WO2015113482A1 - 矿化胶原复合骨粘合及填充材料 - Google Patents

矿化胶原复合骨粘合及填充材料 Download PDF

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WO2015113482A1
WO2015113482A1 PCT/CN2015/071512 CN2015071512W WO2015113482A1 WO 2015113482 A1 WO2015113482 A1 WO 2015113482A1 CN 2015071512 W CN2015071512 W CN 2015071512W WO 2015113482 A1 WO2015113482 A1 WO 2015113482A1
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mineralized collagen
powder
filling material
polymethyl methacrylate
collagen
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PCT/CN2015/071512
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English (en)
French (fr)
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仇志烨
王昶明
崔福斋
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北京奥精医药科技有限公司
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Priority to US15/114,251 priority Critical patent/US20160375176A1/en
Publication of WO2015113482A1 publication Critical patent/WO2015113482A1/zh

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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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0094—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing macromolecular fillers
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/102—Collagen
    • 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
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention belongs to the field of biomedical materials, relates to a bone bonding and filling material, and particularly relates to a mineralized collagen composite polymethyl methacrylate bone bonding and filling material.
  • PMMA Polymethyl methacrylate
  • PVP Percutaneous vertebroplasty
  • PMMA bone cement has been used clinically for decades, and its safety, effectiveness and long-term effects have been confirmed by a large number of theoretical studies and clinical practice.
  • PMMA bone cement will cause some complications after surgery, such as re-fracture of adjacent vertebral bodies after PVP and bone cement damage prosthesis joints after joint replacement. These complications are mainly caused by the mechanical properties and biocompatibility of PMMA bone cement.
  • the elastic modulus of the cured body of the existing PMMA bone cement product is too high, causing wear or even chipping of the autologous bone or implanted prosthesis in contact with the bone cement.
  • the elastic modulus of PMMA bone cement for PVP is usually 2 to 3 GPa, which is much higher than 0.05 to 0.8 GPa of human vertebral cancellous bone elastic modulus.
  • the biocompatibility of PMMA stems from its biological inertness. Therefore, PMMA bone cement cannot form bone-binding with autologous bone tissue, and the cemented cement body is prone to loosening or even falling off at the implantation site. For example, after PVP, the cemented solid body is free in the vertebral body and even detached from the vertebral body. Therefore, the existing PMMA bone cement products still have large defects in clinical application, which easily lead to various complications, and finally have to be renovated through secondary surgery.
  • the elastic modulus of cement solidified body also seriously affects its compressive strength, which can not meet the clinical requirements, and the incorporation of NMP has the risk of causing central nervous system disease.
  • the biosafety of the product needs further evaluation.
  • researchers have used bioglass and chitosan to modify PMMA bone cement to obtain better biocompatibility improvement effect, but reduce the compressive strength of bone cement solidified body to below 50 MPa, which does not meet ISO standards. Regulations and clinical requirements.
  • the currently used PMMA bone cement products have shortcomings such as too high modulus of elasticity and poor biocompatibility.
  • the existing research on the mechanical properties and biocompatibility of PMMA bone cement is not effective.
  • bone cement products that have both high compressive strength and low modulus of elasticity and that have significantly improved biocompatibility compared to PMMA bone cement alone are not available.
  • the present invention provides a mineralized collagen composite PMMA bone bonding and filling material.
  • Mineralized collagen is prepared by in vitro biomimetic mineralization technology. It has the chemical composition and structure of nano-calcium phosphate and collagen molecules self-assembled, thus having a biomimetic mineral structure similar to human natural bone. Mechanical properties, good biocompatibility and osteogenic activity, and biodegradability.
  • the new bone binding and filling materials are prepared by combining mineralized collagen with PMMA.
  • the elastic modulus of the solidified body is significantly lower than that of the existing PMMA bone cement products, and has better biocompatibility and osseointegration ability.
  • the present invention provides a mineralized collagen composite PMMA bone bonding and filling material, which comprises a powder and a liquid.
  • the powder includes mineralized collagen, prepolymerized PMMA powder, and a polymerization initiator
  • the liquid includes a methyl methacrylate (MMA) monomer, a polymerization accelerator, and a stabilizer.
  • the powder may also include a contrast agent, a colorant, and the liquid may also include a colorant.
  • the ratio of the powder to the liquid is 1.5 to 3 g/mL.
  • the content of mineralized collagen is 5 to 30% by weight of the powder
  • the content of the prepolymerized PMMA powder is 70 to 95% by weight of the powder.
  • the content of the polymerization initiator is 0.3 to 0.8% by weight of the powder
  • the content of the MMA monomer is 98 ⁇ 1 vol% of the liquid
  • the content of the polymerization accelerator is 2 ⁇ 1 vol% of the liquid
  • the stabilizer is contained in the liquid in an amount of from 10 to 100 ppm.
  • the content of the contrast agent is 5 to 40% by weight of the powder.
  • the mineralized collagen is a collagen/hydroxyapatite composite solid particle having a particle diameter of 50 to 600 ⁇ m.
  • the mineralized collagen may further include a calcium phosphate material and a polyester as a reinforcing component.
  • the mineralized collagen the preparation method thereof comprises the following steps:
  • Step S1 the collagen is dissolved in any one of hydrochloric acid, nitric acid or acetic acid to prepare an acid solution of collagen, wherein the collagen concentration is 5.0 ⁇ 10 -5 to 5.0 ⁇ 10 -3 g/mL;
  • Step S2 continuously stirring the solution obtained in step S1, slowly adding a solution containing calcium ions, the amount of calcium ions added is 0.01 to 0.16 mol per kg of collagen;
  • Step S5 the mixed system obtained in step S4 is allowed to stand for 24 to 120 hours, the precipitate is separated and the impurity ions are washed away, and then freeze-dried, and the mineralized collagen powder is obtained after grinding;
  • Step S6 weigh a certain amount of the mineralized collagen powder obtained in the step S5, put it into the mold, and then apply pressure to the mold, and the pressure applied to the mineralized collagen powder reaches 900-1200 MPa, and the pressure is maintained at 30-300. Seconds, demoulding to obtain mineralized collagen blocks;
  • Step S7 the mineralized collagen pieces obtained in the step S6 are ground and sieved, and the mineralized collagen particles of the desired particle size are sieved.
  • the step S6 may also be:
  • Step S6 weighing a certain amount of the mineralized collagen powder obtained in step S5, uniformly mixing with a certain amount of calcium phosphate material powder and/or polyester powder, loading into a mold, and then applying pressure to the mold, and applying the material to the material.
  • the pressure on the upper reaches 600 ⁇ 1200MPa, the pressure is maintained for 30 ⁇ 300 seconds, and the mold is heated while maintaining the pressure, so that the temperature of the material in the mold reaches 70-220 °C, and the temperature is cooled down after the end of the pressure, and the mineralized collagen block is obtained by demoulding. .
  • the calcium phosphate material includes hydroxyapatite, ⁇ -tricalcium phosphate, ⁇ -tricalcium phosphate, octacalcium phosphate, and amorphous calcium phosphate, and has a particle diameter of 20 nm to 10 ⁇ m.
  • the polyester includes polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polycaprolactone, a molecular weight of 50,000 to 800,000, and a particle diameter of 1 to 200 ⁇ m.
  • the mineralized collagen content is 10 to 75 wt%
  • the content of calcium phosphate material is 10-40% by weight
  • the polyester content is from 10 to 60% by weight.
  • the prepolymerized PMMA powder has a molecular weight of 150,000 to 600,000 and a particle diameter of 50 to 300 ⁇ m.
  • the polymerization initiator is a substance capable of initiating radical polymerization of MMA to synthesize PMMA.
  • the initiator is benzoyl peroxide (BPO).
  • the contrast agent is an X-ray opaque powder material.
  • the contrast agent is zirconium oxide (ZrO 2 ), barium sulfate (BaSO 4 ) or hydroxyapatite (HA), and has a particle diameter of 0.5 to 2 ⁇ m.
  • the polymerization accelerator is a substance capable of continuously synthesizing PMMA by radical polymerization of MMA.
  • the promoter is N,N-dimethyl-p-toluidine (DMPT).
  • the stabilizer is a substance capable of preventing premature polymerization of MMA.
  • the stabilizer is hydroquinone (HQ).
  • the colorant is a fat-soluble dye having good biocompatibility, and the dye can be dissolved in the MMA monomer.
  • the colorant is chlorophyll (CP).
  • the powder and the liquid are mixed together in a ratio of 1.5 to 3 g/mL, and after rapid stirring, after 2 to 5 minutes of waiting time, the filling or the filling may be performed. Injection operation.
  • the typical working time of the mineralized collagen composite PMMA bone bonding and filling material is 5 to 12 minutes, and the curing time is 10 to 20 minutes.
  • the typical compressive strength of the solidified body is 70-100 MPa
  • the compressive modulus is 0.7-1.5 GPa
  • the bending strength is 40-60 MPa
  • the flexural modulus is 1.7-. 2.5GPa.
  • the new material is more complex with the mechanical properties of human bone tissue than PMMA bone cement, which reduces the risk of wear of the autologous bone, and can also effectively prevent the implanted prosthesis from being damaged by extrusion.
  • mineralized collagen composite PMMA bone bonding and filling materials are rich in mineralized collagen with good osteogenic activity, which can form bone-binding with autologous bone, which is beneficial to improve bone adhesion and filling material in planting.
  • the stability of the entry site makes the use of the new material safer and more reliable. Therefore, the mineralized collagen composite PMMA bone bonding and filling material provided by the invention has obvious advantages, can effectively reduce the current PMMA bone cement complications, and has broad application prospects.
  • FIG. 1 is a flow chart of a process for preparing mineralized collagen according to the present invention
  • Figure 3 is a cross-sectional view of the pure PMMA bone bonding and filling material cured body of the present invention
  • Figure 4 is a cross-sectional view of the bone cement and filler material cured body of the present invention.
  • Figure 5 is a scanning electron microscope observation of the bone cement and filler material cured body of the present invention.
  • Figure 6 is a result of biocompatibility cell evaluation experiments of the bone cement and filler material of the present invention.
  • Figure 1 is a flow chart showing the preparation process of mineralized collagen according to the present invention. According to the procedure shown in Figure 1, four kinds of mineralized collagen particles were prepared by different processes.
  • Step S1 dissolving 5 g of collagen in 10 L of an acetic acid solution having a concentration of 0.5 mol/L to prepare an acid solution of collagen;
  • Step S2 continuously stirring the solution obtained in the step S1, slowly adding 1 L of a CaCl 2 solution having a concentration of 1 mol/L;
  • Step S3 continuously stirring the solution obtained in step S2, slowly adding 1 L of a concentration of 0.6 mol / L of Na 2 HPO 4 solution;
  • Step S5 the mixed system obtained in step S4 is allowed to stand for 48 hours, the precipitate is filtered out, and washed by centrifugation with deionized water for 5 times, followed by freeze-drying, and grinding to obtain mineralized collagen powder;
  • Step S6 weigh 6g of the mineralized collagen powder obtained in step S5, into a mold groove of 11mm diameter, pressurize the mold and reach 100kN, maintain the pressure for 90 seconds, and obtain the mineralized collagen block after demoulding;
  • Step S7 the mineralized collagen pieces obtained in the step S6 are ground, and a series of mineralized collagen particles of different particle diameters are separated by using a stainless steel sieve of 50 ⁇ m, 200 ⁇ m, 300 ⁇ m, 400 ⁇ m, 500 ⁇ m, and 600 ⁇ m.
  • Steps S1 to S5 are the same as steps S1 to S5 described in the above process 1;
  • Step S6 weigh 4.5g of the mineralized collagen powder obtained in step S5, uniformly mix with 1.5g of hydroxyapatite powder having a particle diameter of 200nm to 1 ⁇ m, and then put it into a mold with a diameter of 11mm, and then pressurize the mold and reach 110kN. , maintaining the pressure for 180 seconds, demoulding to obtain a mineralized collagen block;
  • Step S7 is the same as step S7 described in the above Process 1.
  • Steps S1 to S5 are the same as steps S1 to S5 described in the above process 1;
  • Step S6 weigh 4.5g of the mineralized collagen powder obtained in step S5, uniformly mix with 1.5g of polylactic acid powder having a particle diameter of 50-150 ⁇ m, and then put it into a mold with a diameter of 11mm, and then pressurize the mold and reach 65kN, keeping The pressure is 45 seconds, and the mold is heated at the same time, so that the temperature of the material in the mold reaches 180 ° C, and the temperature is cooled down after the end of the pressure, and the mineralized collagen block is obtained by demoulding;
  • Step S7 is the same as step S7 described in the above Process 1.
  • Steps S1 to S5 are the same as steps S1 to S5 described in the above process 1;
  • Step S6 weighing 4 g of the mineralized collagen powder obtained in the step S5, uniformly mixing with 1 g of hydroxyapatite powder having a particle diameter of 200 nm to 2 ⁇ m, and 1 g of polylactic acid powder having a particle diameter of 50 to 150 ⁇ m, and then loading into a mold having a diameter of 11 mm. Then, pressurize the mold and reach 75kN, maintain the pressure for 45 seconds, while heating the mold, so that the temperature of the material in the mold reaches 200 ° C, after the end of the pressure, the natural cooling and cooling, demoulding to obtain mineralized collagen blocks;
  • Step S7 is the same as step S7 described in the above Process 1.
  • the mineralized collagen particle numbers prepared by the above four processes are listed in Table 1.
  • Examples of mineralized collagen composite PMMA bone adhesion and filling materials were prepared according to the components listed in Table 2, and work characteristics, mechanical properties tests and cell biology evaluations were performed. The working characteristics were tested in 5 samples per group and averaged after testing. Mechanical performance test 12 samples per group, according to ISO 5833 standard, the test results are recorded as M ⁇ SD (mean ⁇ standard deviation). Cell culture was evaluated for 5 samples per group, and MC3T3-E1 cells were used for experimental evaluation.
  • the powder components listed in Table 3 15 kinds of comparative examples were prepared, including the content of mineralized collagen, mineralized collagen content is too low / too high, mineralized collagen particle size is too small / too large.
  • the MMA of the liquid component was 9.8 mL
  • the DMPT was 0.2 mL
  • the HQ was 40 ppm, and no coloring agent.
  • PMMA is a powder with a molecular weight of 300,000 to 500,000 and a particle size of 50 to 200 ⁇ m.
  • Contrast agents are all ZrO 2 powders with a particle size of 1.2 ⁇ 0.4 ⁇ m.
  • PMMA is a powder with a molecular weight of 300,000 to 500,000 and a particle size of 50 to 200 ⁇ m.
  • Contrast agents are all ZrO 2 powders with a particle size of 1.2 ⁇ 0.4 ⁇ m.
  • the working characteristics of the mineralized collagen composite PMMA bone bonding and filling material according to the embodiment of the present invention are: mixing time 30 seconds, waiting time 2 to 5 minutes, working time 5 to 12 minutes, curing time 10 to 20 minute.
  • This work characteristic meets the clinical use requirements.
  • the working characteristics are tested in a 23 ° C environment, and the operation time is determined according to factors such as the operating room environment, the type of surgery, the operator's habits, and surgical instruments.
  • the mechanical properties of the mineralized collagen composite PMMA bone bonding and filling materials of the examples and comparative examples were determined according to the method specified in ISO 5833, including compressive strength, compressive modulus, flexural strength and flexural modulus. The results are shown in Table 5. Listed.
  • the mechanical properties of the mineralized collagen composite PMMA bone bonding and filling material according to the embodiment of the invention are: compressive strength 70-100 MPa, compressive modulus 0.7-1.5 GPa, bending strength 40-60 MPa, flexural modulus 1.7 ⁇ 2.5GPa.
  • the above mechanical properties meet the requirements for clinical use.
  • the bone cement and filler material (Comparative Example C1 ⁇ C3) without mineralized collagen has a high compressive modulus, which has a high risk of clinical autologous bone wear.
  • Example E11 is a comparison of stress-strain curves of the mineralized collagen composite PMMA bone bonding and filling material (Example E11) and pure PMMA (Comparative Example C1) compression test of the present invention, wherein the shaded portion is normal for the human body.
  • the compressive modulus of the vertebral cancellous bone is a comparison of stress-strain curves of the mineralized collagen composite PMMA bone bonding and filling material (Example E11) and pure PMMA (Comparative Example C1) compression test of the present invention, wherein the shaded portion is normal for the human body.
  • the compressive modulus of the vertebral cancellous bone is a comparison of stress-strain curves of the mineralized collagen composite PMMA bone bonding and filling material (Example E11) and pure PMMA (Comparative Example C1) compression test of the present invention, wherein the shaded portion is normal for the human body.
  • the compressive modulus of the vertebral cancellous bone is a comparison of stress-strain curves
  • the slope of the linear section of the stress-strain curve of the pure PMMA solidified body is large, that is, the compressive modulus of the material is large, and far exceeds the compression modulus range of the cancellous bone of the normal vertebral body; and the composite of mineralized collagen
  • the elastic modulus of the solidified body is effectively reduced, and is basically in the range of the compressive modulus of the normal cancellous bone of the human body, and is more closely matched with the mechanical properties of the autologous bone, thereby avoiding damage to the autologous bone.
  • FIG. 3 is a cross-sectional view of the pure PMMA (Comparative Example C1) cured body of the present invention
  • FIG. 4 is a view showing the cured body of the mineralized collagen composite PMMA bone bonding and filling material (Example E11) of the present invention. Section observation. It can be seen that the mineralized collagen particles are evenly distributed in the bone cement and the solidified body of the filler material.
  • Fig. 5 is a scanning electron microscope observation of the cured body of the mineralized collagen composite PMMA bone bonding and filling material (Example E11) of the present invention.
  • Mineralized collagen (MC), PMMA and ZrO 2 were determined by energy spectrum detection. It can be seen that the mineralized collagen and the PMMA are tightly combined and have good compatibility with each other, which is advantageous for maintaining the mechanical strength of the solidified body.
  • the biocompatibility of bone adhesion and filling materials was evaluated by in vitro cell experiments using MC3T3-E1 cells derived from rat skull, cultured in vitro in a 48-well plate for 7 days, and the first and third were detected by CCK-8 method. The number of cells in 5 and 7 days (expressed by the absorbance value read by the microplate reader when CCK-8 was detected), and the cell proliferation curve was drawn. Cell experiments were performed in pure DMEM medium as a blank control.
  • Figure 6 shows the results of cell experiments. It can be seen that there is no significant difference in cell growth between the pure PMMA (Comparative C1) solidified body and the blank control group; and the mineralized collagen composite PMMA bone bonding and filling material (Example E11) On the solidified body, the proliferation of the cells was significantly better than that of the pure PMMA group and the blank control group. It indicates that the biocompatibility of mineralized collagen composite PMMA bone adhesion and filling material is better than pure PMMA, which is more favorable for good bone integration with autologous bone and preventing loosening or even falling off in the body.

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Abstract

矿化胶原复合PMMA骨粘合及填充材料，所述矿化胶原采用体外仿生矿化技术，由纳米钙磷盐和胶原分子自组装而成，其具备与人体天然骨相似的仿生矿化结构和机械性能、良好的生物相容性和成骨活性，以及可生物降解性。该材料兼具高抗压强度和低弹性模量，生物相容性较纯PMMA水泥得到改善。该材料能降低患者自体骨受磨损的风险，避免植入假体因挤压而遭到损坏，能与自体骨形成骨性结合，有利于提高骨粘合及填充材料在植入部位的稳定性，从而有效减少并发症的产生。

Description

矿化胶原复合骨粘合及填充材料 技术领域
本发明属于生物医用材料领域，涉及一种骨粘合及填充材料，具体涉及一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料。
技术背景
聚甲基丙烯酸甲酯(polymethyl methacrylate，PMMA)是骨科手术中普遍应用的一种骨粘合及填充材料，也被称为骨水泥，例如用于人工关节置换术中假体的固定、经皮椎体成形术(percutaneous vertebroplasty，PVP)治疗椎体压缩性骨折等等。PMMA骨水泥已经被用于临床几十年，其安全性、有效性和长期效果已经获得大量理论研究证明和临床实践证实。
然而，国内外陆续有报道称PMMA骨水泥在手术后会引起一些并发症，如PVP术后造成相邻椎体再骨折、关节置换术后骨水泥损坏假体关节柄等。这些并发症主要是由PMMA骨水泥的机械性能和生物相容性两方面因素共同造成的。机械性能方面，现有PMMA骨水泥产品的固化体弹性模量过高，会使与骨水泥接触的自体骨或植入假体产生磨损甚至碎裂。例如PVP用PMMA骨水泥固化体弹性模量通常可达2～3GPa，远高于人椎体松质骨弹性模量的0.05～0.8GPa。生物相容性方面，PMMA的生物相容性源于其生物惰性，因此PMMA骨水泥与自体骨组织无法形成骨性结合，骨水泥固化体在植入部位易发生松动甚至脱落。例如PVP术后，骨水泥固化体在椎体内产生游离，甚至脱离出椎体外。因此，现有PMMA骨水泥产品在临床应用中还存在较大缺陷，易导致多方面并发症的产生，最终不得不通过二次手术进行翻修。
目前，人们已经在PMMA骨水泥改性研究方面进行了一些探索。有研究者使用羟基磷灰石(hydroxyapatite，HA)及含锶羟基磷灰石对PMMA骨水泥进行改性，在生物相容性上获得了一定改善；然而HA的掺入使得PMMA骨水泥机械性能大幅下降，掺入的HA达到20％会使PMMA骨水泥抗压强度下降超过35％，从而低于ISO 5833规定 的PMMA骨水泥固化体最小抗压强度70MPa。有研究者从改变PMMA骨水泥的单体成分入手进行改性研究，在骨水泥的液体组分中添加N-甲基吡咯烷酮(N-methyl pyrrolidone，NMP)，然而该改性方法在显著下调骨水泥固化体弹性模量的同时，也严重影响了其抗压强度，无法满足临床要求，且NMP的掺入存在引发中枢神经系统病变的风险，产品生物安全性还有待进一步评价。还有研究者使用生物玻璃和壳聚糖对PMMA骨水泥进行改性，获得了较好的生物相容性改善效果，然而却使骨水泥固化体抗压强度降至50MPa以下，不符合ISO标准的规定和临床要求。
综上所述，目前临床使用的PMMA骨水泥产品存在固化体弹性模量太高、生物相容性不佳等缺点，现有研究对PMMA骨水泥机械性能和生物相容性的改性效果不理想，尚不能提供兼具高抗压强度和低弹性模量，且生物相容性较单纯PMMA骨水泥得到显著改善的骨水泥产品。
发明内容
针对上述现有PMMA骨水泥产品的不足，本发明提供一种矿化胶原复合PMMA骨粘合及填充材料。矿化胶原(mineralized collagen，MC)采用体外仿生矿化技术制备而成，具有纳米钙磷盐和胶原分子自组装而成的化学组成和结构，从而具备与人体天然骨相似的仿生矿化结构和机械性能、良好的生物相容性和成骨活性，以及可生物降解性。利用矿化胶原与PMMA复合制备新型骨粘合及填充材料，其固化体的弹性模量较现有PMMA骨水泥产品显著降低，并具有更好的生物相容性和骨整合能力。
本发明提供的矿化胶原复合PMMA骨粘合及填充材料，包括粉剂和液体两部分。其中，粉剂包括矿化胶原、预聚合PMMA粉末、聚合反应引发剂，液体包括甲基丙烯酸甲酯(methyl methacrylate，MMA)单体、聚合反应促进剂、稳定剂。粉剂还可以包括造影剂、着色剂，液体还可以包括着色剂。所述粉剂和液体的比例为1.5～3g/mL。
所述粉剂中，
矿化胶原的含量为所述粉剂的5～30wt％，
预聚合PMMA粉末的含量为所述粉剂的70～95wt％，
聚合反应引发剂的含量为所述粉剂的0.3～0.8wt％；
所述液体中，
MMA单体的含量为所述液体的98±1vol％，
聚合反应促进剂的含量为所述液体的2±1vol％，
稳定剂在所述液体中的含量为10～100ppm。
当所述粉剂中包括造影剂时，
造影剂的含量为所述粉剂的5～40wt％。
所述矿化胶原为胶原/羟基磷灰石复合固体颗粒，粒径为50～600μm。
所述矿化胶原还可以包括钙磷材料、聚酯作为增强成分。
所述矿化胶原，其制备方法包括以下操作步骤：
步骤S1、将胶原溶于盐酸、硝酸或醋酸中的任何一种，配制成胶原的酸溶液，其中胶原浓度为5.0×10-5～5.0×10-3g/mL；
步骤S2、持续搅拌步骤S1所得溶液，缓慢滴加含钙离子的溶液，钙离子的加入量为每克胶原对应加入钙离子0.01～0.16mol；
步骤S3、持续搅拌步骤S2所得溶液，缓慢滴加含磷酸根离子的溶液，磷酸根离子的加入量与步骤S2中钙离子加入量的摩尔比为Ca/P＝1/1～2/1；
步骤S4、持续搅拌步骤S3所得溶液，缓慢滴加NaOH溶液至混合体系pH＝6～8，当pH＝5～6时，混合体系开始出现沉淀，当pH＝7时，混合体系出现白色悬浊液；
步骤S5、将步骤S4所得混合体系静置24～120小时，分离出沉淀并洗去杂质离子，随后进行冷冻干燥，研磨后获得矿化胶原粉体；
步骤S6、称取一定量步骤S5获得的矿化胶原粉体，装入模具中，然后向模具施加压力，并使施加在矿化胶原粉体上的压强达到900～1200MPa，保持压力30～300秒，脱模得到矿化胶原块；
步骤S7、将步骤S6制得的矿化胶原块研磨并过筛，筛分出所需粒径的矿化胶原颗粒。
所述矿化胶原，其制备方法中，步骤S6还可以为：
步骤S6、称取一定量步骤S5获得的矿化胶原粉体，与一定量钙磷材料粉末和/或聚酯粉末均匀混合后，装入模具中，然后向模具施加压力，并使施加在物料上的压强达到600～1200MPa，保持压力30～300秒，保持压力的同时对模具加热，使模具中物料的温度达到70～220℃，保持压力结束后自然降温冷却，脱模得到矿化胶原块。
所述钙磷材料包括羟基磷灰石、α-磷酸三钙、β-磷酸三钙、磷酸八钙、无定形磷酸钙，粒径为20nm～10μm。
所述聚酯包括聚乳酸、聚羟基乙酸、乳酸-羟基乙酸共聚物、聚己内酯，分子量为50,000～800,000，粒径为1～200μm。
所述矿化胶原/钙磷材料/聚酯混合物中，
矿化胶原含量为10～75wt％；
钙磷材料含量为10～40wt％；
聚酯含量为10～60wt％。
所述预聚合PMMA粉末，其分子量为150,000～600,000，粒径为50～300μm。
所述聚合反应引发剂为能够引发MMA进行自由基聚合反应合成PMMA的物质，优选地，该引发剂为过氧化苯甲酰(benzoyl peroxide，BPO)。
所述造影剂为不透X射线的粉末物质。优选地，该造影剂为氧化锆(ZrO2)、硫酸钡(BaSO4)或羟基磷灰石(hydroxyapatite，HA)，粒径为0.5～2μm。
所述聚合反应促进剂为能使MMA的自由基聚合反应持续进行合成PMMA的物质。优选地，该促进剂为N,N-二甲基对甲苯胺(N,N-dimethyl-p-toluidine，DMPT)。
所述稳定剂为能够阻止MMA过早发生聚合反应的物质。优选地，该稳定剂为对苯二酚(hydroquinone，HQ)。
所述着色剂为具有良好生物相容性的脂溶性染料，该染料能够溶解在MMA单体中。优选地，该着色剂为叶绿素(chlorophyll，CP)。
使用本发明的矿化胶原复合PMMA骨粘合及填充材料，将所述粉剂和液体按照1.5～3g/mL的比例混合在一起，快速搅拌后经过2～5分钟等待时间，即可进行填塞或注射操作。该矿化胶原复合PMMA骨粘合及填充材料的典型工作时间为5～12分钟，固化时间为10～20分钟。
该矿化胶原复合PMMA骨粘合及填充材料固化24小时时固化体的典型抗压强度为70～100MPa，压缩模量为0.7～1.5GPa，弯曲强度为40～60MPa，弯曲模量为1.7～2.5GPa。
实施本发明，可以获得兼具高抗压强度和低弹性模量，且生物相容性较单纯PMMA骨水泥得到显著改善的矿化胶原复合PMMA骨粘合及填充材料。在机械性能方面，该新型材料较单纯PMMA骨水泥更复合人体骨组织的力学特性，降低了自体骨受到磨损的风险，也可以有效避免植入假体因挤压而遭到损坏。在生物相容性方面，矿化胶原复合PMMA骨粘合及填充材料富含具有良好成骨活性的矿化胶原，能够与自体骨形成骨性结合，有利于提高骨粘合及填充材料在植入部位的稳定性，从而使得该新型材料的使用更安全可靠。因此，本发明提供的矿化胶原复合PMMA骨粘合及填充材料优势明显，能够有效减少目前PMMA骨水泥并发症的产生，具有广阔的应用前景。
附图说明
图1为本发明所述矿化胶原制备工艺流程图；
图2为本发明所述矿化胶原复合PMMA骨粘合及填充材料和纯PMMA骨水泥抗压实验的应力-应变曲线对比；
图3为本发明所述纯PMMA骨粘合及填充材料固化体的剖面观察；
图4为本发明所述骨粘合及填充材料固化体的剖面观察；
图5为本发明所述骨粘合及填充材料固化体的扫描电镜观察；
图6为本发明所述骨粘合及填充材料的生物相容性细胞评价实验结果。
具体实施方式
为了更好的说明本发明的内容，下面结合附图和具体实施例对本发明作进一步说明。
图1所示为本发明所述矿化胶原制备工艺流程图。根据图1所示步骤，采用不同工艺制备出4种矿化胶原颗粒。
工艺1：纯矿化胶原颗粒(MC)
步骤S1、将5g胶原溶于10L浓度为0.5mol/L的醋酸溶液，配制成胶原的酸溶液；
步骤S2、持续搅拌步骤S1所得溶液，缓慢滴加1L浓度为1mol/L的CaCl2溶液；
步骤S3、持续搅拌步骤S2所得溶液，缓慢滴加1L浓度为0.6mol/L的Na2HPO4溶液；
步骤S4、持续搅拌步骤S3所得溶液，缓慢滴加1mol/L的NaOH溶液至混合体系pH＝7；
步骤S5、将步骤S4所得混合体系静置48小时，过滤出沉淀，并用去离子水离心洗涤5次，随后进行冷冻干燥，研磨后获得矿化胶原粉；
步骤S6、称取6g步骤S5所得的矿化胶原粉，装入直径11mm的模具凹槽中，向模具加压并达到100kN，保持压力90秒，脱模后获得矿化胶原块；
步骤S7、将步骤S6制得的矿化胶原块进行研磨，并使用50μm、200μm、300μm、400μm、500μm、600μm的不锈钢筛筛分出一系列不同粒径的矿化胶原颗粒。
工艺2：钙磷材料增强矿化胶原颗粒(MC/CaP)
步骤S1～S5同上述工艺1所述步骤S1～S5；
步骤S6、称取4.5g步骤S5所得的矿化胶原粉，与1.5g粒径200nm～1μm的羟基磷灰石粉末均匀混合后，装入直径11mm的模具中，然后向模具加压并达到110kN，保持压力180秒，脱模得到矿化胶原块；
步骤S7同上述工艺1所述步骤S7。
工艺3：聚酯增强矿化胶原颗粒(MC/PET)
步骤S1～S5同上述工艺1所述步骤S1～S5；
步骤S6、称取4.5g步骤S5所得的矿化胶原粉，与1.5g粒径50～150μm的聚乳酸粉末均匀混合后，装入直径11mm的模具中，然后向模具加压并达到65kN，保持压力45秒，同时对模具加热，使模具中物料的温度达到180℃，保持压力结束后自然降温冷却，脱模得到矿化胶原块；
步骤S7同上述工艺1所述步骤S7。
工艺4：钙磷/聚酯复合增强矿化胶原颗粒(MC/CaP/PET)
步骤S1～S5同上述工艺1所述步骤S1～S5；
步骤S6、称取4g步骤S5所得的矿化胶原粉，与1g粒径200nm～2μm的羟基磷灰石粉末、1g粒径50～150μm的聚乳酸粉末均匀混合后，装入直径11mm的模具中，然后向模具加压并达到75kN，保持压力45秒，同时对模具加热，使模具中物料的温度达到200℃，保持压力结束后自然降温冷却，脱模得到矿化胶原块；
步骤S7同上述工艺1所述步骤S7。
上述4种工艺制备的矿化胶原颗粒编号如表1所列。
表1 不同工艺制备的矿化胶原颗粒编号
Figure PCTCN2015071512-appb-000001
按照表2所列组分配制17种矿化胶原复合PMMA骨粘合及填充材料实施例，并进行工作特性、机械性能测试和细胞生物学评价。工作特性测试每组5个样品，测试后取平均值。机械性能测试每组12个样品，按照ISO 5833标准进行，测试结果记录为M± SD(平均值±标准差)。细胞生物学评价每组5个样品，利用MC3T3-E1细胞进行实验评价。
同时，还按照表3所列粉剂组分配制15种对比例，包括不含矿化胶原、矿化胶原含量过低/过高、矿化胶原粒径过小/过大等情况。所述对比例中，液体组分里MMA均为9.8mL，DMPT均为0.2mL，HQ均为40ppm，无着色剂。
表2 各组实施例中各组分含量
Figure PCTCN2015071512-appb-000002
注：*PMMA均为分子量300,000～500,000，粒径50～200μm粉末。
**造影剂均为ZrO2粉末，粒径为1.2±0.4μm。
表3 各组对比例中粉剂的各组分含量
Figure PCTCN2015071512-appb-000003
Figure PCTCN2015071512-appb-000004
注：*PMMA均为分子量300,000～500,000，粒径50～200μm粉末。
**造影剂均为ZrO2粉末，粒径为1.2±0.4μm。
骨粘合及填充材料工作特性测定
对实施例和对比例的矿化胶原复合PMMA骨粘合及填充材料进行工作特性测定，记录混合时间、等待时间、工作时间和固化时间等数据。所有测试均在23℃环境中进行，结果如表4所列。
表4 本发明骨粘合及填充材料的工作特性
                                        (单位：秒)
样品编号 混合时间 等待时间 工作时间 固化时间
E1 30 180 450 900
E2 30 180 450 960
E3 30 270 660 1200
E4 30 150 360 1140
E5 30 180 450 900
E6 30 180 450 900
E7 30 180 450 900
E8 30 180 450 1020
E9 30 120 300 600
E10 30 165 450 1020
E11 30 180 450 900
E12 30 180 450 1020
E13 30 120 300 600
E14 30 180 450 900
E15 30 180 450 900
E16 30 180 450 900
E17 30 180 450 900
C1 30 180 450 900
C2 30 180 450 900
C3 30 180 450 900
C4 无法搅拌 N/A N/A N/A
C5 30 180 450 900
C6 30 180 450 900
C7 无法搅拌 N/A N/A N/A
C8 30 180 450 900
C9 30 180 450 900
C10 30 180 450 900
C11 30 180 450 900
C12 30 90 210 1800
C13 30 180 450 900
C14 30 180 450 900
C15 30 180 450 900
可以看出，本发明实施例所述矿化胶原复合PMMA骨粘合及填充材料的工作特性为：混合时间30秒，等待时间2～5分钟，工作时间5～12分钟，固化时间10～20分钟。该工作特性符合临床使用要求。该工作特性是在23℃环境中测试所得，具体使用时还需根据手术室环境、手术类型、操作者习惯、手术器械等因素确定操作时间。
值得注意的是，当矿化胶原微粒的粒径太小(<50μm)时，直接影响骨粘合及填充材料初期的混合搅拌，无法得到可用的骨粘合及填充材料(见对比例C4和C7)。这主要是由于过小粒径的矿化胶原比表面积很大，导致大量MMA单体被吸附在矿化胶原颗粒的间隙中，不能为混合物提供足够的流动相，从而使得混合物无法搅拌，得不到可用的骨粘合及填充材料。
即使过小粒径的矿化胶原和稍大粒径的矿化胶原混合使用，也严重影响骨粘合及填充材料的等待时间和工作时间。如对比例C12，将粒径为<50μm和50～200μm的MC/CaP/PET等比例混合使用，导致等待时间和工作时间太短，不适合临床操作。并且由于大量MMA单体被吸附在小颗粒的间隙中，会导致聚合反应时间过长，如对比例C12的固化时间长达30分钟；此外还可能导致聚合反应不完全，对固化体强度有影响，且固化体中有单体残留，对患者健康留下长期隐患。
骨粘合及填充材料机械性能测定
按照ISO 5833规定的方法对实施例和对比例的矿化胶原复合PMMA骨粘合及填充材料进行机械性能测定，包括抗压强度、压缩模量、弯曲强度和弯曲模量。结果如表5 所列。
表5 本发明骨粘合及填充材料的机械性能
                                        (单位：MPa)
样品编号 抗压强度 压缩模量 弯曲强度 弯曲模量
E1 80.4±7.7 780±41 42.7±1.6 1893±90
E2 87.0±5.9 1247±36 48.6±2.9 2024±101
E3 82.1±7.3 857±34 44.5±3.0 1906±80
E4 74.6±8.9 720±43 42.9±2.5 1850±72
E5 81.4±9.7 1043±41 43.2±2.9 1766±69
E6 95.0±12.2 1354±38 54.2±4.5 2406±82
E7 85.8±7.0 1155±52 52.0±3.7 2258±70
E8 86.9±9.5 1209±45 50.4±2.4 2083±105
E9 90.4±11.2 1367±62 55.3±4.5 2435±118
E10 77.9±10.2 909±44 46.2±4.2 1991±67
E11 85.8±9.6 1224±57 51.8±2.7 2174±52
E12 88.2±8.4 1287±50 51.9±3.3 2072±120
E13 92.8±10.5 1358±68 57.4±2.6 2479±114
E14 79.5±8.0 1029±42 42.9±3.5 1919±110
E15 84.6±11.2 1179±62 53.4±2.9 2350±106
E16 86.3±12.6 1287±51 53.0±3.4 2368±96
E17 85.7±9.4 1230±54 52.2±3.5 2314±107
C1 105.5±3.2 2221±39 58.3±2.1 2510±39
C2 111.5±4.1 2308±29 59.9±2.9 2358±53
C3 115.7±3.4 2386±50 61.0±2.2 2009±47
C4 N/A N/A N/A N/A
C5 84.5±9.3 1250±49 37.7±3.6 1582±55
C6 82.9±7.0 1177±62 38.2±3.9 1628±86
C7 N/A N/A N/A N/A
C8 80.7±9.2 1189±65 38.8±4.2 1669±61
C9 76.4±11.1 803±45 38.2±3.5 1640±53
C10 101.4±3.9 1826±42 58.1±3.0 2488±97
C11 86.7±10.0 1227±56 37.5±2.8 1524±61
C12 62.8±8.2 627±49 35.9±4.0 1482±63
C13 99.3±5.8 1740±52 56.6±3.1 2379±112
C14 80.5±6.9 837±43 38.4±3.9 1660±73
C15 86.1±6.8 1179±54 35.8±3.4 1383±80
可以看出，本发明实施例所述矿化胶原复合PMMA骨粘合及填充材料的机械性能为：抗压强度70～100MPa，压缩模量0.7～1.5GPa，弯曲强度40～60MPa，弯曲模量1.7～2.5GPa。以上机械性能符合临床使用要求。
从对比例中可以看出，
不含矿化胶原的骨粘合及填充材料(对比例C1～C3)固化体具有很高的压缩模量，临床上造成患者自体骨磨损的风险较高；
当矿化胶原含量过高(大于30wt％)时(对比例C5、C8、C9、C14)，骨粘合及填 充材料固化体弯曲强度均较低(小于40MPa)，临床上发生破裂的风险较高；
当矿化胶原含量过低(小于5wt％)时(对比例C10、C13)，骨粘合及填充材料固化体依然具有很高的压缩模量，临床上造成患者自体骨磨损的风险较高；
当矿化胶原粒径过大(大于600μm或部分大于600μm)时(对比例C6、C11、C15)，骨粘合及填充材料固化体弯曲强度均较低(小于40MPa)，临床上发生碎裂的风险较高；
当矿化胶原粒径过小(小于50μm或部分小于50μm)时(对比例C4、C7、C12)，如前所述，对比例C4和C7无法搅拌，因而获得固化体，对比例C12固化体抗压强度和弯曲强度均较低，临床上发生碎裂的风险较高。
图2所示为本发明所述矿化胶原复合PMMA骨粘合及填充材料(实施例E11)和纯PMMA(对比例C1)抗压实验的应力-应变曲线对比，图中阴影部分为人体正常椎体松质骨的压缩模量。可以看到，纯PMMA固化体的应力应变曲线线性段斜率较大，即该材料压缩模量较大，且远远超出人体正常椎体松质骨的压缩模量范围；而矿化胶原的复合使固化体的弹性模量得到有效降低，基本处于人体正常椎体松质骨的压缩模量范围之中，与自体骨力学特性更加匹配，从而避免对自体骨造成损伤。
图3所示为本发明所述纯PMMA(对比例C1)固化体的剖面观察；图4所示为本发明所述矿化胶原复合PMMA骨粘合及填充材料(实施例E11)固化体的剖面观察。可以看到，矿化胶原颗粒均匀分布在骨粘合及填充材料固化体中。
图5所示为本发明所述矿化胶原复合PMMA骨粘合及填充材料(实施例E11)固化体的扫描电镜观察。通过能谱检测确定矿化胶原(MC)、PMMA和ZrO2等成分。可以看到，矿化胶原和PMMA结合紧密，彼此间相容性很好，有利于维持固化体的机械强度。
骨粘合及填充材料的生物相容性通过体外细胞实验进行评价，细胞选用大鼠颅骨来源的MC3T3-E1细胞，在48孔板中体外培养7天，利用CCK-8方法检测第1、3、5、7天的细胞数量(用CCK-8检测时酶标仪读取的吸光值表示)，并绘制细胞增殖曲线。细胞实验以纯DMEM培养基为空白对照。
图6所示为细胞实验结果，可见纯PMMA(对比例C1)固化体上，细胞的生长情况与空白对照组没有显著性差异；而矿化胶原复合PMMA骨粘合及填充材料(实施例E11)固化体上，细胞的增殖显著优于纯PMMA组和空白对照组。表明矿化胶原复合PMMA骨粘合及填充材料的生物相容性优于纯PMMA，更有利于与自体骨形成良好的骨整合，防止在体内松动乃至脱落。

Claims (19)

  1. 一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，包括粉剂和液体两部分，粉剂包括矿化胶原、预聚合聚甲基丙烯酸甲酯粉末、聚合反应引发剂，液体包括甲基丙烯酸甲酯单体、聚合反应促进剂、稳定剂，粉剂还包括造影剂、着色剂，液体还包括着色剂，所述粉剂和液体的比例为1.5～3.0g/mL，其中，
    所述粉剂中，
    矿化胶原的含量为所述粉剂的5～30wt％，
    预聚合聚甲基丙烯酸甲酯粉末的含量为所述粉剂的70～95wt％，
    聚合反应引发剂的含量为所述粉剂的0.3～0.8wt％；
    所述液体中，
    聚甲基丙烯酸甲酯单体的含量为所述液体的98±1vol％，
    聚合反应促进剂的含量为所述液体的2±1vol％，
    稳定剂在所述液体中的含量为10～100ppm。
    当所述粉剂中包括造影剂时，
    造影剂的含量为所述粉剂的5～40wt％。
  2. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述矿化胶原为胶原/羟基磷灰石复合固体颗粒，粒径为50～600μm。
  3. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述矿化胶原为胶原/羟基磷灰石复合固体颗粒，粒径为200～500μm。
  4. 根据权利要求2、3任意一条所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述矿化胶原包括钙磷粉体、聚酯作为增强成分。
  5. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述预聚合聚甲基丙烯酸甲酯粉末，其分子量为150,000～600,000，粒径为50～300μm。
  6. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述预聚合聚甲基丙烯酸甲酯粉末，其分子量为300,000～500,000，粒径为50～200μm。
  7. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述聚合反应引发剂为能够引发甲基丙烯酸甲酯进行自由基聚合反应合成 聚甲基丙烯酸甲酯的物质，优选地，该引发剂为过氧化苯甲酰。
  8. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述造影剂为不透X射线的粉末物质，优选地，该造影剂为氧化锆、硫酸钡或羟基磷灰石，粒径为0.5～2μm。
  9. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述聚合反应促进剂为能使甲基丙烯酸甲酯的自由基聚合反应持续进行合成聚甲基丙烯酸甲酯的物质，优选地，该促进剂为N,N-二甲基对甲苯胺。
  10. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述稳定剂为能够阻止甲基丙烯酸甲酯过早发生聚合反应的物质，优选地，该稳定剂为对苯二酚。
  11. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，使用本发明的骨粘合及填充材料，将所述粉剂和液体按照1.5～3g/mL的比例混合在一起，快速搅拌后经过2～5分钟等待时间，即可进行填塞或注射操作。
  12. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，该骨粘合及填充材料典型的工作时间为5～12分钟，固化时间为10～20分钟。
  13. 根据权利要求1所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，该骨粘合及填充材料固化24小时时固化体的典型抗压强度为70～100MPa，压缩模量为0.7～1.5GPa，弯曲强度为40～60MPa，弯曲模量为1.7～2.5GPa。
  14. 根据权利要求2、3任意一条所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述矿化胶原制备方法包括以下操作步骤：
    步骤S1、将胶原溶于盐酸、硝酸或醋酸中的任何一种，配制成胶原的酸溶液，其中胶原浓度为5.0×10-5～5.0×10-3g/mL；
    步骤S2、持续搅拌步骤S1所得溶液，缓慢滴加含钙离子的溶液，钙离子的加入量为每克胶原对应加入钙离子0.01～0.16mol；
    步骤S3、持续搅拌步骤S2所得溶液，缓慢滴加含磷酸根离子的溶液，磷酸根离子的加入量与步骤S2中钙离子加入量的摩尔比为Ca/P＝1/1～2/1；
    步骤S4、持续搅拌步骤S3所得溶液，缓慢滴加NaOH溶液至混合体系pH＝6～8，当pH＝5～6时，混合体系开始出现沉淀，当pH＝7时，混合体系出现白色悬浊液；
    步骤S5、将步骤S4所得混合体系静置24～120小时，分离出沉淀并洗去杂质离子， 随后进行冷冻干燥，研磨后获得矿化胶原粉体；
    步骤S6、称取一定量步骤S5获得的矿化胶原粉体，装入模具中，然后向模具施加压力，并使施加在矿化胶原粉体上的压强达到900～1200MPa，保持压力30～300秒，脱模得到矿化胶原块；
    步骤S7、将步骤S6制得的矿化胶原块研磨并过筛，筛分出所需粒径的矿化胶原颗粒。
  15. 根据权利要求14所述的矿化胶原制备方法，其特征在于，步骤S6还为：
    步骤S6、称取一定量步骤S5获得的矿化胶原粉体，与一定量钙磷材料粉末和/或聚酯粉末均匀混合后，装入模具中，然后向模具施加压力，并使施加在物料上的压强达到600～1200MPa，保持压力30～300秒，保持压力的同时对模具加热，使模具中物料的温度达到70～220℃，保持压力结束后自然降温冷却，脱模得到矿化胶原块。
  16. 根据权利要求14所述的矿化胶原制备方法，其特征在于，所述钙磷材料包括羟基磷灰石、α-磷酸三钙、β-磷酸三钙、磷酸八钙、无定形磷酸钙，粒径为20nm～10μm。
  17. 根据权利要求14所述的矿化胶原制备方法，其特征在于，所述聚酯包括聚乳酸、聚羟基乙酸、乳酸-羟基乙酸共聚物、聚己内酯，分子量为50,000～800,000，粒径为1～200μm。
  18. 根据权利要求14所述的矿化胶原制备方法，其特征在于，所述矿化胶原/钙磷材料/聚酯混合物中，
    矿化胶原含量为10～75wt％；
    钙磷材料含量为10～40wt％；
    聚酯含量为10～60wt％。
  19. 根据权利要求2、3任意一条所述的一种矿化胶原复合聚甲基丙烯酸甲酯骨粘合及填充材料，其特征在于，所述矿化胶原为通过权利要求12～16任意一条所述方法所制备的颗粒。
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