WO2012174837A1 - 具有层状结构的仿生骨修复支架体及制备方法 - Google Patents

具有层状结构的仿生骨修复支架体及制备方法 Download PDF

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Publication number
WO2012174837A1
WO2012174837A1 PCT/CN2011/084411 CN2011084411W WO2012174837A1 WO 2012174837 A1 WO2012174837 A1 WO 2012174837A1 CN 2011084411 W CN2011084411 W CN 2011084411W WO 2012174837 A1 WO2012174837 A1 WO 2012174837A1
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Prior art keywords
bone
sheet material
component
growth factor
stent body
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PCT/CN2011/084411
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English (en)
French (fr)
Inventor
李玉宝
左奕
江虹
张利
李吉东
邹琴
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四川大学
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Publication of WO2012174837A1 publication Critical patent/WO2012174837A1/zh

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    • 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
    • A61F2002/2835—Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
    • A61F2002/2839—Bone plugs or bone graft dowels
    • 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 a bionic bone repair scaffold having a layered structure and a preparation method thereof, which can be used for replacing and repairing defects of bone tissue in the field of biomedicine.
  • Bone tissue defects are common clinical diseases and can be caused by trauma, tumors, bone diseases and abnormal bone growth.
  • the development of high-performance clinical medical materials to replace and repair bone defect has long been a major topic in biomaterial research.
  • the ideal bone repair material should have similar biological characteristics to natural bone, including: (1) Biocompatibility: no cytotoxicity and inflammatory reaction, which is conducive to cell adhesion and proliferation; (2) Biomechanical properties: certain The mechanical strength can provide mechanical support for the new tissue; (3) Three-dimensional porous structure: The material should have a three-dimensional porous structure, and the pore size should allow cell adhesion growth and vascular and nerve growth, and the pores should be mutually connected. In order to facilitate the transfer of nutrients and the discharge of cellular metabolic waste.
  • the materials currently used for bone repair are mainly integrally formed block porous supports, which are characterized by various techniques for making holes during the forming process of the material.
  • the more common methods of pore making include gas foaming, solution casting/particle leaching, phase separation/emulsification, melt molding, fiber bonding, freeze drying, and the like.
  • the publication of the publication No. CN1765423A proposes a method for preparing a bioactive porous scaffold, which utilizes the principle that the surfactant can stabilize the bubbles, and enables the porous material to have a controlled porosity and good pore penetration.
  • due to the limitations of the material structure of the bulk porous scaffold in order to achieve better pore penetration, it is necessary to sacrifice the mechanical strength of the material.
  • the porous structure of the scaffold can easily collapse and deform, which will affect the bone tissue repair effect.
  • WO 2008/082766 A2 proposes an intervertebral disc repair stent and a cartilage joint repair stent constructed with a nested closed loop structure as a base unit, with a torus as an external structure and a central portion with a specific microstructure or hydrogel.
  • the nucleus pulposus The osteochondral scaffold comprises a bone portion connected to the interface of the cartilage portion, the bone portion being connected to the opening of the recipient bone by a fixation device.
  • the stent body can provide sufficient and effective mechanical properties for bone repair. And during use, it does not cause replacement failure due to movement or even falling off between the annular structures. This design defect therefore has fatal damage to the scaffold material used for bone or cartilage repair and is not suitable for clinical applications.
  • a more ideal bone repair scaffold in clinical application should at least provide the clinically required mechanical support to maintain good structural stability even during material degradation, supporting the growth of new tissue until it has its own Biomechanical properties, and further can have a three-dimensional porous network structure, maintaining a high degree of pore penetration, which is conducive to the completion of bone tissue repair and functional reconstruction.
  • the present invention first provides a bionic bone repair stent body having a layered structure, which can have a more desirable effect in replacing and repairing bone tissue defects.
  • the invention further provides a method of preparing the bone repair stent body.
  • the bionic bone repairing stent body having a layered structure of the present invention is composed of at least one stent unit body.
  • the bracket unit body is a column structure in which a sheet material is continuously tightly wrapped from the inside to the outside and has a spiral cross section.
  • the diameter of the bracket unit body is 0.1 mm to 50 mm.
  • the stent unit body is a monolithic structure in which the sheet material is continuously tightly wrapped from the inside to the outside, there is a Harvard system similar to the natural bone (between the natural long bone inner ring layer and the outer ring bone layer layer)
  • the distributed longitudinally arranged bone unit has a high biomimetic effect, which can well achieve the mechanical transmission between the defect site and the normal bone tissue, and the layered structure will not move or fall off during use, even after degradation.
  • the structure can also maintain good structural stability, complete the repair and functional reconstruction of bone tissue.
  • by controlling the thickness, and/or height of the sheet material, and/or the number of layers of the wrap it is also possible to flexibly adjust the three-dimensional size of the bone repairing support body to meet different practical needs and to be plastic.
  • the above-mentioned cylindrical structure form unit body has a diameter of 0.1 mm to 50 mm, which can be adapted to more usage modes and has a wider application range.
  • the preferred thickness of the sheet material for constituting the stent unit body is 0.01 mm to 1 mm.
  • the above-mentioned sheet material which can be used for constituting the above-mentioned stent unit body, and a through-hole having a pore diameter of 50 ⁇ m to 800 ⁇ m is dispersed in the extending surface thereof in a better manner. More preferably, the porosity of the through-pores of the dispersed distribution is such that it accounts for 70% to 95% of the volume of the sheet material. Since the bracket unit body is continuously tightly wrapped from the inner layer and the outer side by the sheet material, the through pores distributed on the sheet material can be formed to penetrate each other in the structure after being wound to form the bracket unit body.
  • the special form of network structure can contribute to cell adhesion growth and the growth of blood vessels and nerves, as well as the transfer of nutrients and the discharge of cellular metabolic waste, which is conducive to the promotion of bone tissue repair at the site of use of the repair stent.
  • Reconstruction function reconstruction can contribute to cell adhesion growth and the growth of blood vessels and nerves, as well as the transfer of nutrients and the discharge of cellular metabolic waste, which is conducive to the promotion of bone tissue repair at the site of use of the repair stent.
  • the sheet material constituting the stent unit body as described above is generally a medical material acceptable to the living body, and includes various medical materials which are degradable or non-degradable in the living body. However, at least materials whose surface layer is degradable are preferred.
  • the sheet material may be coated on the surface of a structure composed of a non-degradable medical polymer, a non-degradable medical metal or metal alloy, a non-degradable bioceramic, or a non-degradable biocomposite.
  • the layer can increase the biocompatibility and osteoconductivity of the bone repair material, which is beneficial to the fixation and ingrowth of the tissue.
  • the sheet material is directly embedded from, for example, polyester, polyurethane, polyamide, polyanhydride, polyphosphazene, polyamino acid, polyhydroxyalkanoate, amide-ester.
  • Segment copolymers genetically engineered proteins, conductive and plastic protein-based polymers, natural or semi-synthetic polysaccharide-based composite polymers such as starch-based, cellulose-based and lignin composite polymers, and inorganic high-polymer polyphosphoric acid Biodegradable biopolymer components; biodegradable medical metals such as medical magnesium-based alloys and iron or alloys thereof; such as calcium carbonate biodegradable ceramics, degradable calcium phosphate bioceramics, calcium silicate biodegradable ceramics, degradable calcium Biodegradable bioceramics such as phosphorus bioglass ceramics; or composed of composite components of these different components, such as inorganic active apatite/polyester degradable composites, surface
  • biodegradable material When it is selected as a biodegradable material, it can be used in the form of a single biodegradable component, especially in the form of a composite component composed of at least two biodegradable polymers, degradable metals or metal alloys.
  • a composite component composed of at least two biodegradable polymers, degradable metals or metal alloys.
  • degradable metal or metal alloy used Preferably, to facilitate the selection and adjustment of the type and/or proportion of the biodegradable polymer, degradable metal or metal alloy used, according to different use sites and/or needs, to achieve the desired and suitable optimal degradation. Rate effect.
  • the material of the stent unit body layer can be selected and adjusted according to the type and/or proportion of the biodegradable component. Further, a fiber component having a diameter of 10 ⁇ to 100 ⁇ may be further dispersed therein. In such a mixed or composite composition, the ultrafine or conventional fibrous material can enhance the mechanical properties of the bone repairing stent body.
  • the ultrafine fiber or ordinary fiber component may be a natural fiber, or may be prepared by a process of electrospinning, composite spinning, blend spinning, flash spinning, etc., using a degraded or non-degraded biopolymer component as a raw material. At least one of the artificial fibers.
  • cellulose fibers ie, plant fibers
  • natural cellulose fibers such as cotton, ramie, linen, etc.
  • natural regenerated fibers including cotton, ramie, linen, etc.
  • Plain fiber such as viscose fiber, bamboo fiber, cellulose acetate fiber, etc., and regenerated cellulose modified fiber such as methyl cellulose fiber (the fiber has good toughness, long degradation cycle), protein fiber (such as wool, silk) , peanut protein and soy protein fiber, such fibers have good ductility, short degradation cycle), polylactic acid fiber, polycaprolactone fiber, polyamide fiber, polypropylene fiber and other synthetic polymer fiber (the mechanical properties and degradation
  • the cycle can be designed to regulate and control a variety of fiber components. Experiments have shown that the content of the ultrafine or ordinary fiber component can be usually from 1% to 60%, preferably from 5% to 20% by weight based on the total weight of the sheet material.
  • the use of a sheet material in the form of a combination of the biopolymer component and the nano-bone apatite component is another preferred mode of the above-mentioned bone repairing stent unit body sheet material.
  • the nano-bone apatite crystal composition not only enhances the mechanical properties of the bone-repairing scaffold, but also contains calcium and phosphorus components for bone tissue repair and regeneration.
  • the proportion of the nano-bone apatite component can be from 1% to 80% of the total weight of the sheet material, and a further preferred ratio is from 40% to 60% of the total weight of the sheet material.
  • the molar ratio of the nano-bone apatite component is preferably 1.2 to 2.0: 1 which is close to or similar to the ratio of natural bone tissue.
  • the better choice of the nano-bone apatite component is the nano-apatite needle crystal, rod crystal or platelet crystal prepared by chemically reacting the calcium salt compound with phosphoric acid or phosphate. ingredient.
  • the preparation method can be referred to, for example, ZL02133949.X, and Li Yubao, J. de Wijn, CPAT Klein, Svd Meer and K. de Groot, Preparation and Characterization of Nanograde Osteoapatite-like Rod Crystals, J. Mater.
  • the pharmaceutical composition and/or tissue growth factor may also be contained in the material for constituting the bone repair scaffold unit body layer, which is 0.05% to 20%, preferably 0.05% to 5%, based on the total weight thereof. It is also a further preferable one.
  • the pharmaceutical composition may include at least one of antibiotics, cephalosporins, ⁇ -lactams, aminoglycosides, fluoroquinolones, notoginseng, scorpion, and scutellaria commonly used in bone tissue repair and rehabilitation.
  • the tissue growth factor comprises at least one of bone morphogenetic protein, transforming growth factor- ⁇ , fibroblast growth factor, erythropoietin, thrombopoietin, and platelet-derived growth factor.
  • these same or different types of pharmaceutical ingredients and/or tissue growth factors may be used in a single manner or in combination.
  • the bone repairing stent unit body is wrapped by a biodegradable material sheet material, the bone repairing stent can also have a slow release of these drug components and/or tissue growth factors and induce tissue regeneration. Release carrier or as a tissue engineering scaffold is more beneficial and promotes bone tissue repair, and has broad application prospects in the biomedical field.
  • the bracket unit body formed by continuously and tightly wrapping the sheet material from the inside to the outside may be a sheet in the form of a single layer.
  • the layer material is tightly wrapped, and may also be wrapped by a sheet material of two or more layers in a plane stack.
  • a preferred method is to use a sheet material containing different compositions, for example, a biodegradable polymer in various forms, a degradable metal. Or a composite component of a metal alloy, or one or more of the above biodegradable components, respectively, with a microfiber or a common fiber component, a nano-bone apatite component, and/or a pharmaceutical ingredient, and/or a tissue growth factor, etc.
  • the composite component or the above-mentioned sheet material in the form of a composite component of one or more degradable metal or metal alloy components and a pharmaceutical ingredient and/or tissue growth factor, is tightly wrapped in a planar stack.
  • the individual needs to better adapt to different repair objects can be adjusted, and the stent body implanted in the living body can be adjusted in different repair stages. Functional and / or degradation rate purposes.
  • the bone repairing stent body of the present invention may be directly constituted by the single stent body unit of the above various forms, or may be a parallel method in which two or more of the stent structural monomers are parallel in the longitudinal direction thereof.
  • the form of the combined structure that is tightly fixed to each other depends on the needs of clinical use.
  • the basic method for preparing the bionic bone repairing stent body according to the present invention is to form a sheet material made of the above-mentioned appropriate components or materials, and the extending surface thereof is spirally and continuously wrapped tightly from the inside to the outside to a diameter of 0.1 mm to 50 mm. After wrapping the structure, the end of the extended surface is wrapped around the edge to be fixed to the surface of the wrapped structure by bonding or the like, that is, the support unit body is obtained.
  • the single bracket unit body or two or more of the bracket unit bodies are closely adhered to each other in parallel in the longitudinal direction thereof to form an integrated structure having a sufficient joint strength, that is, Become the so-called bone repair stent body.
  • the sheet material may be a biopolymer material as described above, or a bioceramic, or a medical metal or alloy material, or a composite material of these materials, particularly a sheet material having a thickness of preferably 0.01 mm to 1 mm. .
  • CN101391113A polyurethane medical composite film and preparation method
  • CN1488407A a composite film preparation for guiding tissue regeneration.
  • Method CN1107742A (tissue guided regeneration collagen membrane), CN101516292A (implant composed of biodegradable metal and manufacturing method thereof), CN1626702 (preparation method of bioceramic membrane), CN101054708A (Preparation of hydroxyphosphorus by plasma micro-arc oxidation method) The method of gray stone bioceramic film) and the related methods have been reported/used.
  • a degradable/bioactive coating plasma spray method, thermochemical method, electrodeposition method, sol-gel method, etc., which have been reported and/or used, may be employed in the organism.
  • the surface of a base material of a degradable or non-degradable sheet material such as a polymer material or a medical metal or an alloy material thereof is coated with a bone-inducing coating containing a calcium compound such as hydroxyapatite, tricalcium phosphate, and octacalcium phosphate. And other calcium-containing compounds or mixtures thereof.
  • CN1443871A manufactured method of ceramic coating
  • CN102059209A hydroxyapatite coating method on titanium implant surface
  • CN102030915A a polyimide film surface modified nano hydroxyphosphorus
  • the sheet material is prepared by using the biopolymer material as a raw material
  • the non-dissolved state in which the total mass of the film-forming component is 1% to 60% is further mixed in the solvent dispersion system of the film-forming raw material in a uniform dispersion manner.
  • the ultrafine fiber or the ordinary fiber component or at least one of the nano-bone apatite crystal components which are 1% to 80% of the total mass of the film-forming component.
  • a sheet material containing a microfiber or ordinary fiber component and/or a nano-bone apatite crystal component in the structure can be obtained.
  • the ultrafine fiber or ordinary fiber component is at least one of natural fibers or artificial fibers having a diameter of 10 ⁇ to 100 ⁇ .
  • the nano-bone apatite crystal component is a nano-apatite needle crystal, rod crystal or platelet crystal obtained by reacting a calcium salt compound with phosphoric acid or phosphate.
  • the specific preparation method can be referred to Li Yubao et al. Mater. Sci: Mater, in Med.)), 1994, 5: 326-331 or ((Biomaterials)), 1994, 15: 835-841 and other reports.
  • the through pores obtained to obtain a dispersed distribution in the expanded surface of the sheet material may be treated by mechanical perforation according to the desired pore size and/or distribution porosity after the sheet material is formed, in particular
  • a preferred method is in the preparation process by particle leaching, gas foaming, investment casting, electrodeposition, or the like. Through-holes having a diameter of 50 ⁇ m to 800 ⁇ m are formed on the stretched surface.
  • the particle leaching agent when prepared by particle leaching, may have a particle size of 50 ⁇ to 800 ⁇ , and the amount is 40% to 80% of the total mass of the solvent dispersion of the molding material.
  • the particle leaching agent to be used may be at least one of usual sodium chloride particles, potassium chloride particles, glucose particles, magnesium sulfate particles, silicon carbide particles, manganese dioxide particles, alumina particles and the like.
  • the amount of the gas foaming agent can generally be 1% to 10% of the total mass of the solvent dispersion system of the molding material, and the gas foaming agent can be selected from commonly used dodecane.
  • the gas foaming agent can be selected from commonly used dodecane.
  • the sponge pore model can be firstly made from the high melting point liquid material, then the liquid metal is poured into the mold to be cooled and solidified, and then the high melting point material is removed, and finally the porous metal material is obtained.
  • the high melting point material may generally be selected from a mixture such as a phenol resin, mullite, calcium carbonate or gypsum.
  • the polymer material can be first formed into a high-porosity three-dimensional network structure, and a metal layer is plated on the surface of the polymer skeleton by electroplating, and then the internal polymer material is removed by calcination. Porous metal material.
  • a foamed plastic such as polyurethane, epoxy resin, polystyrene or polyvinyl chloride can be generally selected.
  • CN1200043C composite bioactive porous material in the form of nano-hydroxyapatite/medical polyamide 66 and preparation method
  • CN1225290C nano-hydroxyapatite/medical polyamide component composite tissue engineering scaffold material
  • CN1230210C polyamide/nano Method for preparing hydroxyapatite series biomedical composite material
  • CN1887365A biomaterial film with porous structure and preparation method thereof
  • CN1911457A composite nano hydroxyapatite/medical polymer material tissue engineering scaffold material and preparation method thereof
  • CN1765423A Preparation method of nano-apatite/medical polymer component bioactive porous scaffold material
  • CN1460526A porous bone restoration of hydroxyapatite/medical polyamide component
  • CN101721921A a porous metal film
  • a drug component and/or a tissue growth factor which is 0.05% to 20% of the total mass of the film-forming component in a uniform dispersion manner can be obtained.
  • the structure is also loaded with a bone repair scaffold in the form of a desired pharmaceutical ingredient and/or tissue growth factor.
  • the pharmaceutical composition includes at least one of an antibiotic, a cephalosporin, a ⁇ -lactam, an aminoglycoside, a fluoroquinolone, a notoginseng, a sputum, and a scutellaria; the tissue growth factor includes bone formation.
  • Protein, transforming growth factor-beta, fibroblast growth factor, erythropoiesis At least one of a hormone, a thrombopoietin, and a platelet-derived growth factor.
  • the target product of the stent body obtained by wrapping and fixing the sheet material containing no the pharmaceutical ingredient and/or tissue growth factor may be immersed in the drug component and/or In the solution of the tissue growth factor, the scaffold structure is loaded with a pharmaceutical ingredient and/or tissue growth factor in an amount of 0.05% to 20% by weight.
  • CN1911457A composite nano-hydroxyapatite/medical polymer material tissue engineering scaffold material and preparation method
  • CN101214228A can be used for loading drugs
  • Water-soluble chitosan microspheres and preparation methods thereof Water-soluble chitosan microspheres and preparation methods thereof
  • the sheet material of the above-mentioned form is continuously wound tightly from the inside to the outside in a manner of two or more layers in a planar manner, and the cylindrical structure is spirally wound into a cylindrical structure having a cross section.
  • Said bracket unit body The composite structure in which the single bracket body unit or at least two of the bracket structure monomers are closely fixed in parallel in the longitudinal direction thereof is the bracket structure of the present invention.
  • the structure of natural bone is precisely this anisotropic orientation structure, and thus has the structure of the best mechanical and material advantages.
  • the above-mentioned bone repairing bracket body in the form of a multi-layer cylindrical structure in which the sheet material is spirally tightly wrapped from the inside to the outside is designed based on this principle, and has a simulation degree with the height of the natural bone Harvard system.
  • the oriented three-dimensional network structure can well realize the mechanical transmission between the defect site and the normal bone tissue.
  • the repair stent body can provide a certain mechanical support for the bone defect site, and form a suitable bone bond with the bone tissue under the force stimulation.
  • this special network structure can ensure the pore penetration, facilitate cell adhesion growth and the growth of blood vessels and nerves, and facilitate the transfer of nutrients and the discharge of cellular metabolic waste.
  • the stent is composed of a degradable material
  • the structure can form a strong biological fit with the new bone tissue, and can maintain good structural stability during the degradation process.
  • the degradation products have no toxic side effects and can be excreted with the body's natural physiological metabolism.
  • the repair and functional reconstruction of bone tissue, while the bone repair is completed, the scaffold material can degrade itself, and its degradation products have no toxic side effects and high biosafety.
  • the biomimetic structure degradable bone repairing stent body of the invention has good repairing ability, and the mechanical properties of the membrane wound structure repairing stent body of the invention are significantly superior to those of the prior art.
  • the preparation method of the repairing stent body of the invention is simple, the condition is mild and easy to control, and has the characteristics of strong plasticity. According to the needs of clinical use, the size of the bone repairing stent body can be controlled by controlling the thickness of the sheet material and/or The height, and the number of layers of the wrap, are adjusted flexibly and conveniently. Therefore, the biomimetic structure degradable bone repair scaffold of the present invention has an ideal promotion and application value in the field of biomedical materials.
  • FIG. 1 is a schematic view showing the structure of a monolithic material constituting a unit body of a bone repairing stent of the present invention.
  • Fig. 2 is a schematic view showing the unit body of the bone repairing stent wrapped by the sheet material shown in Fig. 1.
  • Fig. 3 is a schematic view showing the structure of a composite structural body bone repairing stent body composed of a plurality of stent unit bodies shown in Fig. 2.
  • Figure 4 is a schematic illustration of a planar stacked multi-ply material constituting a bone repair stent unit body.
  • Figure 5 is a schematic illustration of a bone repair stent unit body wrapped by a planar stacked multi-ply material as shown in Figure 4.
  • Fig. 6 is a schematic view showing the structure of a composite structural body bone repairing stent body composed of a plurality of stent unit bodies shown in Fig. 5.
  • Figure 8 Schematic diagram of the procedure: (a) normal rabbit ulna and humerus, (b) defect in the middle of the tibia (length lcm, height 3mm) and placed in the material, (c) use surgical suture to fix the material.
  • Figure 10 Yield strength of the PA66/HA (40 % HA) composite compression test: (a) porous monolithic stent, (b) porous membrane coil stent.
  • the chitosan porous support unit body 4 having a spirally wound cylindrical structure is obtained, as shown in Fig. 2.
  • the pores 3 are interpenetrated.
  • the average pore diameter is 250.4 ⁇ , and the porosity is 79%.
  • the stent unit body 4 can be used alone as a bone repairing stent body.
  • the spiral wound wrapping in the embodiment of the present invention refers to continuously compressing the laminated film material from the inside to the outside. Wrap it into a cylindrical structure with a spiral cross section.
  • polycaprolactone 2 g was dissolved in 50 mL of dimethyl sulfoxide, and 50 g of 40 to 60 mesh NaCl particles were added, and the salt particles were uniformly stirred to form a viscous film-forming liquid.
  • the film-forming liquid was poured into a glass dish, spread horizontally into a sheet shape, and dried under vacuum at 50 °C.
  • the granules were repeatedly immersed in distilled water to remove the NaCl particles in the film to obtain a porous polycaprolactone film material 2 having a thickness of 0.21 mm in a wet state.
  • the film is cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is etched with a small amount of dimethyl sulfoxide to adhere to the spirally wound cylinder. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • the polycaprolactone porous support unit body 4 having a spirally wound cylindrical structure was obtained, and the pores 3 were interpenetrated with an average pore diameter of 223.1 ⁇ and a porosity of 65%.
  • the stent unit body 4 can be used alone as a bone repair stent.
  • polyamide 66 Under the catalysis of calcium chloride, 10 g of polyamide 66 was dissolved in a 100 mL absolute ethanol solution at 70 ° C to 80 ° C, and thoroughly stirred to form a viscous film-forming liquid. After cooling to room temperature, the film-forming liquid was poured into a glass dish, spread horizontally into a sheet shape, and dried at 60 ° C to a thickness of 0.15 mm. The mixture was repeatedly immersed in distilled water, washed, and dried at 70 ° C to obtain a porous polyamide 66 membrane material 2.
  • the film is cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is etched with a small amount of a solution containing calcium chloride in ethanol and adhered to the spirally wound cylinder. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a polyamide 66 porous support unit body 4 having a spirally wound cylindrical structure is obtained, and between the pores 3 Interpenetrating, the average pore diameter is 68.0 ⁇ , and the porosity is 81%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the titanium powder and the ammonium bicarbonate powder having a particle diameter of 200 ⁇ m to 600 ⁇ m are thoroughly mixed and placed in a mold, and then taken out under a pressure of 100 MPa for 2 to 3 minutes, and then the pressed sample is placed in a high temperature diffusion furnace, and protected by hydrogen. Sintering was carried out in an atmosphere, and the heating rate was 100 ° C / h, 200 ° C for 5 h, and 1200 ° C for 2 h. The furnace was cooled to room temperature to obtain a porous titanium film having a wall thickness of 0.31 mm.
  • the film is cut into a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is fixed on the spirally wound cylindrical body by external physical force, and is taken out after sintering at 850 ° C for 30 minutes to obtain a spirally wound cylindrical body structure.
  • the metal titanium porous support unit body 4 has pores 3 interpenetrating with an average pore diameter of 326.2 ⁇ m and a porosity of 77%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the magnesium powder and the urea powder with the particle size of 200 ⁇ 400 ⁇ are thoroughly mixed into the mold, and then taken out under the pressure of 100 MPa for 2 ⁇ 3 min, and then the pressed sample is placed in a high temperature diffusion furnace in a hydrogen atmosphere. Sintering was carried out, the heating rate was 100 ° C / h, the temperature was kept at 200 ° C for 5 h, and the temperature was kept at 500 ° C for 2 h. The furnace was cooled to room temperature to obtain a porous titanium film having a thickness of 0.2 mm.
  • the film is cut into a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is fixed on the spirally wound cylindrical body by external physical force, and is taken out after sintering at 600 ° C for 30 minutes to obtain a spirally wound cylindrical body structure.
  • the metal magnesium porous support unit body 4 has pores 3 interpenetrating with an average pore diameter of 200.6 ⁇ m and a porosity of 63%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • a molten magnesium alloy (Mg-9 wt% Al-1 wt% Zn-0.2 wt% Mn) was injected into a gypsum mold having a through-hole structure at 600 ° C under vacuum to sufficiently infiltrate the magnesium liquid into the gypsum mold.
  • the plaster mold is sprayed with water to rupture the plaster mold, and sufficiently washed to obtain a porous magnesium alloy film having a thickness of 0.14 mm.
  • the film is cut into a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is fixed on the spirally wound cylindrical body by external physical force, and is taken out after sintering at 600 ° C for 30 minutes to obtain a spirally wound cylindrical body structure.
  • the magnesium alloy porous support unit body 4 has pores 3 interpenetrating with an average pore diameter of 287.3 ⁇ and a porosity of 65%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • a porous titanium film prepared in the same manner as in Example 4 was used as an anode, and stainless steel was used as a cathode, which was immersed in a solution containing sodium hexametaphosphate (100 g/L) and calcium nitrate (10 g/L) in a pH of 12.
  • alternating current 600V, frequency 1500Hz, duty cycle 20%, current density 1200mA/cm 2 , micro-arc oxidation for 10min under the condition of 40cm pole distance forming a layer with thickness of about 70 ⁇ on the surface of porous titanium film.
  • X-ray diffraction analysis showed that the layer was composed of titanium dioxide and CaTi 4 (P0 4 )6 hydroxyapatite and had good biological activity.
  • the thickness of the film was 0.43 mm.
  • the porous titanium film with the bioactive coating is cut into a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is fixed on the spirally wound cylindrical body by external physical force, and is taken out after sintering at 850 ° C for 30 minutes.
  • a metal titanium porous support unit body 4 having a spirally wound cylindrical structure with a bioactive coating was obtained, and the pores 3 were interpenetrated with an average pore diameter of 226.3 ⁇ m and a porosity of 78%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the lg chitosan was dissolved in 80 mL of a 1 vol% acetic acid solution, and the mixture was thoroughly stirred to completely dissolve and uniformly disperse the chitosan.
  • 100 mg of MgS0 4 was added to 20 mL of a 1 vol% acetic acid solution, and dissolved by stirring. Continuous mixing Next, the above MgS0 4 solution was slowly added to the above chitosan solution, and the pH was adjusted to 5.5 with 5% NaOH, and reacted for 3 hours. .
  • the chitosan magnesium gel solution was cast into a glass dish and dried at room temperature.
  • a chitosan-magnesium composite film having a film thickness of 0.10 mm in a wet state.
  • the obtained chitosan-magnesium membrane material 2 was sufficiently hydrated and swollen, and was perforated by a mechanical pore-forming method with a pore pitch of 1.5 mm and a pore size of about 200 ⁇ m.
  • the perforated film was cut to a suitable size, tightly wrapped in a spiral, and the edge portion was etched with a small amount of 2 vol% acetic acid solution and bonded to the spirally wound cylinder.
  • Example 9 A chitosan-magnesium porous scaffold unit 4 having a spirally wound cylindrical structure was obtained, and the pores 3 were interpenetrated with a pore size of about 200 ⁇ m and a porosity of 90%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • chitosan and 0.4 g of sodium carboxymethylcellulose were added to 50 mL of deionized water, and the mixture was thoroughly stirred to completely dissolve sodium carboxymethylcellulose, and the chitosan was uniformly dispersed in the solution.
  • 20 mL of a 2 vol% acetic acid solution was gradually added dropwise to the original solution.
  • the viscous film-forming liquid was quickly poured into a glass dish, spread horizontally into a film shape, and dried at 60 ° C. The thickness of the film under wet state was 0.24 mm.
  • the solution was neutralized with a 1% NaOH solution to neutralize the residual acetic acid in the membrane, washed thoroughly with distilled water, and then air-dried.
  • the obtained chitosan/carboxymethyl cellulose sodium membrane material 2 was sufficiently swelled by water absorption and perforated by a mechanical pore method with a pore spacing of 2.0 mm and a pore size of about 350 ⁇ m.
  • the perforated film was cut to a suitable size, tightly wrapped in a spiral, and the edge portion was etched with a small amount of 2 vol% acetic acid solution to adhere to the spirally wound cylinder. After cooling, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a chitosan/carboxymethylcellulose sodium porous scaffold unit 4 having a spirally wound cylindrical structure was obtained, and the pores 3 were interpenetrated with a pore size of about 350 ⁇ m and a porosity of 85%.
  • the stent unit body 4 can be used alone as a bone repair stent.
  • the lg chitosan was dissolved in 50 mL of a 2 vol% acetic acid solution, and the mixture was thoroughly stirred to completely dissolve the chitosan and uniformly disperse.
  • Add 50 mL of collagen swelling solution to the acetic acid solution of chitosan (the preparation of collagen solution can be referred to the literature "Journal of Biomedical Engineering” 1999: 16 (2): 147-150 Wu Zhigu, Sheng Zhiyong, etc. ), stir well, dissolve the collagen swelling solution in the chitosan solution and mix well.
  • the resulting film was sufficiently swelled by water absorption, cut into a suitable size, tightly wound up, and the end edge portion 1 was etched with a small amount of a 2 vol% acetic acid solution, and bonded to the spirally wound cylindrical body. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a chitosan/collagen porous scaffold unit 4 having a spirally wound cylindrical structure was obtained, in which the pores 3 were interpenetrated with an average pore diameter of 200.5 ⁇ m and a porosity of 93%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the film-forming liquid was poured into a glass dish, spread horizontally into a sheet shape, and dried under vacuum at 50 ° C, and the film thickness in the wet state was 0.23 mm.
  • the granules were removed by repeated soaking and washing with distilled water to remove the NaCl particles in the film to obtain a porous polylactic acid/nano-apatite film material 2.
  • the film was cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 was etched with a small amount of dimethyl sulfoxide to adhere to the spirally wound cylinder.
  • a polylactic acid/nano-apatite porous support unit body 4 having a spirally wound cylindrical structure was obtained, and the pores 3 were interpenetrated with an average pore diameter of 225.2 ⁇ m and a porosity of 82%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • chitosan 1.5 g was dissolved in 50 mL of a 2 vol% acetic acid solution, and the mixture was thoroughly stirred to completely dissolve and uniformly disperse the chitosan. Under continuous stirring, 10mL of nano-apatite slurry with a concentration of 10wt% (preparation of nano-apatite slurry can be found in Li Yubao, K.de Groot, J.de Wy'n, CPAT Klein and Svd Meer , J. Mater.
  • the obtained chitosan/nano-apatite film sheet 2 was sufficiently swelled by water absorption and perforated by a mechanical pore-forming method with a pore spacing of 2.5 mm and a pore size of about 400 ⁇ m.
  • the perforated film was cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 was etched with a small amount of 2 vol% acetic acid solution and bonded to the spirally wound cylinder. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • the chitosan/nano-apatite porous scaffold unit 4 having a spirally wound cylindrical structure is obtained, and the nano-apatite content is 40 wt%, and the pores 3 are interpenetrated, the pore size is about 400 ⁇ m, and the porosity is 89%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • 0.5 g of chitosan and 0.5 g of sodium carboxymethylcellulose were added to 50 mL of a 1.5 wt% nano-apatite slurry (preparation of nano-apatite slurry can be found in Li Yubao, K. de Groot, J. de Wy'n, CPAT Klein and Svd Meer, J. Mater. Sci: Mater, in Med., 5 (1994): 326-331), fully stirred to completely dissolve sodium carboxymethylcellulose, and to make the shell
  • the polysaccharide and nano-apatite are uniformly dispersed in the solution. Under continuous stirring, 12.5 mL of a 2 vol% acetic acid solution was gradually added to the mixed solution.
  • the viscous film-forming liquid was quickly poured into a glass dish, spread horizontally into a film shape, and dried at 60 ° C. It was soaked with lwt% NaOH solution to neutralize the residual acetic acid in the membrane, washed thoroughly with distilled water and then air-dried. The thickness of the membrane wall in the wet state was 0.33 mm.
  • the obtained chitosan/carboxymethylcellulose sodium/nano-hydroxyapatite film material 2 was sufficiently water-swelled and perforated by mechanical pore-forming method, the pore spacing was 2.5 mm, the pore size was about 400 ⁇ m, and the porosity was 78. %.
  • the perforated film was cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 was etched with a small amount of 2 vol% acetic acid solution and bonded to the spirally wound cylindrical body. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • the chitosan/carboxymethylcellulose sodium/nano-hydroxyapatite porous scaffold unit 4 having a spirally wound cylindrical structure is obtained, and the pores 3 are interpenetrated.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the lg chitosan was dissolved in 50 mL of a 2 vol% acetic acid solution, and the mixture was thoroughly stirred to completely dissolve and uniformly disperse the chitosan.
  • Add 50 mL of collagen swelling solution to the acetic acid solution of chitosan (the preparation of collagen solution can be referred to the literature "Journal of Biomedical Engineering” 1999: 16 (2): 147-150 Wu Zhigu, Sheng Zhiyong, etc. ), Stir well, dissolve the collagen swelling solution in the chitosan solution and mix well.
  • nano-apatite slurry with a concentration of 10wt% (preparation of nano-apatite slurry can be found in Li Yubao, K.de Groot, J.de Wijn, CPAT Klein and Svd Meer, J Mater. Sci: Mater, in Med., 5(1994): 326-331) slowly added dropwise to the chitosan/collagen solution, and thoroughly stirred to uniformly disperse the nano-apatite in the system to obtain no visible particles. A viscous film-forming liquid of matter.
  • the resulting membrane material 2 was sufficiently swelled by water absorption, cut into a suitable size, tightly wound up, and the end edge portion 1 was etched with a small amount of 2 vol% acetic acid solution, and adhered to the spirally wound cylindrical body. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a chitosan/collagen/nano-apatite porous scaffold unit 4 having a spirally wound cylindrical structure was obtained, as shown in FIG.
  • the chitosan/collagen/nano-apatite weight ratio was 1:1:3, and the pores 3 in the scaffold unit were interpenetrated with an average pore diameter of 221.4 ⁇ m and a porosity of 88%.
  • the stent unit body 4 can be used alone as a bone repairing stent body, and a plurality of the above-mentioned stent unit bodies 4 can be arranged in parallel, and adjacent portions are etched with a small amount of 2 vol% acetic acid solution to wrap a plurality of spiral coils.
  • the cylinders are bonded together, dried and then thoroughly immersed and rinsed with distilled water to remove residual solvent, thereby obtaining a combined porous bone repairing stent body 5, as shown in FIG.
  • the lg chitosan was dissolved in 50 mL of a 2 vol% acetic acid solution, and the mixture was thoroughly stirred to completely dissolve and uniformly disperse the chitosan.
  • Add 50 mL of collagen swelling solution to the acetic acid solution of chitosan (the preparation of collagen solution can be referred to the literature "Journal of Biomedical Engineering” 1999: 16 (2): 147-150 Wu Zhigu, Sheng Zhiyong, etc. ), stir well, dissolve the collagen swelling solution in the chitosan solution and mix well.
  • polycaprolactone ultrafine fiber 0.5 g is added to the chitosan/collagen mixture (for preparation, Yi Zuo, Fang Yang, Joop GC Wolke, Yubao Li and John A. Jansen, Acta Biomater., 6 (2010) ): 1238-1247), fully stirred to evenly disperse in the system.
  • 2 g of cetyltrimethylammonium chloride and 2 g of sodium lauroyl sarcosinate were added to the mixed solution, and stirred at 1000 rpm for 30 minutes, and then a small amount of 0.25 vol% of glutaraldehyde solution was added, and the mixture was stirred uniformly.
  • the film After pouring into a glass dish, the film was spread horizontally into a sheet shape, frozen at -20 ° C, and dried under vacuum. At lwt% solution of N a OH and residual acetic acid, washed with distilled water and freeze-dried to obtain a porous chitosan / collagen / polycaprolactone film material 2, the wall thickness of the wet film is 0.36mm.
  • the resulting membrane material 2 was sufficiently swelled by water absorption, cut into a suitable size, tightly wound up, and the end edge portion 1 was etched with a small amount of 2 vol% acetic acid solution, and adhered to the spirally wound cylindrical body. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a chitosan/collagen/polycaprolactone porous scaffold unit 4 having a spirally wound cylindrical structure, wherein the chitosan/collagen/polycaprolactone weight ratio is 2:2:1, in the scaffold unit
  • the pores 3 are interpenetrated with an average pore diameter of 186.4 ⁇ and a porosity of 73%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the lg chitosan was dissolved in 50 mL of a 2 vol% acetic acid solution, and the mixture was thoroughly stirred to completely dissolve and uniformly disperse the chitosan.
  • Add 50 mL of collagen swelling solution to the acetic acid solution of chitosan (the preparation of collagen solution can be referred to the literature "Journal of Biomedical Engineering” 1999: 16 (2): 147-150 Wu Zhigu, Sheng Zhiyong, etc. ), stir well, dissolve the collagen swelling solution in the chitosan solution and mix well.
  • chitosan/collagen mixture 0.5 g of polylactic acid microfiber (for preparation, refer to Yi Zuo, Fang Yang, Joop GC Wolke, Yubao Li and John A. Jansen, Acta Biomater., 6 (2010): 1238-1247), and stir well to make it uniform. Dispersed in the system. 2 g of cetyltrimethylammonium chloride and 2 g of sodium lauroyl sarcosinate were added to the mixed solution, and stirred at 1000 rpm for 30 minutes, and then a small amount of 0.25 vol% of glutaraldehyde solution was added, and the mixture was stirred uniformly.
  • the film After pouring into a glass dish, the film was spread horizontally into a sheet shape, frozen at -20 ° C, and dried under vacuum. At lwt% solution of N a OH and residual acetic acid, washed with distilled water and freeze-dried to obtain a porous chitosan / collagen / PLA film material 2, the wall thickness of the wet film is 0.35mm.
  • the resulting membrane material 2 was sufficiently swelled by water absorption, cut into a suitable size, tightly wound up, and the end edge portion was etched with a small amount of 2 vol% acetic acid solution, and adhered to the spirally wound cylindrical body. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a chitosan/collagen/polylactic acid porous scaffold unit 4 having a spirally wound cylindrical structure was obtained, wherein the chitosan/collagen/polylactic acid weight ratio was 2:2:1, and the pores in the scaffold unit body were 3 Interpenetrating, the average pore diameter is 180.8 ⁇ , and the porosity is 80%.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the polylactic acid/nano-apatite porous membrane material 2 prepared in the same manner as in Example 11 was planarly stacked with the chitosan/collagen/polylactic acid porous membrane material 22 prepared in the same manner as in Example 16. Place them together, as shown in Figure 3.
  • the two layers of the film material 2, 22 which are superposed on the plane are tightly wound, and the end edge portions 1 and 11 of the two film sheets 2 and 22 are respectively etched with a small amount of dimethyl sulfoxide, and are bonded to the spiral. Wrap on the cylinder. After cooling, it was thoroughly soaked and rinsed with distilled water to remove residual solvent.
  • a polylactic acid/nanoapatite/chitosan/collagen porous scaffold unit 4 having a double-layer spirally wound cylindrical structure was obtained, as shown in Fig. 5.
  • the stent unit body 4 can be used as a bone repairing stent body alone, and a plurality of the above-mentioned stent unit bodies are arranged in parallel, and the adjacent portions are etched with a small amount of dimethyl sulfoxide to bond the plurality of spirally wound cylindrical bodies. Together, after drying and immersing and rinsing with distilled water to remove residual solvent, a combined porous bone repairing stent body 5 can be obtained, as shown in FIG.
  • the polycaprolactone porous membrane material prepared in the same manner as in Example 2, and the chitosan/carboxymethylcellulose sodium porous membrane material prepared in the same manner as in Example 9 and Example 14 The chitosan/collagen/nanoapatite porous membrane material prepared by the method is superposed on the plane, and is tightly spirally wound, and the end edge portion is etched with a small amount of dimethyl sulfoxide to adhere to the spiral wound. On the cylinder. After drying, it was thoroughly soaked and rinsed with distilled water to remove residual solvent. A three-layer spirally wrapped cylindrical structure of polycaprolactone/chitosan/carboxymethylcellulose sodium/collagen/nanoapatite porous scaffold unit 4 was obtained.
  • the stent unit body 4 can be used alone as a bone repair stent body.
  • the chitosan/carboxymethylcellulose sodium/nano-hydroxyapatite porous scaffold unit 4 prepared in the same manner as described in Example 7 will have 15 mg of xanthine (or antibiotics, cephalosporins, ⁇ -lactams, Aminoglycosides, fluoroquinolones, notoginseng, saponins, etc.) are dispersed in 10 ml of distilled water to prepare a drug-containing solution, and the stent unit is immersed in the above drug-containing solution, soaked at 4 ° C for 3 hours, after lyophilization Preservation at 4 ° C gave a porous scaffold unit with drug sustained release function.
  • xanthine or antibiotics, cephalosporins, ⁇ -lactams, Aminoglycosides, fluoroquinolones, notoginseng, saponins, etc.
  • the chitosan/collagen/nanoapatite porous scaffold unit 4 prepared in the same manner as described in Example 8 will have 10 mg of bone morphogenetic protein (or transforming growth factor- ⁇ , fibroblast growth factor, erythropoietin). , thrombopoietin, platelet-derived growth factor, etc.) dispersed in 10ml of distilled water to form a growth factor solution, immersed in the above growth factor-containing solution, soaked at 4 ° C for 24 hours, lyophilized and stored at 4 ° C, Get induced tissue regeneration The porous scaffold unit body.
  • bone morphogenetic protein or transforming growth factor- ⁇ , fibroblast growth factor, erythropoietin
  • thrombopoietin platelet-derived growth factor, etc.
  • the film is cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 is etched with a small amount of a solution containing calcium chloride in ethanol and adhered to the spirally wound cylindrical body. After cooling, it was thoroughly soaked and rinsed with distilled water to remove residual solvent. A polyamide 66 porous scaffold unit body having a drug sustained release function was obtained.
  • chitosan-hydroxyapatite viscous film-forming liquid prepared in the manner described in Example 12 was added, and 200 mg of notoginseng (or antibiotics, cephalosporins, ⁇ -lactams, aminoglycosides) was added.
  • Chitosan microspheres (average diameter 15 ⁇ ) and 100 mg of transforming growth factor- ⁇ (or bone morphogenetic protein, fibroblast growth factor, erythropoietin), class, fluoroquinolone, notoginseng, scutellaria, scutellaria, etc.
  • Collagen microspheres (average diameter ⁇ ), thrombopoietin, platelet-derived growth factor, etc., were stirred for 40 min, poured into glass plates, spread horizontally into a patch, and air-dried at room temperature. Wash thoroughly with distilled water and then air dry.
  • the obtained chitosan/nanoapatite film material 2 was sufficiently water-absorbed and perforated by a mechanical pore-forming method with a pore spacing of 2.0 mm and a pore size of about 300 ⁇ m.
  • the perforated film was cut to a suitable size, tightly wrapped in a spiral, and the end edge portion 1 was etched with a small amount of 2 vol% acetic acid solution and bonded to the spirally wound cylindrical body.
  • porous support ⁇ 66/ ⁇ (40% ⁇ ) porous support, ⁇ 66/ ⁇ (4 ⁇ % ⁇ ) porous membrane.
  • ⁇ 66 is polyamide 66.
  • HA is hydroxyapatite, and the percentage refers to the mass percentage of HA to the total mass of the material.
  • the porous scaffold referred to in this test example is an integrally formed monolithic scaffold, and the preparation method can be referred to the literature by Huanan Wang, Yubao Li, Yi Zuo, Jihua Li, Sansi Ma and Lin Cheng, Biomaterials 28 (2007): 3338-3348; The preparation method of the porous membrane can be referred to the patent CN1887365A.
  • Culture conditions The material was placed in a 24-well plate, and the cells were seeded at a density of 2 ⁇ 10 4 cells/well. The cells were changed every other day, cultured for 4 days, fixed with glutaraldehyde, dehydrated with ethanol gradient, replaced with isoamyl acetate, critical The spot was dried and observed by SEM (JSM-6510LV, Japan, 20KV).
  • the cell morphology of the surface of the two materials is polygonal or fusiform.
  • the cells protrude from the pseudopod and the pseudopods of the adjacent cells. Some cells cross the pores at both ends, and some grow into the large pores of the material. The cell spread is in good condition.
  • the experiment shows that both the porous monolithic stent and the porous membrane material have good cell affinity, which is beneficial to the adhesion, spreading and proliferation of osteoblast-like cells.
  • Test Example 2 Animal experiment Materials: CS/NaCMC/HA (60% HA) film roll holder (film thickness: 180 ⁇ , pore size: 300 ⁇ , film roll holder bottom diameter: 3 mm, height: lcm). Among them, CS is chitosan, NaCMC is sodium carboxymethyl cellulose HA is light hydroxyapatite, and percentage refers to the mass percentage of HA to the total mass of the material.
  • the film roll holder used in this test example was prepared in the same manner as in Example 13.
  • the new bone growth of the material group of the invention is better than that of the blank group, and it can be observed by the X-ray film that the edge portion of the material has been long together with the new bone, and the material The middle new bone runs completely through the growth.
  • PA66/HA C40wi%HA Porous scaffold, PA66/HA (40 ⁇ ⁇ % ⁇ ) porous membrane roll holder.
  • ⁇ 66 is polyamide 66 (polyamide 66) HA is hydroxyapatite, and the percentage refers to the mass percentage of HA to the total mass of the material.
  • the porous scaffold referred to in this test example is an integrally formed monolithic scaffold, and the preparation method can be referred to the literature by Huanan Wang, Yubao Li, Yi Zuo, Jihua Li, Sansi Ma and Lin Cheng, Biomaterials 28 (2007): 3338-3348;
  • a porous film can be prepared by referring to the method of the patent CN1887365A, and a porous film roll holder can be prepared by the method of the present invention.
  • Material size PA66/HA (40% HA) porous scaffold (cuboid) length: lcm, width: lcm, height: 2cm porosity (85%-90%), pore size 300 ⁇ 800 ⁇ .
  • the yield strength (0.812 ⁇ 0.127 MPa) of the porous membrane coil stent is significantly higher than that of the porous monolithic stent (0.447 ⁇ 0.153 MPa) for the same component, porous stent with similar porosity and porous membrane coil stent.
  • the biomimetic structure degradable bone repairing stent body of the present invention has good repairing ability, and the present invention
  • the mechanical properties of the membrane roll structure repair scaffold body are significantly better than those of the prior art scaffold structure.
  • the preparation method of the repairing stent body of the invention is simple, the condition is mild and easy to control, and has the characteristics of strong plasticity.
  • the size of the bone repairing stent body can be controlled by controlling the thickness of the sheet material and/or The height, and the number of layers of the spiral wrap, are flexibly and conveniently adjusted. Therefore, the biomimetic structure degradable bone repair scaffold of the present invention has an ideal promotion and application value in the field of biomedical materials. Industrial applicability
  • the biomimetic structure degradable bone repairing stent body of the invention has good repairing ability, and the mechanical property thereof is remarkably superior to the scaffold structure in the prior art; meanwhile, the preparation method of the repairing scaffold body of the invention is simple, the condition is mild and easy to control, and It has strong plasticity and excellent clinical application and industrialization prospects.

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Abstract

公开了一种具有层状结构的仿生骨修复支架体及其制备方法。所述支架体由至少一个支架单元体（4）构成，该支架单元体（4）为由片层材料（2）由内向外连续紧密卷裹、截面呈螺旋状的柱体结构，其直径为0.1mm~50mm。该结构类似于自然骨的哈佛系统，具有高度的仿生效果，能很好地实现缺损位与正常骨组织间的力学传递，即使在降解过程中也能维持良好的结构稳定性，完成骨组织的修复和功能重建。通过控制片层材料（2）的厚度、高度以及卷裹的层数，可以灵活调整骨修复支架体的三维尺寸，以满足不同的使用需要。

Description

说 明 书
具有层状结构的仿生骨修复支架体及制备方法 技术领域
本发明涉及一种具有层状结构的仿生骨修复支架体及其制备方法，在生物医学领域中 可用于替代和修复骨组织的缺损。
背景技术
骨组织缺损是临床上的常见病， 可由创伤、肿瘤、骨疾以及骨生长异常等原因所造成。 长期以来， 开发高性能的临床医用材料来替代和修复骨组织缺损一直是生物材料研究的重 点课题。
理想的骨修复材料应该具有与自然骨相似的生物特性， 包括： （1) 生物相容性： 无细 胞毒性和炎症反应，有利于细胞的粘附和增值； （2) 生物力学性能： 具有一定的机械强度， 能够为新生组织提供力学支撑； （3)三维多孔结构： 材料应具有三维立体多孔结构， 孔径 尺寸应能允许细胞粘附生长以及血管和神经的长入， 且孔间应相互贯通， 以利于营养物质 的传递和细胞代谢废物的排出。
目前用于骨修复的材料主要为整体成型的块体多孔支架， 其特点是在材料的成型过程 中用各种技术制孔。 较为常见的制孔方法有气体发泡、 溶液浇铸 /粒子沥滤、 相分离 /乳化、 熔融成型、 纤维粘接、 冷冻干燥等。 公开号 CN1765423A的文献中提出了一种生物活性多 孔支架的制备方法， 利用表面活性剂能稳定气泡的原理制孔， 能使多孔材料具有可控的孔 隙率和较好的孔隙贯通性。 但是由于块体多孔支架材料结构的局限性， 为了达到较好的孔 隙贯通性， 必须以牺牲材料的力学强度为代价。 特别是对于生物可降解材料而言， 孔隙贯 通性较好的块体支架材料如果一旦开始降解， 其多孔结构的支架易很快坍塌变形， 会影响 骨组织修复的效果。
WO 2008/082766 A2提出了一种以嵌套式的闭合环状结构为基础单元构筑的椎间盘修 复支架和软骨关节修复支架， 以环面为外部结构， 中央部以特定的微结构或水凝胶为髓核。 这种骨软骨支架包括了与软骨部分界面相连的骨部分， 骨部分通过固定装置与受体骨的开 口连接。 在其嵌套式的环状结构体中， 由于相互独立的各环状结构间没有任何技术要点保 持其结构的紧密度， 从而难以保证其支架体能提供足够和有效的力学性能用于骨修复， 且 在使用过程中其不会因各环状结构间的移动甚至脱落而导致替换失败。 因此这一设计缺陷 对用于骨或软骨修复的支架材料具有致命的损害， 并不适于临床应用。
因此， 在临床应用中更为理想的骨修复支架， 至少应能提供临床所需的力学支撑， 即 使在材料降解过程中仍能维持良好的结构稳定性， 支撑新生组织的生长直至其具有自身的 生物力学性能， 且进一步还能具有三维多孔网络结构， 保持高度的孔隙贯通性， 有利于完 成骨组织修复和功能重建。
发明内容
针对上述情况， 本发明首先提供了一种具有层状结构的仿生骨修复支架体， 在用于替 代和修复骨组织缺损中能有更为理想的效果。 本发明进一步还提供了该骨修复支架体的制 备方法。 本发明的具有层状结构的仿生骨修复支架体， 由至少一个支架单元体构成。 该支架单 元体为由片层材料由内向外连续紧密卷裹、 截面呈螺旋状的柱体结构， 支架单元体的直径 为 0.1mm〜50mm。 由于该支架单元体是由片层材料由内向外连续紧密卷裹而成的整体型结 构， 因此既有类似于自然骨的哈佛系统 （在自然长骨内环骨板层与外环骨板层间分布的纵 向排列的骨单位）， 因而具有高度的仿生效果，能很好地实现缺损位与正常骨组织间的力学 传递， 在使用过程中层状结构间也不会移动或脱落， 即使在降解过程中也能维持良好的结 构稳定性， 完成骨组织的修复和功能重建。 而且通过控制片层材料的厚度， 和 /或高度， 和 /或卷裹的层数，还可以实现灵活调整骨修复支架体的三维尺寸，满足不同的实际使用需要， 可塑性强。
由于生物体骨组织中骨单位的平均直径通常为 190〜230μηι。 因此上述柱体结构形式支 架单元体的直径为 0.1mm〜50mm， 能适应其较多的使用方式和具有较宽的适用范围。 研究 和实验显示， 用于构成支架单元体的片层材料的优选厚度是 0.01mm〜lmm。
上述可用于构成上述支架单元体的片层材料， 进一步在其延展面中分散分布有孔径为 50μηι〜800μηι的贯通孔隙是一种更好的方式。 其中， 更优选的是使所说该分散分布的贯通 孔隙的孔隙率，达到占片层材料体积的 70%〜95%。由于该支架单元体是由片层材料由内向 外连续紧密卷裹而成的， 因此分布于片层材料上的这些贯通孔隙， 经卷裹形成支架单元体 后， 在其结构中可以形成相互贯穿的特殊形式的网络结构， 因而能有助于细胞粘附生长以 及血管和神经的长入， 也便于营养物质的传递和细胞代谢废物的排出， 有利于促进该修复 支架体使用部位骨组织修的复和功能重建。
上述所说的构成支架单元体的片层材料， 通常都应为生物体可以接受的医用材料， 包 括在生物体内可具有降解性的或不具有降解性的多种医用材料。 但其中至少以其表层为可 降解性的材料为佳。 例如， 该片层材料可以为在由非降解性的医用高分子、 非降解性的医 用金属或金属合金、 非降解性的生物陶瓷、 非降解性的生物复合材料的结构体表面， 被覆 有目前已有使用和 /或报道的如羟基磷灰石、 磷酸三钙、 磷酸八钙， 以及其它含钙化合物， 或者这些成分的混合物等可降解材料层的形式， 特别是这些钙的磷酸盐材料涂层， 可增加 骨修复材料的生物相容性和骨传导性， 有利于组织的固定和长入。
而更优选的方式，是使片层材料直接由目前已有报道 /使用的如聚酯、聚氨酯、聚酰胺、 聚酸酐、 聚膦腈、 聚氨基酸、 聚羟基烷羧酸酯、 酰胺-酯嵌段共聚物、 基因工程蛋白质、 传 导性和塑性蛋白质基聚合物、 天然的或半合成的多糖基复合高分子如淀粉基、 纤维素基和 木质素复合高分子、 以及无机高分子聚磷酸等可生物降解的生物高分子成分； 如医用镁基 合金和铁等可生物降解的医用金属或其合金； 如碳酸钙生物降解陶瓷、 可降解磷酸钙生物 陶瓷、 硅酸钙生物降解陶瓷、 可降解钙磷生物玻璃陶瓷等可生物降解的生物陶瓷； 或是由 这些不同成分的复合成分组成， 如无机活性磷灰石 /聚酯可降解复合材料、表面活性涂层医 用镁合金材料、 聚乳酸-聚己内酯复合材料等。
在选用为生物可降解材料时， 除可以采用由单一种生物可降解成分组成的形式外， 特 别以采用由至少两种生物可降解高分子、 可降解金属或金属合金的复合成分组成形式更为 优选， 以利于临床上根据不同使用部位和 /或需要， 通过对所用生物可降解高分子、 可降解 金属或金属合金的种类和 /或比例的选择或调整， 达到所需以及适合的最佳降解速率效果。
所说的支架单元体片层材料，除可以对生物可降解成分的种类和 /或比例进行选择和调 整外， 进一步还可以在其中分散分布有直径为 10ηηι〜100μηι的纤维成分。 在这种混合或复 合组成中， 所说的该超细或普通纤维材料可以增强该骨修复支架体的力学性能。 所说的超 细纤维或普通纤维成分， 可以为天然纤维， 或是以降解或非降解生物高分子成分为原料经 静电纺丝、 复合纺丝、 共混纺丝、 闪蒸纺丝等工艺制备而成的人工纤维中的至少一种。 例 如， 可以选择已有报道和 /使用的医学允许使用的降解速率不同、力学性能各异的纤维素纤 维（即植物纤维）， 包括天然纤维素纤维如棉、 苎麻、 亚麻等纤维， 天然再生纤维素纤维如 粘胶纤维、竹纤维、醋酸纤维素纤维等， 以及再生纤维素改性纤维如甲基纤维素纤维等（该 类纤维韧性佳， 降解周期较长）、蛋白质纤维（如羊毛、蚕丝、花生蛋白及大豆蛋白纤维等， 该类纤维延展性好， 降解周期短）、聚乳酸纤维、 聚己内酯纤维、聚酰胺纤维、聚丙烯晴纤 维等合成高分子纤维 （其力学性能和降解周期可设计调控） 等多种纤维成分。 实验显示， 所说的超细或普通纤维成分的含量， 通常可以为片层材料总重量的 1%〜60%， 优选为 5wt%〜20wt%。
采用由所说的生物高分子成分与纳米类骨磷灰石成分共同组成形式的片层材料， 是上 述骨修复支架单元体片层材料的另一种优选方式。 所说的纳米类骨磷灰石晶体成分不仅同 样可以增强该骨修复支架体的力学性能， 而且其所含的钙、 磷成分还可以为骨组织修复和 再生过程所利用。 所说的纳米类骨磷灰石成分的比例， 可以达到片层材料总重量的 1%〜80%， 进一步的优选比例是片层材料总重量的 40%〜60%。 所说纳米类骨磷灰石成分中 的 · /憐摩尔比， 优选为与天然骨组织比例接近或相似的 1.2〜2.0: 1。
在此基础上， 所说的纳米类骨磷灰石成分的更好选择， 是采用以化学方式由钙盐化合 物与磷酸或磷酸盐反应制备得到的纳米磷灰石针晶、 棒晶或片晶成分。 其制备方法可以参 照如 ZL02133949.X, 以及 Li Yubao, J.de Wijn, C.P.A.T. Klein, S.v.d. Meer and K.de Groot, Preparation and Characterization of Nanograde Osteoapatite-like Rod Crystals, J. Mater. Sci.: Mater, in Med., 5(1994): 252-255； Li Yubao, K.de Groot, J.de Wijn, C.P.A.T. Klein and S.v.d. Meer, Morphology and Composition of Nanograde Calcium Phosphate Needle-Like Crystals Formed by Simple Hydrothermal Treatment, J. Mater. Sci: Mater, in Med., 5(1994): 326-331； Yi ZUO, Yubao LI, Jie WEI and Yonggang YAN, Influence of Ethylene Glycol on the Formation of Calcium Phosphate Nanocrystals, Journal of Materials Science and Technology, Vol. 19, No.6, 2003, 628-630) 等文献所报道的方式进行。
根据不同的使用需要和 /或情况，在用于构成骨修复支架单元体片层材料中还含有其总 重量 0.05%〜20%， 优选为 0.05%〜5%的药物成分和 /或组织生长因子， 也是可以进一步优选 的一种方式。 所说的药物成分可以包括在骨组织修复和康复过程中常用的抗生素、 头孢菌 素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺酮类、 三七、 小蓟、 黄芪中的至少一种； 所说的 组织生长因子包括骨形成蛋白、 转化生长因子 -β、 成纤维细胞生长因子、 红细胞生成素、 血小板生成素、 血小板衍生生长因子中的至少一种。 根据临床需要， 这些同类型或不同类 型的药物成分和 /或组织生长因子， 可以单一方式使用， 也可以适当方式联合使用。 当该骨 修复支架单元体是由生物可降解材料片层材料卷裹而成时， 该骨修复支架同时还可兼有能 使这些药物成分和 /或组织生长因子缓释和诱导组织再生的缓释载体或用作组织工程支架， 更有利和促进骨组织修复， 在生物医学领域具有广阔的应用前景。
上述由片层材料由内向外连续紧密卷裹而成的该支架单元体， 可以为由单层形式的片 层材料紧密卷裹而成， 也可以由平面叠置的两层或更多层形式的片层材料卷裹而成。 在采 用由两层或更多层形式的片层材料时， 一种优选的方式， 是采用分别含有不同成分的片层 材料， 例如可以为由多种形式的生物可降解高分子、 可降解金属或金属合金的复合成分， 或上述由一种或多种生物可降解成分分别与超细纤维或普通纤维成分、 纳米类骨磷灰石成 分、 和 /或药物成分、 和 /或组织生长因子等复合成分， 或者是上述由一种或多种可降解金 属或金属合金成分与药物成分和 /或组织生长因子等复合成分形式的片层材料， 以平面叠置 方式紧进行密卷裹。 通过不同片层材料所具有的不同功能、 特性， 或是具有不同的降解速 率等， 达到更好地适应不同修复对象的个体需要， 调控植入生物体内的支架体在不同修复 阶段中所需要的功能和 /或降解速率目的。
本发明所述的骨修复支架体， 可以直接由上述各种形式的单一支架体单元构成， 也可 以采用由两个或更多个所说该支架结构单体， 以其长度方向平行的并列方式相互紧密固定 所成的组合式结构体的形式， 可视临床使用的需要而定。
本发明所述的仿生骨修复支架体制备的基本方法， 是将由上述适当成分或材料制成的 片层材料， 以其延展面由内向外螺旋状连续紧密卷裹成直径为 0.1mm〜50mm的卷裹结构体 后， 将延展面的末端卷裹边缘以粘接等方式固定于卷裹结构体表面， 即得到所说的支架单 元体。 以该单一的支架单元体， 或者是将两个或更多个该支架单元体， 以其长度方向平行 的并列方式相互紧密粘接固定， 成一具有足够结合强度的整体形式的组合体结构， 即成为 所说的骨修复支架体。 其中， 所说片层材料， 可以为如前述的生物高分子材料、 或者生物 陶瓷、 或者医用金属或合金材料， 或者这些材料的复合材料等， 特别是厚度优选为 0.01mm〜lmm的片层材料。
上述的片层材料体中， 一些常用的医用膜片材料的具体制备方式、 条件等， 可以参照 如 CN101391113A (聚氨酯医用复合膜及制备方法）、 CN1488407A (一种用于引导组织再 生的复合膜制备方法）、 CN1107742A (组织引导再生胶原膜）、 CN101516292A (由生物可 降解金属构成的植入物及其制造方法）、 CN1626702 (生物陶瓷膜的制备方法）、 CN101054708A (等离子微弧氧化法制备羟基磷灰石生物陶瓷膜的方法） 等目前已有报道 / 使用的相关方法。
采用在片层材料表面被覆可降解 /生物活性涂层的方式时， 可以采用等离子喷涂法、热 化学法、 电沉积法、 溶胶凝胶法等目前已有报道和 /或使用的方式， 在生物高分子材料或医 用金属及其合金材料等可降解或非降解性片层材料的基体表面， 被覆上具有骨引导性的含 钙化合物涂层， 如羟基磷灰石、磷酸三钙、磷酸八钙以及其它含钙化合物或它们的混合物。 具体操作方法， 可参考如 CN1443871A (—种陶瓷涂层的制备方法）、 CN102059209A (钛 种植体表面的羟基磷灰石涂层方法）、 CN102030915A (一种聚酰亚胺薄膜表面修饰纳米羟 基磷灰石涂层的简易方法） 等相关文献的内容。
以生物高分子材料为原料制备所说的片层材料时， 进一步还可以在制膜原料溶剂分散 体系中， 以均匀分散方式混合有为成膜成分总质量 1%〜60%的非溶解态的超细纤维或普通 纤维成分， 或含有为成膜成分总质量 1%〜80%的纳米类骨磷灰石晶体成分中的至少一种。 从而可以得到结构中还含有超细纤维或普通纤维成分和 /或纳米类骨磷灰石晶体成分的片 层材料。 此时， 作为分散体系的溶剂 （分散剂） 以选择对于所使用的超细纤维或普通纤维 和 /或纳米类骨磷灰石成分而言难溶的溶剂为宜， 以使其在制膜原料溶剂分散体系中保持非 溶解状态。 如上述， 所说的超细纤维或普通纤维成分为直径 10ηηι〜100μηι的天然纤维或人 工纤维中的至少一种。
所说的纳米类骨磷灰石晶体成分， 为由钙盐化合物与磷酸或磷酸盐反应所得到的纳米 磷灰石针晶、棒晶或片晶， 具体制备方法可参照李玉宝等在《J. Mater. Sci: Mater, in Med.)) ， 1994, 5: 326-331或 ((Biomaterials)) ， 1994, 15: 835-841等文献中的报道。
为在片层材料的延展面中得到分散分布的所说贯通孔隙， 除可以在片层材料成型后， 根据所需的孔径大小和 /或分布的孔隙率， 以机械穿孔方式处理外， 特别是在以生物高分子 材料为原料制备所说的片层材料时， 一种优选的方式， 是通过在粒子沥滤法、气体发泡法、 熔模铸造法、 电沉积法等方式制备过程中， 在其延展面上形成所说分散分布的直径为 50μηι〜800μηι的贯通孔隙。
例如， 采用粒子沥滤法制备时， 所用的粒子沥滤剂粒径可以为 50μηι〜800μηι， 用量为 制模原料的溶剂分散体系总质量的 40%〜80%。 所用的粒子沥滤剂可以为常用的氯化钠颗 粒、 氯化钾颗粒、 葡萄糖颗粒、 硫酸镁颗粒、 碳化硅颗粒、 二氧化锰颗粒、 氧化铝颗粒等 中的至少一种。
又如， 采用气体发泡法制备时， 气体发泡剂用量一般可以为制模原料的溶剂分散体系 总质量的 1%〜10%， 所说的气体发泡剂可以选用如常用的十二烷基硫酸钠、 月桂酰肌氨酸 钠、 脂肪醇聚氧乙烯醚硫酸钠、 聚氧乙烯脂肪酸酯、 氢化钛、 氢化锆、 碳酸钙、 碳酸镁等 中的至少一种。
采用熔模铸造法制备时， 可以先由高熔点液态材料制成海绵孔隙模型， 然后将液态金 属浇入铸型中冷却和凝固， 再去除高熔点材料， 最终得到多孔金属材料。 所说的高熔点材 料一般可以选择如酚醛树脂、 莫来石、 碳酸钙或石膏的混合物等。
如采用电沉积法制备， 则可以先使高分子材料形成高孔隙的三维网状结构， 采用电镀 工艺在其高分子骨架表面镀覆一层金属， 再经焙烧除去内部的高分子材料， 制得多孔金属 材料。 所说的高分子材料， 一般可以选择如聚氨酯、 环氧树脂、 聚苯乙烯、 聚氯乙烯等泡 沫塑料。
上述各种具体的制备方法， 均可以参照目前已有报道和 /使用的方式。 如 CN1200043C (纳米羟基磷灰石 /医用聚酰胺 66 形式的复合生物活性多孔材料及制备方法）、 CN1225290C (纳米羟基磷灰石 /医用聚酰胺成分复合组织工程支架材料）、 CN1230210C (聚 酰胺 /纳米羟基磷灰石系列生物医用复合材料的制备方法）、 CN1887365A (具有多孔结构的 生物材料膜及其制备方法）、 CN1911457A (复合型纳米羟基磷灰石 /医用高分子材料组织工 程支架材料及制备方法）、 CN1765423A (纳米磷灰石 /医用高分子成分生物活性多孔支架材 料的制备方法）、 CN1460526A (羟基磷灰石 /医用聚酰胺类成分的多孔型骨修复体）、 CN101721921A (一种多孔金属膜的制备方法）、 CN101818367A (多孔金属材料及制备方 法）、 CN101824558A (一种带状发泡树脂基材及多孔金属材料的制备方法） 等。
在上述的制备过程中， 在所说的制膜原料溶剂分散体系中， 以均匀分散方式还含有为 成膜成分总质量 0.05%〜20%的药物成分和 /或组织生长因子，即可以得到在结构中还负载有 所需的药物成分和 /或组织生长因子形式的骨修复支架体。所说的药物成分包括抗生素、头 孢菌素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺酮类、 三七、 小蓟、 黄芪中的至少一种； 所 说的组织生长因子包括骨形成蛋白、 转化生长因子 -β、 成纤维细胞生长因子、 红细胞生成 素、 血小板生成素、 血小板衍生生长因子中的至少一种。
此外， 另一种可行的方式， 是可以将由不含所说药物成分和 /或组织生长因子的片层材 料卷裹固定所得到所说支架体目标产物，浸泡于含有所说药物成分和 /或组织生长因子的溶 液中， 使支架结构体中负载有为总重量 0.05%〜20%的药物成分和 /或组织生长因子。
上述在支架体上负载药物成分和 /或组织生长因子的具体方法， 可以参照如 CN1911457A (复合型纳米羟基磷灰石 /医用高分子材料组织工程支架材料及制备方法）、 CN101214228A (可用于负载药物的水溶性壳聚糖微球及其制备方法） 等文献内容。
将上述形式的片层材料以单层， 或以平面叠置方式的两层或更多层的方式， 由内向外 连续紧密卷裹成截面呈螺旋状的所说柱体结构， 即成为本发明所说的支架单元体。 以单一 该支架体单元， 或由至少两个该支架结构单体以其长度方向平行的并列方式相互紧密固定 成的组合式的结构体， 即成为本发明所说的支架结构体。
研究表明， 从结构学上讲， 在采用同样原材料的前提下， 取向性结构材料能具有更高 的强度， 力学耐受性也更强。 自然骨的结构正是这种各向异性的取向结构， 因而能具有最 佳力学优势和材料优势的结构。 本发明上述由片层材料由内向外呈螺旋状紧密卷裹所成的 多层圆筒状结构形式的骨修复支架体， 正是基于此原理设计的， 具有与自然骨哈佛系统高 度的仿真性， 该取向性的三维网络结构能很好地实现缺损位与正常骨组织间的力学传递。 在植入生物体的初期， 该修复支架体能够为骨缺损部位提供一定的力学支撑， 在力刺激下 与骨组织形成适宜的骨性结合。 特别是在还含有相互贯穿的孔隙时， 这种特殊的网络结构 既能保证孔隙贯通性， 有利于细胞粘附生长以及血管和神经的长入， 也便于营养物质的传 递和细胞代谢废物的排出。 当支架由可降解材料构成时， 该结构能与新生骨组织之间形成 牢固的生物嵌合， 也能在降解过程中维持良好的结构稳定性。 随着骨细胞以及血管和神经 的长入， 新骨逐渐恢复自身的生物力学性能的同时， 材料也逐步降解， 其降解产物无毒副 作用并能随着机体的自然生理代谢而排出体外， 以完成骨组织的修复和功能重建， 在完成 骨修复的同时支架材料能够自行降解， 其降解产物无毒副作用， 生物安全性高。
本发明仿生结构可降解骨修复支架体具有良好的修复能力， 并且， 本发明的膜卷结构 修复支架体的力学性能显著优于现有技术中的支架结构。 本发明修复支架体的制备方法简 单， 条件温和易控制， 且具有可塑性强的特点， 根据临床使用需要， 该骨修复支架体的大 小尺寸， 可以通过控制所说的片层材料的厚度和 /或高度， 以及卷裹的层数等方式， 灵活方 便地进行调整， 因此， 本发明的仿生结构可降解骨修复支架体在生物医学材料领域中具有 理想的推广和应用价值。
以下结合由附图所示实施例的具体实施方式， 对本发明的上述内容再作进一步的详细 说明。 但不应将此理解为本发明上述主题的范围仅限于以下的实例。 在不脱离本发明上述 技术思想情况下， 根据本领域普通技术知识和惯用手段做出的各种替换或变更， 均应包括 在本发明的范围内。
附图说明
图 1是构成本发明所说骨修复支架单元体的一种单片层材料结构示意图。
图 2是由图 1所示的片层材料卷裹而成骨修复支架单元体的示意图。
图 3是由多个图 2所示支架单元体构成的组合结构体形式骨修复支架体的结构示意图。 图 4是构成骨修复支架单元体的一种平面叠置多片层材料的示意图。 图 5是由图 4所示的平面叠置多片层材料卷裹而成的骨修复支架单元体的示意图。 图 6是由多个图 5所示支架单元体构成的组合结构体形式骨修复支架体的结构示意图。 图 Ί PA66/HA(40%HA)复合材料表面 MG63细胞培养 4天的扫描电镜照片： （a) 多孔 整体支架， （b) 多孔膜。
图 8手术示意图： （a) 正常兔尺骨和桡骨， （b)桡骨中段制造缺损 (长 lcm， 高 3mm) 并放入材料， （c) 用手术缝线固定材料。
图 9 手术后 2 个月 X 光观察兔桡骨部分缺损： （a)空白组， （b)为本发明
CS/NaCMC/HA(60%HA) 膜卷支架组。
图 10 PA66/HA (40 %HA)复合材料压縮测试的屈服强度： （a)多孔整体支架， （b)多 孔膜卷支架。
具体实施方式
实施例 1
将 2g壳聚糖溶于 50mL浓度为 2 (v)%的醋酸溶液中，充分搅拌使壳聚糖完全溶解并均 匀分散。 在壳聚糖溶液中加入 lg吐温 -20和 lg吐温 -80， 在 1000转 /分转速下持续搅拌 30 分钟，迅速将富含泡沫的成膜液倾注到玻璃平皿中，水平铺展成膜片状，于 -20°C冷冻成型， 真空干燥。 用 l(w)°/^ NaOH溶液浸泡以中和膜内残留的醋酸， 用蒸馏水充分洗涤并冷冻 干燥， 得到含有孔隙 3的多孔壳聚糖膜片材料 2， 如图 1所示， 湿态下厚度为 0.40mm。 将 该膜片材料 2充分吸水溶胀， 裁剪成适合的尺寸， 紧密螺旋卷裹后， 将末端卷裹边缘部分 1用少量 2( ％的醋酸溶液溶蚀表面，粘合在螺旋卷裹圆筒体状卷裹体上。凉干后用蒸馏水 充分浸泡和漂洗以除去残留溶剂。得到螺旋卷裹圆筒体状结构的壳聚糖多孔支架单元体 4， 如图 2所示。 孔隙 3间相互贯通， 平均孔径为 250.4μηι， 孔隙率为 79%。 该支架单元体 4 可以单独作为骨修复支架体使用。 本发明实施例中所称螺旋卷裹均指， 将片层膜材料由内 向外连续紧密卷裹， 使其成为截面呈螺旋状的柱体结构。
实施例 2
将 2g聚己内酯溶于 50mL二甲亚砜， 加入 40〜60目的 NaCl颗粒 50g， 充分搅拌使盐 粒分布均匀， 制成粘稠状成膜液。 将成膜液倾注到玻璃平皿中， 水平铺展成膜片状， 50°C 真空干燥。 用蒸馏水反复浸泡、 洗漆， 以除去膜内的 NaCl颗粒， 得到多孔的聚己内酯膜 片材料 2， 湿态下厚度为 0.21mm。 将膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1 用少量二甲亚砜溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗 以除去残留溶剂。 得到螺旋卷裹圆筒体状结构的聚己内酯多孔支架单元体 4， 孔隙 3间相 互贯通， 平均孔径为 223.1μηι， 孔隙率为 65%。 该支架单元体 4可以单独作为骨修复支架 体使用。
实施例 3
在氯化钙催化作用下， 将 10g聚酰胺 66溶于 70°C〜80°C的 lOOmL无水乙醇溶液中， 充分搅拌均匀， 制成粘稠状成膜液。 冷却至室温后将成膜液倾注到玻璃平皿中， 水平铺展 成膜片状， 60°C烘干， 厚度为 0.15mm。 用蒸馏水反复浸泡、 洗涤， 70°C烘干， 得到多孔 的聚酰胺 66膜片材料 2。 将膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 含氯化钙的乙醇溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂 洗以除去残留溶剂。得到螺旋卷裹圆筒体状结构的聚酰胺 66多孔支架单元体 4， 孔隙 3间 相互贯通， 平均孔径为 68.0μηι， 孔隙率为 81%。该支架单元体 4可以单独作为骨修复支架 体使用。
实施例 4
将钛粉和粒径为 200μηι〜600μηι的碳酸氢氨粉料充分混合放入模具中， 在 lOOMPa的 压力下保温 2〜3min后取出， 将压制成的样品放入高温扩散炉中， 在氢气保护气氛环境下 进行烧结， 升温速率为 100°C/h， 200°C保温 5h， 1200°C保温 2h。 随炉冷却至室温， 得到 多孔钛膜， 筒壁厚度为 0.31mm。 将膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1 用外加物理作用力固定在螺旋卷裹圆筒体上， 于 850°C烧结 30min后取出， 得到螺旋卷裹 圆筒体状结构的金属钛多孔支架单元体 4， 孔隙 3间相互贯通， 平均孔径为 326.2μηι， 孔 隙率为 77%。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 5
将镁粉和粒径为 200μηι〜400μηι的尿素粉料充分混合放入模具中， 在 lOOMPa的压力 下保温 2〜3min后取出， 将压制成的样品放入高温扩散炉中， 在氢气保护气氛环境下进行 烧结， 升温速率为 100°C/h， 200°C保温 5h， 500°C保温 2h。 随炉冷却至室温， 得到多孔钛 膜， 厚度为 0.2mm。 将膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用外加物理 作用力固定在螺旋卷裹圆筒体上， 于 600°C烧结 30min后取出， 得到螺旋卷裹圆筒体状结 构的金属镁多孔支架单元体 4， 孔隙 3间相互贯通， 平均孔径为 200.6μηι， 孔隙率为 63%。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 6
在 600°C， 真空条件下， 将熔融镁合金（Mg-9wt%Al-lwt%Zn-0.2wt%Mn)注入到具有 通孔结构的石膏铸型中， 使镁液充分渗入石膏铸型的狭窄通道内， 完成浇注后， 用水喷淋 石膏铸型使石膏模破裂， 充分清洗， 得到多孔镁合金膜， 厚度为 0.14mm。 将膜裁剪成适 合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用外加物理作用力固定在螺旋卷裹圆筒体上， 于 600°C烧结 30min后取出， 得到螺旋卷裹圆筒体状结构的镁合金多孔支架单元体 4， 孔 隙 3间相互贯通， 平均孔径为 287.3μηι， 孔隙率为 65%。 该支架单元体 4可以单独作为骨 修复支架体使用。
实施例 7
将按照实施例 4的方式制备而得的多孔钛膜作为阳极， 不锈钢作为阴极， 将其浸泡在 含有六偏磷酸钠 （100g/L) 和硝酸钙 （10g/L)， pH为 12的溶液中， 采用交流电 600V, 频 率 1500Hz, 占空比 20%， 电流密度 1200mA/cm2，在极距为 40cm的条件下微弧氧化 10min， 在多孔钛膜表面形成厚度约为 70μηι的图层。 X射线衍射分析表明该图层由二氧化钛、 CaTi4(P04)6 羟基磷灰石构成， 具有良好的生物活性。膜的厚度为 0.43mm。将带有生物活 性涂层的多孔钛膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用外加物理作用力 固定在螺旋卷裹圆筒体上， 于 850°C烧结 30min后取出， 得到带有生物活性涂层的螺旋卷 裹圆筒体状结构的金属钛多孔支架单元体 4， 孔隙 3间相互贯通， 平均孔径为 226.3μηι， 孔隙率为 78%。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 8
将 lg壳聚糖溶于 80mL浓度为 lvol%的醋酸溶液中， 充分搅拌使壳聚糖完全溶解并均 匀分散。 将 lOOmg MgS04加入 20mL浓度为 lvol%的醋酸溶液中， 搅拌溶解。 在持续搅拌 下，将上述 MgS04溶液缓慢加入上述壳聚糖溶液，并用 5%的 NaOH调 pH值至 5.5，反应 3h。。 将壳聚糖镁凝胶溶液流延至玻璃平皿中， 室温干燥。用 5%的 NaOH溶液浸泡 4h， 以中和残 留的醋酸， 50°C烘箱中干燥， 得到壳聚糖 -镁复合膜， 湿态下膜厚度为 0.10mm。 将所得的 壳聚糖 -镁膜片材料 2充分吸水溶胀， 用机械制孔法穿孔， 孔间距为 1.5mm， 孔径大小约为 200μηι。 将穿孔后的膜裁剪成适合的尺寸， 紧密螺旋卷裹， 边缘部分用少量 2vol%的醋酸 溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶 剂。 得到螺旋卷裹圆筒体状结构的壳聚糖 -镁多孔支架单元体 4， 孔隙 3间相互贯通， 孔径 大小约为 200μηι， 孔隙率为 90%。 该支架单元体 4可以单独作为骨修复支架体使用。 实施例 9
将 0.4g壳聚糖和 0.4g羧甲基纤维素钠加入 50mL去离子水中，充分搅拌使羧甲基纤维 素钠完全溶解，并使壳聚糖在溶液中均匀分散。在持续搅拌作用下，将 20mL浓度为 2vol% 的醋酸溶液逐渐滴加到原溶液中。 待醋酸溶液滴加完毕， 迅速将粘稠状成膜液倾注到玻璃 平皿中， 水平铺展成膜片状， 60°C烘干， 湿态下膜的厚度为 0.24mm。 用 1^%的 NaOH溶 液浸泡以中和膜内残留的醋酸， 用蒸馏水充分洗涤后自然风干。将所得的壳聚糖 /羧甲基纤 维素钠膜片材料 2 充分吸水溶胀， 用机械制孔法穿孔， 孔间距为 2.0mm， 孔径大小约为 350μηι。 将穿孔后的膜裁剪成适合的尺寸， 紧密螺旋卷裹， 边缘部分用少量 2vol%的醋酸 溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶 剂。 得到螺旋卷裹圆筒体状结构的壳聚糖 /羧甲基纤维素钠多孔支架单元体 4， 孔隙 3间相 互贯通， 孔径大小约为 350μηι， 孔隙率为 85%。 该支架单元体 4可以单独作为骨修复支架 体使用。
实施例 10
将 lg壳聚糖溶于 50mL浓度为 2vol%的醋酸溶液中，充分搅拌使壳聚糖完全溶解并均 匀分散。在壳聚糖的醋酸溶液中加入 50mL浓度为 2wt%的胶原溶胀液（胶原溶液的制备可 参照文献《生物医学工程学杂志》 1999: 16 (2) :147-150吴志谷， 盛志勇等报道的方法）， 充分搅拌，使胶原溶胀液溶解于壳聚糖溶液中并混合均匀。在混合溶液中加入 2g十六烷基 三甲基氯化铵和 2g 月桂酰肌氨酸钠， 在转速 1000 转 /分下搅拌 30 分钟， 再加入少量 0.25vol%的戊二醛溶液， 搅拌均匀以后倾注到玻璃平皿中， 水平铺展成膜片状， 于 -20°C冷 冻成型， 真空干燥， 湿态下膜厚度为 0.32mm。 以 1^%的 NaOH溶液中和残余醋酸， 用蒸 馏水充分洗涤并冷冻干燥，得到多孔的壳聚糖 /胶原膜片材料 2。将所得的膜充分吸水溶胀， 裁剪成合适的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 2vol%的醋酸溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到螺旋卷 裹圆筒体状结构的壳聚糖 /胶原多孔支架单元体 4， 其中的孔隙 3间相互贯通， 平均孔径为 200.5μηι, 孔隙率为 93%。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 11
按照文献 Li Yubao, K.de Groot, J.de Wy'n, C.P.A.T. Klein and S.v.d. Meer, J. Mater. Sci: Mater, in Med., 5(1994): 326-331所制备的纳米磷灰石浆料， 经离心脱水后用二甲亚砜分散， 得到浓度为 10wt%的纳米磷灰石浆料。将 1.5g聚乳酸溶于 50mL二甲亚砜，在持续搅拌下， 加入 10mL以二甲亚砜为分散剂的 10wt%纳米磷灰石浆料， 并使其均匀分散在体系中。 再 加入 40〜60目的 NaCl颗粒 60g， 充分搅拌使盐粒分布均匀， 制成粘稠状成膜液。将成膜液 倾注到玻璃平皿中， 水平铺展成膜片状， 50°C真空干燥， 湿态下膜厚度为 0.23mm。 用蒸 馏水反复浸泡、 洗涤， 以除去膜内的 NaCl颗粒， 得到多孔的聚乳酸 /纳米磷灰石膜片材料 2。将膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量二甲亚砜溶蚀表面， 粘 合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到螺旋卷裹 圆筒体状结构的聚乳酸 /纳米磷灰石多孔支架单元体 4， 孔隙 3 间相互贯通， 平均孔径为 225.2μηι, 孔隙率为 82%。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 12
将 1.5g壳聚糖溶于 50mL浓度为 2vol%的醋酸溶液中， 充分搅拌使壳聚糖完全溶解并 均匀分散。 持续搅拌作用下， 将 10mL浓度为 10wt%的纳米磷灰石浆料 （纳米磷灰石浆料 的制备可参照文献 Li Yubao, K.de Groot, J.de Wy'n, C.P.A.T. Klein and S.v.d. Meer, J. Mater. Sci: Mater, in Med., 5(1994): 326-331 )缓慢滴加至壳聚糖溶液中， 充分搅拌， 使纳米磷灰石 均匀分散在壳聚糖溶液中， 得到无可见颗粒状物的粘稠成膜液。 将成膜液倾注到玻璃平皿 中， 水平铺展成膜片状， 60°C烘干。 用 lwt%的 NaOH溶液浸泡以中和膜内残留的醋酸， 用蒸馏水充分洗涤后自然风干， 膜的厚度为 0.35mm。 将所得的壳聚糖 /纳米磷灰石膜片材 料 2充分吸水溶胀， 用机械制孔法穿孔， 孔间距为 2.5mm， 孔径大小约为 400μηι。 将穿孔 后的膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 2vol%的醋酸溶液溶蚀 表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到 螺旋卷裹圆筒体状结构的壳聚糖 /纳米磷灰石多孔支架单元体 4，纳米磷灰石含量为 40wt%， 孔隙 3间相互贯通， 孔径大小约为 400μηι， 孔隙率为 89%。 该支架单元体 4可以单独作为 骨修复支架体使用。
实施例 13
将 0.5g壳聚糖和 0.5g羧甲基纤维素钠加入 50mL浓度为 1.5wt%的纳米磷灰石浆料中 (纳米磷灰石浆料的制备可参照文献 Li Yubao, K.de Groot, J.de Wy'n, C.P.A.T. Klein and S.v.d. Meer, J. Mater. Sci: Mater, in Med., 5(1994): 326-331 ), 充分搅拌使羧甲基纤维素钠完 全溶解， 并使壳聚糖和纳米磷灰石在溶液中均匀分散。 在持续搅拌作用下， 将 12.5mL浓 度为 2vol%的醋酸溶液逐渐递加到混合溶液中。 待醋酸溶液滴加完毕， 迅速将粘稠状成膜 液倾注到玻璃平皿中， 水平铺展成膜片状， 60°C烘干。 用 lwt%的NaOH溶液浸泡以中和 膜内残留的醋酸， 用蒸馏水充分洗涤后自然风干， 湿态下膜壁厚度为 0.33mm。 将所得的 壳聚糖 /羧甲基纤维素钠 /纳米羟基磷灰石膜片材料 2充分吸水溶胀， 用机械制孔法穿孔， 孔间距为 2.5mm，孔径大小约为 400μηι，孔隙率为 78%。将穿孔后的膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 2vol%的醋酸溶液溶蚀表面， 粘合在螺旋卷裹圆筒 体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到螺旋卷裹圆筒体状结构的壳 聚糖 /羧甲基纤维素钠 /纳米羟基磷灰石多孔支架单元体 4， 孔隙 3间相互贯通。该支架单元 体 4可以单独作为骨修复支架体使用。
实施例 14
将 lg壳聚糖溶于 50mL浓度为 2vol%的醋酸溶液中，充分搅拌使壳聚糖完全溶解并均 匀分散。在壳聚糖的醋酸溶液中加入 50mL浓度为 2wt%的胶原溶胀液（胶原溶液的制备可 参照文献《生物医学工程学杂志》 1999: 16 (2) :147-150吴志谷， 盛志勇等报道的方法）， 充分搅拌， 使胶原溶胀液溶解于壳聚糖溶液中并混合均匀。 持续搅拌作用下， 将 30mL浓 度为 10wt%的纳米磷灰石浆料 （纳米磷灰石浆料的制备可参照文献 Li Yubao, K.de Groot, J.de Wijn, C.P.A.T. Klein and S.v.d. Meer, J. Mater. Sci: Mater, in Med., 5(1994): 326-331 )缓慢 滴加至壳聚糖 /胶原溶液中， 充分搅拌使纳米磷灰石均匀分散在体系中， 得到无可见颗粒状 物的粘稠成膜液。 在混合溶液中加入 2g十六烷基三甲基氯化铵和 2g月桂酰肌氨酸钠， 在 转速 1000转 /分下搅拌 30分钟， 再加入少量 0.25vol%的戊二醛溶液， 搅拌均匀以后倾注到 玻璃平皿中， 水平铺展成膜片状， 于 -20°C冷冻成型， 真空干燥。 以 lwt%的NaOH溶液中 和残余醋酸， 用蒸馏水充分洗涤并冷冻干燥， 得到多孔的壳聚糖 /胶原 /纳米磷灰石膜片材 料 2，湿态下膜壁厚度为 0.38mm。将所得的膜片材料 2充分吸水溶胀，裁剪成合适的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 2vol%的醋酸溶液溶蚀表面， 粘合在螺旋卷裹圆筒 体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到螺旋卷裹圆筒体状结构的壳 聚糖 /胶原 /纳米磷灰石多孔支架单元体 4， 如图 2所示。 其中壳聚糖 /胶原 /纳米磷灰石重量 比为 1 :1 :3， 支架单元体中孔隙 3间相互贯通， 平均孔径为 221.4μηι， 孔隙率为 88%。
该支架单元体 4除可以单独作为骨修复支架体使用外， 也可以将多个上述支架单元体 4并行排列组合， 相邻部分用少量 2vol%的醋酸溶液溶蚀表面， 将多个螺旋卷裹圆筒体粘 合在一起， 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂， 即得到组合体式的多孔骨修 复支架体 5， 如图 3所示。
实施例 15
将 lg壳聚糖溶于 50mL浓度为 2vol%的醋酸溶液中，充分搅拌使壳聚糖完全溶解并均 匀分散。在壳聚糖的醋酸溶液中加入 50mL浓度为 2wt%的胶原溶胀液（胶原溶液的制备可 参照文献《生物医学工程学杂志》 1999: 16 (2) :147-150吴志谷， 盛志勇等报道的方法）， 充分搅拌， 使胶原溶胀液溶解于壳聚糖溶液中并混合均匀。 在壳聚糖 /胶原混合液中加入 0.5g聚己内酯超细纤维 （其制备可参照文献 Yi Zuo, Fang Yang, Joop G.C. Wolke, Yubao Li and John A. Jansen, Acta Biomater., 6(2010): 1238-1247), 充分搅拌使其均匀分散在体系中。 在混合溶液中加入 2g十六烷基三甲基氯化铵和 2g月桂酰肌氨酸钠， 在转速 1000转 /分下 搅拌 30分钟， 再加入少量 0.25vol%的戊二醛溶液， 搅拌均匀以后倾注到玻璃平皿中， 水 平铺展成膜片状， 于 -20°C冷冻成型， 真空干燥。 以 lwt%的NaOH溶液中和残余醋酸， 用 蒸馏水充分洗涤并冷冻干燥， 得到多孔的壳聚糖 /胶原 /聚己内酯膜片材料 2， 湿态下膜壁厚 度为 0.36mm。 将所得的膜片材料 2充分吸水溶胀， 裁剪成合适的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 2vol%的醋酸溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用 蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到螺旋卷裹圆筒体状结构的壳聚糖 /胶原 /聚己 内酯多孔支架单元体 4， 其中壳聚糖 /胶原 /聚己内酯重量比为 2:2:1，支架单元体中的孔隙 3 间相互贯通， 平均孔径为 186.4μηι， 孔隙率为 73%。 该支架单元体 4可以单独作为骨修复 支架体使用。
实施例 16
将 lg壳聚糖溶于 50mL浓度为 2vol%的醋酸溶液中，充分搅拌使壳聚糖完全溶解并均 匀分散。在壳聚糖的醋酸溶液中加入 50mL浓度为 2wt%的胶原溶胀液（胶原溶液的制备可 参照文献《生物医学工程学杂志》 1999: 16 (2) :147-150吴志谷， 盛志勇等报道的方法）， 充分搅拌， 使胶原溶胀液溶解于壳聚糖溶液中并混合均匀。 在壳聚糖 /胶原混合液中加入 0.5g聚乳酸超细纤维 （其制备可参照文献 Yi Zuo, Fang Yang, Joop G.C. Wolke, Yubao Li and John A. Jansen, Acta Biomater., 6(2010): 1238-1247),充分搅拌使其均匀分散在体系中。在混 合溶液中加入 2g十六烷基三甲基氯化铵和 2g月桂酰肌氨酸钠， 在转速 1000转 /分下搅拌 30分钟， 再加入少量 0.25vol%的戊二醛溶液， 搅拌均匀以后倾注到玻璃平皿中， 水平铺展 成膜片状， 于 -20°C冷冻成型， 真空干燥。 以 lwt%的NaOH溶液中和残余醋酸， 用蒸馏水 充分洗涤并冷冻干燥， 得到多孔的壳聚糖 /胶原 /聚乳酸膜片材料 2， 湿态下膜壁厚度为 0.35mm。 将所得的膜片材料 2充分吸水溶胀， 裁剪成合适的尺寸， 紧密螺旋卷裹， 末端边 缘部分用少量 2vol%的醋酸溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充 分浸泡和漂洗以除去残留溶剂。 得到螺旋卷裹圆筒体状结构的壳聚糖 /胶原 /聚乳酸多孔支 架单元体 4， 其中壳聚糖 /胶原 /聚乳酸重量比为 2:2: 1， 支架单元体中的孔隙 3间相互贯通， 平均孔径为 180.8μηι， 孔隙率为 80%。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 Π
将按实施例 11的方式制备而得的聚乳酸 /纳米磷灰石多孔膜片材料 2， 与按实施例 16 的方式制备而得的壳聚糖 /胶原 /聚乳酸多孔膜片材料 22平面叠置重合在一起，如图 3所示。 将该平面叠置重合的两层膜片材料 2， 22紧密螺旋卷裹，两膜片材 2和 22的末端边缘部分 1和 11分别用少量二甲亚砜溶蚀表面后， 均粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充 分浸泡和漂洗以除去残留溶剂。 得到双层螺旋卷裹圆筒体状结构的聚乳酸 /纳米磷灰石 /壳 聚糖 /胶原多孔支架单元体 4， 如图 5所示。
该支架单元体 4除可以单独作为骨修复支架体使用外， 将多个上述支架单元体并行排 列组合， 相邻部分用少量二甲亚砜溶蚀表面， 将多个螺旋卷裹圆筒体粘合在一起， 凉干后 用蒸馏水充分浸泡和漂洗以除去残留溶剂， 可以得到组合体式的多孔骨修复支架体 5， 如 图 6所示。
实施例 18
将按实施例 2的方式制备而得的聚己内酯多孔膜片材料， 与按实施例 9的方式制备而 得的壳聚糖 /羧甲基纤维素钠多孔膜片材料以及按实施例 14的方式制备而得的壳聚糖 /胶原 /纳米磷灰石多孔膜片材料平面叠置重合后， 紧密螺旋卷裹， 末端边缘部分均用少量二甲亚 砜溶蚀表面，粘合在螺旋卷裹圆筒体上。凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到三层螺旋卷裹圆筒体状结构的聚己内酯 /壳聚糖 /羧甲基纤维素钠 /胶原 /纳米磷灰石多 孔支架单元体 4。 该支架单元体 4可以单独作为骨修复支架体使用。
实施例 19
同实施例 7所述的方式制备的壳聚糖 /羧甲基纤维素钠 /纳米羟基磷灰石多孔支架单元 体 4， 将 15mg黄芪 （或抗生素、 头孢菌素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺酮类、 三 七、 小蓟等） 分散在 10ml蒸馏水中， 制成含药液， 把支架单元体浸渍于上述含药溶液中， 4°C浸泡 3小时， 冷冻干燥后 4°C保存， 得到具有药物缓释功能的多孔支架单元体。
实施例 20
同实施例 8所述的方式制备而得的壳聚糖 /胶原 /纳米磷灰石多孔支架单元体 4，将 10mg 骨形成蛋白 （或转化生长因子 -β、 成纤维细胞生长因子、 红细胞生成素、 血小板生成素、 血小板衍生生长因子等） 分散在 10ml蒸馏水中， 制成生长因子液， 把支架浸渍于上述含 生长因子的溶液中， 4°C浸泡 24小时， 冷冻干燥后 4°C保存， 得到具有诱导组织再生功能 的多孔支架单元体。
实施例 21
取按照实施例 3所述的方式制备的聚酰胺 66粘稠状成膜液 20g， 冷却至室温后， 加入 lOOmg载抗生素 （或头孢菌素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺酮类、 三七、 小蓟、 黄芪等） 的壳聚糖微球 （平均直径为 15μηι)， 搅拌 30min后， 倾注到玻璃平皿中， 水平铺 展成膜片状， 室温风干。 用蒸馏水反复浸泡、 洗涤， 室温风干， 得到多孔的聚酰胺 66膜片 材料 2。 将膜裁剪成适合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量含氯化钙的乙醇 溶液溶蚀表面， 粘合在螺旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶 剂。 得到具有药物缓释功能的聚酰胺 66多孔支架单元体。
实施例 22
取按照实施例 12所述的方式制备的壳聚糖 -羟基磷灰石粘稠状成膜液 30g，加入 200mg 载三七 （或抗生素、 头孢菌素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺酮类、 三七、 小蓟、 黄芪等） 的壳聚糖微球 （平均直径为 15μηι)和 lOOmg载转化生长因子 -β (或骨形成蛋白、 成纤维细胞生长因子、 红细胞生成素、 血小板生成素、 血小板衍生生长因子等） 的胶原微 球 （平均直径为 ΙΟμηι), 搅拌 40min后， 倾注到玻璃平皿中， 水平铺展成膜片状， 室温风 干。用蒸馏水充分洗涤后再自然风干。将所得的壳聚糖 /纳米磷灰石膜片材料 2充分吸水溶 胀， 用机械制孔法穿孔， 孔间距为 2.0mm， 孔径大小约为 300μηι。 将穿孔后的膜裁剪成适 合的尺寸， 紧密螺旋卷裹， 末端边缘部分 1用少量 2vol%的醋酸溶液溶蚀表面， 粘合在螺 旋卷裹圆筒体上。 凉干后用蒸馏水充分浸泡和漂洗以除去残留溶剂。 得到具有药物缓释功 能和诱导组织再生功能的壳聚糖 /纳米磷灰石多孔支架单元体。 具体通过如下试验例来说明本发明的有益效果。
试验例 1 细胞实验
材料： ΡΑ66/ΗΑ (40 %ΗΑ)多孔支架、 ΡΑ66/ΗΑ (4θ %ΗΑ)多孔膜。 其中， ΡΑ66为 聚酰胺 66 (polyamide 66) HA为羟基磷灰石（hydroxyapatite), 百分比是指 HA占材料总 质量的质量百分比。 本试验例中所指的多孔支架是一体成型的整体多孔支架， 制备方法可 参照文献 Huanan Wang, Yubao Li, Yi Zuo, Jihua Li, Sansi Ma and Lin Cheng, Biomaterials 28 (2007): 3338-3348； 多孔膜的制备方法可参照专利 CN1887365A。
细胞： MG63
培养基： F12
培养条件： 将材料置于 24孔板内， 以 2x l04个 /孔的密度接种细胞， 隔天换液， 培养 4 天后， 用戊二醛固定， 乙醇梯度脱水， 乙酸异戊酯替换， 临界点干燥， SEM (JSM-6510LV， Japan, 20KV)观察。
结果见图 7。
根据结果可知： 两种材料表面的细胞形态都呈多边形或梭型， 细胞伸出伪足与旁边细 胞的伪足相互接触， 有的细胞两端跨越孔隙， 有的长入材料的大孔中， 细胞铺展情况良好。 实验说明无论是多孔整体支架还是多孔膜材料， 都具有良好的细胞亲和性， 有利于成骨样 细胞的黏附、 铺展和增殖。
试验例 2 动物实验 材料： CS/NaCMC/HA(60%HA)膜卷支架 （膜厚度： 180μηι， 孔径： 300μηι， 膜卷支 架底面直径： 3mm， 高： lcm)。 其中， CS为壳聚糖 （chitosan)、 NaCMC为羧甲基纤维素 钠 ( sodium carboxymethyl cellulose ) HA为轻基磷灰石 (hydroxyapatite), 百分比是指 HA 占材料总质量的质量百分比。 本试验例所用膜卷支架是按实施例 13的方法制备得到的。
实验条件： 兔桡骨部分缺损 (长 lcm，高 3mm)， 将膜卷支架放入缺损， 用缝线固定 （如 图 8所示）。 空白组制造同样尺寸的缺损， 不植入材料， 直接缝合伤口。 手术后 2个月， X 光观察。
结果见图 9。
根据结果可知： 空白组的缺损处长出部分新骨； 本发明材料组的新骨生长情况要好于 空白组， 通过 X光片可以观察到， 材料边缘部分已与新骨长在一起， 并且材料中间新骨完 全贯穿生长。
试验例 3 力学测试
材料： PA66/HA C40wi%HA)多孔支架、 PA66/HA (40ν ί%ΗΑ)多孔膜卷支架。其中， ΡΑ66 为聚酰胺 66 (polyamide 66) HA为羟基磷灰石（hydroxyapatite), 百分比是指 HA占材料 总质量的质量百分比。 本试验例中所指的多孔支架是一体成型的整体多孔支架， 制备方法 可参照文献 Huanan Wang, Yubao Li, Yi Zuo, Jihua Li, Sansi Ma and Lin Cheng, Biomaterials 28 (2007): 3338-3348； 多孔膜卷支架， 可先参照专利 CN1887365A的方法制备多孔膜， 再 采用本发明方法制备得到多孔膜卷支架。
材料尺寸： PA66/HA (40 %HA)多孔支架（长方体）一长： lcm， 宽： lcm， 高： 2cm 孔隙率 （85%-90%)， 孔径 300μηι〜800μηι。
ΡΑ66/ΗΑ (40 %ΗΑ)多孔膜卷支架（圆柱体）一底面直径： lcm， 高： 2cm， 孔隙率 （85%-90%)， 膜厚度： 330μηι， 孔径 3μηι〜800μηι。
测试条件： 压縮速度： 0.5mm/min
温度： 室温 湿度： 75%RH
结果见表 1、 图 10。
表 1
Figure imgf000016_0001
根据结果可知： 对于相同组分、 相似孔隙率的多孔支架和多孔膜卷支架， 多孔膜卷支 架的屈服强度 （0.812 ± 0.127 MPa) 要明显高于多孔整体支架 （0.447 ± 0.153 MPa)。 综上所述， 本发明仿生结构可降解骨修复支架体具有良好的修复能力， 并且， 本发明 的膜卷结构修复支架体的力学性能显著优于现有技术中的支架结构。 本发明修复支架体的 制备方法简单， 条件温和易控制， 且具有可塑性强的特点， 根据临床使用需要， 该骨修复 支架体的大小尺寸， 可以通过控制所说的片层材料的厚度和 /或高度， 以及螺旋卷裹的层数 等方式， 灵活方便地进行调整因此， 本发明的仿生结构可降解骨修复支架体在生物医学材 料领域中具有理想的推广和应用价值。 工业应用性
本发明仿生结构可降解骨修复支架体具有良好的修复能力， 并且 ， 其力学性能显著优 于现有技术中的支架结构； 同时， 本发明修复支架体的制备方法简单， 条件温和易控制， 且具有可塑性强的特点， 具有极好的临床应用和工业化前景。

Claims

权 利 要 求 书
1.具有层状结构的仿生骨修复支架体， 其特征是由至少一个支架单元体 （4) 构成， 该支架单元体（4)为由片层材料（2) 由内向外连续紧密卷裹、截面呈螺旋状的柱体结构， 其直径为 0.1mm〜50mm。
2.如权利要求 1 所述的骨修复支架体， 其特征是在所说的片层材料 （2 ) 的厚度为 0.01mm〜lmm。
3.如权利要求 1所述的骨修复支架体， 其特征是在所说的片层材料 （2) 的延展面中 分散分布有孔径为 50μηι〜800μηι的贯通孔隙 （3)。
4.如权利要求 3所述的骨修复支架体， 其特征是所说的分散分布的贯通孔隙 （3 ) 在 片层材料 （2) 的延展面中以均匀或大体均匀分散的方式分布。
5.如权利要求 3所述的骨修复支架体， 其特征是所说的分散分布的贯通孔隙 （3 ) 的 孔隙率为占片层材料 （2) 体积的 70%〜95%。
6.如权利要求 1所述的骨修复支架体， 其特征是所说的片层材料 （2) 至少其表层为 可降解材料。
7.如权利要求 6所述的骨修复支架体， 其特征是所说的片层材料 （2) 为在由非降解 性的医用高分子、 非降解性的医用金属或金属合金、 非降解性的生物陶瓷、 非降解性的生 物复合材料的结构体表面， 被覆有可降解材料层的形式。
8.如权利要求 6所述的骨修复支架体， 其特征是所说的片层材料 （2) 为由可生物降 解的生物高分子成分、 可生物降解的医用金属或其合金、 可生物降解的生物陶瓷， 或是由 这些不同成分的复合成分组成。
9.如权利要求 8所述的骨修复支架体， 其特征是片层材料 （2) 由所说的生物高分子 成分与混合状分散分布的直径为 10ηηι〜100μηι的纤维成分共同组成， 所说的纤维成分为天 然纤维或人工制备纤维中的至少一种。
10.如权利要求 9所述的骨修复支架体， 其特征是所说的纤维成分为片层材料（2)总 重量的 1%〜60%。
11.如权利要求 10所述的骨修复支架体， 其特征是所说的纤维成分为片层材料 （2) 总重量的 5%〜20%。
12. 如权利要求 1至 11之一所述的骨修复支架体， 其特征是在所说的片层材料 （2) 的表面被覆有具有骨传导生物活性的钙的磷酸盐材料涂层。
13.如权利要求 8所述的骨修复支架体， 其特征是片层材料（2)由所说的生物高分子 成分与纳米类骨磷灰石成分共同组成， 所说的纳米类骨磷灰石成分为片层材料（2)总重量 的 1%〜80%， 纳米类骨磷灰石成分中的钙 /憐摩尔比为 1.2〜2.0: 1。
14.如权利要求 13所述的骨修复支架体， 其特征是所说片层材料 （2) 中的纳米类骨 磷灰石的含量为片层材料 （2) 总重量的 40%〜60%。
15.如权利要求 13或 14所述的骨修复支架体， 其特征是所说的纳米类骨磷灰石成分 为由钙盐化合物与磷酸或磷酸盐反应所得到的纳米磷灰石针晶、 棒晶或片晶成分。
16. 如权利要求 1至 11、 13、 14之一所述的骨修复支架体， 其特征是所说的片层材料 (2) 中还含有其总重量 0.05%〜20%的药物成分和 /或组织生长因子， 所说的药物成分包括 抗生素、 头孢菌素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺酮类、 三七、 小蓟、 黄芪中的至 少一种； 所说的组织生长因子包括骨形成蛋白、 转化生长因子 -β、 成纤维细胞生长因子、 红细胞生成素、 血小板生成素、 血小板衍生生长因子中的至少一种。
17. 如权利要求 1至 11、 13、 14之一所述的骨修复支架体， 其特征是所说的支架结构 单体（4)为由单层或平面叠置的至少两层分别含有不同成分的所说片层材料（2)， 以所说 的连续紧密卷裹形式的状柱体结构。
18. 如权利要求 1至 11、 13、 14之一所述的骨修复支架体， 其特征是支架体由至少两 个所说的支架结构单体（4)， 以其长度方向平行的并列方式紧密固定所成的组合体（5 )的 形式。
19. 制备权利要求 1所述的仿生骨修复支架体的方法， 其特征是将适当成分的片层材 料（2)， 以其延展面由内向外螺旋状连续紧密卷裹成直径为 0.1mm〜50mm的卷裹结构体后 ， 将延展面的末端卷裹边缘（1 ) 固定于卷裹结构体的对应表面， 得到支架单元体（4)， 以 该单一的支架单元体 （4) 或者将至少两个支架单元体 （4) 以其长度方向平行的并列方式 紧密粘接固定成组合体（5 )， 构成相应的骨修复支架体， 所说片层材料（2) 的成分为生物 高分子材料、 或者生物陶瓷、 或者医用金属或合金材料， 或者这些材料的复合材料。
20. 如权利要求 19所述的制备方法， 其特征是所说的片层材料 （2) 为在以粒子沥滤 法、气体发泡法、熔模铸造法、 电沉积法制备时， 或是在片层材料成型后经机械穿孔方式， 在其延展面上形成分散分布的直径为 50μηι〜800μηι的贯通孔隙 （3 )。
21. 如权利要求 19所述的制备方法， 其特征是以医用高分子成分为制膜原料， 在其溶 解于溶剂的分散体系中， 还均匀分散有成膜成分总质量 1%〜60%的非溶解态的纤维成分， 或含有成膜成分总质量 1%〜80%的纳米类骨磷灰石晶体成分中的至少一种， 所说的纤维成 分为直径 10ηηι〜100μηι的天然纤维或人工纤维中的至少一种， 所说的纳米类骨磷灰石晶体 成分为由钙盐化合物与磷酸或磷酸盐反应所得到的纳米磷灰石针晶、 棒晶或片晶。
22. 如权利要求 19所述的制备方法， 其特征是在以医用高分子成分为制膜原料， 在其 溶解于溶剂的分散体系中，还均匀分散有成膜成分总质量 0.05%〜20%的药物成分和 /或组织 生长因子， 所说的药物成分包括抗生素、 头孢菌素类、 β-内酰胺类、 氨基糖甙类、 氟喹诺 酮类、 三七、 小蓟、 黄芪中的至少一种； 所说的组织生长因子包括骨形成蛋白、 转化生长 因子 -β、 成纤维细胞生长因子、 红细胞生成素、 血小板生成素、 血小板衍生生长因子中的 至少一种。
23. 如权利要求 19所述的制备方法， 其特征是在以医用高分子成分为制膜原料， 在片 层材料成型后， 或得到所说的支架单元体 （4) 后， 以浸渍方式将药物成分和 /或组织生长 因子沉淀于其浸渍表面上， 所说的药物成分包括抗生素、 头孢菌素类、 β-内酰胺类、 氨基 糖甙类、 氟喹诺酮类、 三七、 小蓟、 黄芪中的至少一种； 所说的组织生长因子包括骨形成 蛋白、 转化生长因子 -β、 成纤维细胞生长因子、 红细胞生成素、 血小板生成素、 血小板衍 生生长因子中的至少一种。
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Publication number Priority date Publication date Assignee Title
WO2019165395A1 (en) * 2018-02-26 2019-08-29 The Board Of Trustees Of The Leland Stanford Junior University Graft for segmental bone defect repair

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN111388756B (zh) * 2020-03-28 2021-05-11 四川大学 一种具有三层结构和各向异性的软骨支架及其制备方法
CN113713178B (zh) * 2021-08-31 2023-03-24 山东百多安医疗器械股份有限公司 一种促再生、防移位的人工髓核假体及其制备方法
CN115227719B (zh) * 2022-07-18 2024-06-21 西南交通大学 过氧化物酶活性优良的钙磷纳米酶

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040249463A1 (en) * 2003-06-05 2004-12-09 Bindseil James J. Bone strip implants and method of making same
CN1697634A (zh) * 2002-09-18 2005-11-16 Sdgi控股股份有限公司 天然组织装置和移植方法
CN1819806A (zh) * 2003-06-05 2006-08-16 Sdgi控股股份有限公司 融合植入物及其制造方法
US20070061015A1 (en) * 2005-09-09 2007-03-15 Peder Jensen System and method for tissue generation and bone regeneration
CN1997410A (zh) * 2004-07-05 2007-07-11 Ucl商业有限公司 非细胞依赖性制造组织等效物
CN101052362A (zh) * 2004-09-08 2007-10-10 株式会社钟化 生物体留置用支架
CN101754730A (zh) * 2007-07-18 2010-06-23 生物动力有限责任公司 用于肌骨损伤、矫形重建和软组织修复的可植入网状物
US20100310623A1 (en) * 2009-06-05 2010-12-09 Laurencin Cato T Synergetic functionalized spiral-in-tubular bone scaffolds

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN2778234Y (zh) * 2004-07-30 2006-05-10 李鼎锋 含化疗药物的医用诱导骨基质人工关节假体
CN101862230A (zh) * 2009-04-17 2010-10-20 华中科技大学同济医学院附属协和医院 控释型多层载药人工骨及其制备方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1697634A (zh) * 2002-09-18 2005-11-16 Sdgi控股股份有限公司 天然组织装置和移植方法
US20040249463A1 (en) * 2003-06-05 2004-12-09 Bindseil James J. Bone strip implants and method of making same
CN1819806A (zh) * 2003-06-05 2006-08-16 Sdgi控股股份有限公司 融合植入物及其制造方法
CN1997410A (zh) * 2004-07-05 2007-07-11 Ucl商业有限公司 非细胞依赖性制造组织等效物
CN101052362A (zh) * 2004-09-08 2007-10-10 株式会社钟化 生物体留置用支架
US20070061015A1 (en) * 2005-09-09 2007-03-15 Peder Jensen System and method for tissue generation and bone regeneration
CN101754730A (zh) * 2007-07-18 2010-06-23 生物动力有限责任公司 用于肌骨损伤、矫形重建和软组织修复的可植入网状物
US20100310623A1 (en) * 2009-06-05 2010-12-09 Laurencin Cato T Synergetic functionalized spiral-in-tubular bone scaffolds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019165395A1 (en) * 2018-02-26 2019-08-29 The Board Of Trustees Of The Leland Stanford Junior University Graft for segmental bone defect repair

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