Beijing Zhongjinyan New Material Technology Co., Ltd.
  • P34HB raw material 50g was extracted by Soxhlet extractor to remove endotoxin.
  • the extraction process is as follows: (1) Turn on the circulating water switch; (2) Set the program: use chloroform extraction and leaching at a temperature of 140°C, and the time is 3h and 2h respectively. After leaching, the chloroform volatilization time is 1h. Wait for the temperature of the material to drop to 40°C, take out the extraction cylinder, and completely volatilize the solvent to obtain 30g of P34HB crude extraction material, with a loss rate of 40%. Add 300ml of chloroform to 30g of P34HB crude extraction material, spin to dissolve, and filter the solution through double-layer gauze to filter out insoluble impurities.
  • the micro-nano double-layer structure antibacterial scaffold (P34HB+0.5% ZnO) of the present invention is prepared.
  • FIG. 1 and FIG. 2 The P34HB+0.5%ZnO antibacterial stent prepared in this example was scanned by a scanning electron microscope, and the scanning results are shown in FIG. 1 and FIG. 2 .
  • Figure 1 shows the microporous structure layer
  • Figure 2 shows the nanoporous structure layer. It can be seen from Fig. 1 and Fig. 2 that the antibacterial stent prepared in this embodiment has a double-layer structure, and the pore size and structure on the double-layer structure are different.
  • the pore structure of the nanoporous structure layer is denser, with a pore size between 200 and 800 nm, while the pore diameter of the microporous structure layer is between 1 and 10 ⁇ m, and the porosity can reach 60 to 90%.
  • X-ray energy spectrum analysis was performed on the P34HB+0.5%ZnO antibacterial stent prepared in this example, and the results are shown in Figure 3a, Figure 3b, Figure 3c, and Figure 3d.
  • the energy spectrum analysis diagram shows the microscopic distribution of carbon (red), oxygen (green), and zinc (blue) on the material.
  • the element distributions of oxygen (green) and zinc (blue) are basically recombined into cyan, indicating that the nano-zinc oxide particles have been successfully modified on the P34HB scaffold.
  • the P34HB+0.5% ZnO antibacterial support prepared in Example 1 was cut into a suitable circle according to the aperture size of the 96-well plate and placed in a 96-well plate. Incubate for 1, 4, and 7 days in a CO 2 incubator. And the P34HB material purified in Example 1 was used as a blank, and the antibacterial scaffold (P34HB+1%ZnO) with a nano-zinc oxide concentration of 1% prepared according to the method of Example 1 was used as a control to carry out the experiment. Three replicate wells were set up for each treatment and repeated three times.
  • the scaffolds of the four treatment groups were gently washed with PBS three times, and then 10 ⁇ L of CCK-8 solution (Dojindo, Japan) was added to 100 ⁇ L of DMEM medium, and incubated for 2 hours at 37 °C in the dark. Transfer the co-culture solution to a new 96-well plate, 100 ⁇ L per well. Then use a microplate reader (Multiskan FC, Thermofisher, the U.S.) to read the absorbance value of the mixed solution at a wavelength of 450nm, and the results are shown in Figure 4.
  • CCK-8 solution Dojindo, Japan
  • P34HB+0.5%ZnO antibacterial scaffold has the best cytocompatibility of human gingival fibroblasts, which is conducive to cell proliferation, and the cell proliferation rate of P34HB+0.5%ZnO antibacterial scaffold is higher than that of P34HB scaffold. , together with the porous structure of the scaffold, it can synergistically promote cell growth.
  • the P34HB+0.5% ZnO antibacterial scaffold prepared in Example 1 was cut into a suitable circle and placed in a 48 - well plate according to the aperture size of the 48-well plate. Incubate for 24 hours in a 5% CO 2 incubator. And the P34HB material purified in Example 1 was used as a blank, and the antibacterial scaffold (P34HB+1%ZnO) with a nano-zinc oxide concentration of 1% prepared according to the method of Example 1 was used as a control to carry out the experiment. Three replicate wells were set up for each treatment and repeated three times.
  • the scaffolds of the 4 treatment groups were gently washed with PBS three times, and then fixed with 4% paraformaldehyde at 4° C. for 30 minutes.
  • the cells were infiltrated with 0.3% Triton X-100 for 5 min, washed three times with PBS, and incubated with rhodamine-phalloidin (Yeason, China) for 30 min at room temperature to stain the cytoskeleton (red).
  • DAPI Invitrogen, USA was used to stain for 5 minutes to stain the nuclei (blue), and then observed under a confocal laser microscope. The observation results are shown in FIG. 5 .
  • the human gingival fibroblasts used in this example were obtained from the excess gingiva generated during the operation of healthy patients who underwent third molar extraction.
  • the experimental protocol for cell extraction was approved by the Biomedical Ethics Committee of Peking University Stomatological Hospital (Ethics Approval Number: PKUSSIRB-202058148).
  • Rats were anesthetized before implantation, and a 5.0 ⁇ 1.5mm 2 , 1.0mm deep full-thickness palatal mucosal defect was created in the center of each rat’s palatal mucosa with a No. 11 scalpel blade to expose the bone tissue. Then, each scaffold material was cut into a suitable size and shape with surgical sterile scissors, and implanted in the wound. When implanted, the nanoporous structure layer is close to the bottom layer of the defect, sticks to the bone tissue below the wound, and isolates the soft tissue of the defect from the bone tissue below.
  • Streptococcus mutans, Porphyromonas gingivalis and Fusobacterium nucleatum were applied in the mouth (in and around the defect) in each treatment group for 3 consecutive days.
  • All rats ate a standard diet (produced according to the American NIH-41 standard, crude protein ⁇ 18%, crude fat ⁇ 5%, crude fiber ⁇ 5%, crude ash ⁇ 8%) after the operation, and the rod-shaped feed was broken with a wall breaker, and the rats were allowed to eat and drink freely.
  • the rats were euthanized 7 days (1 week) after the formation of palatal wounds, and the implanted stents were removed to observe the wound healing. The result is shown in Figure 6.

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Abstract

La présente invention concerne une endoprothèse antibactérienne ayant une structure à micro-nano-double couche, son procédé de préparation et son utilisation, qui appartiennent au domaine technique des produits médicaux oraux. Le procédé de préparation de l'endoprothèse antibactérienne ayant une structure à micro-nano-double couche selon la présente invention comprend les étapes suivantes consistant à : (1) mélanger un matériau de polyhydroxyalcanoate avec un nano-médicament antibactérien, et dissoudre celui-ci au moyen de l'ajout d'un solvant organique de façon à obtenir une solution de polyhydroxyalcanoate ; (2) verser la solution de polyhydroxyalcanoate dans un moule, immerger le moule rempli de la solution de polyhydroxyalcanoate dans un mauvais solvant du matériau de polyhydroxyalcanoate, et effectuer un remplacement de solution pour obtenir une endoprothèse semi-solide ; et (3) lyophiliser l'endoprothèse semi-solide pour obtenir ensuite une endoprothèse antibactérienne ayant une structure à micro-nano-double couche. L'endoprothèse antibactérienne ayant une structure à micro-nano-double couche selon la présente invention présente une bonne compatibilité cellulaire et une bonne propriété antibactérienne, et peut favoriser efficacement l'adhérence et la prolifération de fibroblastes gingivaux et réduire l'infection bactérienne de plaies.
PCT/CN2023/072758 2022-01-21 2023-01-18 Endoprothèse antibactérienne ayant une structure à micro-nano-double couche, son procédé de préparation et son utilisation Ceased WO2023138593A1 (fr)

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