CN107670119B - Bone induction carbon-based composite material bone fracture plate and preparation method thereof - Google Patents

Bone induction carbon-based composite material bone fracture plate and preparation method thereof Download PDF

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CN107670119B
CN107670119B CN201710819210.7A CN201710819210A CN107670119B CN 107670119 B CN107670119 B CN 107670119B CN 201710819210 A CN201710819210 A CN 201710819210A CN 107670119 B CN107670119 B CN 107670119B
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carbon
bone
fracture plate
bone fracture
based composite
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CN107670119A (en
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李专
肖鹏
江天慧
肖涛
雷霆
于澍
刘立宏
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Central South University
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Abstract

The invention relates to a bone-inducing carbon-based composite material bone-knitting plate material and a preparation method thereof. The bone fracture plate comprises carbon fibers, a pyrolytic carbon matrix, a SiC surface layer and a functional layer containing BMP active protein; the pyrolytic carbon matrix layer is uniformly coated on the carbon fiber; the functional layer containing the BMP active protein is inlaid and/or coated on the SiC surface layer; the SiC surface layer is positioned between the functional layer containing the BMP active protein and the pyrolytic carbon matrix; the density of the bone induction carbon-based composite bone fracture plate is 1.8-2.0 g/cm3(ii) a The functional layer containing the BMP active protein accounts for 0.5-1.0% of the total mass of the bone fracture plate. The preparation method comprises the following steps: weaving a prefabricated body, releasing stress at high temperature, preparing a pyrolytic carbon layer, machining and carrying out secondary densification, preparing a SiC surface layer after the secondary densification, and finally carrying active protein molecules containing BMP after oxidation activation treatment.

Description

Bone induction carbon-based composite material bone fracture plate and preparation method thereof
Technical Field
The invention belongs to the technical field of carbon-based composite materials and the technical field of biomedical materials, and particularly relates to a bone-inducing carbon-based composite material bone-knitting plate material and a preparation method thereof.
Background
The internal fixation of the metal bone fracture plate is the most common operation mode for treating the fracture at present, but the metal bone fracture plate has the defects of stress shielding, fracture blood circulation damage at the fracture part, fracture healing influence, in-vivo electrochemical reaction corrosion and the like, and can not directly promote the fracture healing, so that the metal bone fracture plate becomes an orthopedic product which is most prone to postoperative complications in clinic. On the other hand, patients are often severely affected when they are examined by X-ray, CT and MRI. Therefore, researches on the bone fracture plate material can replace a metal bone fracture plate, enhance the safety and the effectiveness of the bone fracture plate, and produce the novel bone fracture plate material which meets the international standard and can be popularized to the broad consumer groups and products thereof are particularly urgent.
The carbon material has stable chemical and physiological properties and excellent biocompatibility, and is widely used for preparing artificial implants such as heart valves, artificial ligaments and tendons. The composite material reinforced by the carbon fiber and the fabric thereof, as a biomedical material, has the advantages of good toughness, high strength, corrosion resistance, particularly the elasticity modulus close to that of bones, no strength loss under the condition of bearing periodic load and the like, so that the composite material has better application prospect in the fields of human bone replacement and bone repair, such as the application of the carbon-based composite material artificial tooth root in human tooth repair with mature technology.
The carbon-based composite material applied to the bone fracture plate at the present stage is mainly a carbon fiber reinforced pyrolytic carbon (C/C) composite material or a carbon fiber reinforced resin-based composite material, which are all biological inert materials, the surface of the carbon-based composite material is hydrophobic, the carbon-based composite material is only mechanically combined with the surface of a bone tissue, the function of inducing the regeneration of the bone tissue is not provided, and the formation of an interface requires a long period. Therefore, in order to ensure the stability of the implant, enable the implant to be chemically bonded with bone tissues and accelerate the growth of new bone tissues, avoid generating some unknown influences on human bodies, reduce the generation of friction carbon fragments and pollute surrounding tissues, and can construct a bioactive coating on the surface of the implant.
Bone Morphogenetic Protein (BMP) is an important promoter of in vivo osteogenesis, and studies have confirmed that it has significant osteoinductivity for the regeneration of new bone tissue both in vitro and in vivo, and the united states food and drug administration approved bone morphogenetic protein 2 and absorbable collagen sponge complex (trade name INFUSE) for clinical treatment of open tibial fractures in 2004. The microspheres wrapping the BMP are loaded on the surface of the carbon-based composite material, so that effective slow release can be achieved, formation and growth of new bones are promoted, and the defects that the BMP is implanted into a body only and is diffused too fast, has short half-life period, is easy to be hydrolyzed and absorbed by protease and is difficult to fully exert the osteogenesis inducing effect in the whole process of forming the new bones are overcome.
Disclosure of Invention
The invention aims at the problems of osteoporosis and metal stress shielding caused by the fact that the elasticity modulus of the existing metal bone fracture plate is not matched with that of human bones and the defects of the existing C/C composite material applied to the bone fracture plate. Provides a bone induction carbon-based composite material bone fracture plate and a preparation method thereof.
The invention relates to a bone induction carbon-based composite bone fracture plate; the bone fracture plate comprises carbon fibers, a pyrolytic carbon matrix, a SiC surface layer and a functional layer containing BMP active protein; the pyrolytic carbon matrix layer is uniformly coated on the carbon fiber; the functional layer containing the BMP active protein is inlaid and/or coated on the SiC surface layer; the SiC surface layer is positioned between the functional layer containing the BMP active protein and the pyrolytic carbon matrix; the density of the bone induction carbon-based composite bone fracture plate is 1.8-2.0 g/cm3(ii) a The functional layer containing the BMP active protein accounts for 0.5-1.0% of the total mass of the bone fracture plate.
The invention relates to a bone induction carbon-based composite bone fracture plate; the mass of the SiC surface layer accounts for 6-20% of the total mass of the bone fracture plate. (ii) a
The invention relates to a bone induction carbon-based composite bone fracture plate; the bone fracture plate comprises carbon fibers, a pyrolytic carbon matrix, a SiC surface layer and a functional layer containing BMP active protein; the pyrolytic carbon matrix layer is uniformly coated on the carbon fiber; filling the pores with the SiC matrix and coating the SiC matrix on the pyrolytic carbon layer to obtain a bone fracture plate blank; the SiC surface layer is coated on the surface of the bone plate blank; the functional layer containing the BMP active protein is inlaid and/or coated on the SiC surface layer.
The invention relates to a bone induction carbon-based composite bone fracture plate; the bone fracture plate is also reserved with bolt holes for fixing.
The invention relates to a bone induction carbon-based composite bone fracture plate; the functional layer containing the BMP active protein is a gelatin slow-release microsphere coating containing the BMP active protein molecules.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; the method comprises the following steps:
step one preparation of preforms
Sequentially laminating continuous carbon fibers and a carbon fiber net tire, then needling in the axial direction, introducing longitudinal carbon fibers, and needling a prefabricated blank according to the required appearance of the bone fracture plate; the density of the prefabricated blank is 0.4-0.55 g/cm3(ii) a In the needling process, graphite cylinders are pre-embedded at bolt holes of the bone fracture plate;
step two high temperature heat treatment
Carrying out high-temperature heat treatment on the prefabricated blank obtained in the step one under the protective atmosphere; the temperature of the high-temperature heat treatment is more than or equal to 600 ℃;
step three first densification
Placing the prefabricated blank obtained in the second step after heat treatment in a deposition furnace; preparing pyrolytic carbon by a thermal gradient chemical vapor infiltration method; the obtained density is 0.8-1.0 g/cm3The porous blank of (a);
step four machining
Unloading the graphite cylinders pre-buried in the prefabricated blank, roughly processing the porous blank obtained in the step three, removing burrs and adhesive substances on the surface of the blank, processing the peripheral size to a set size, and processing the bolt connecting holes into through holes; obtaining a machining blank;
step five, second densification
Preparing a pyrolytic carbon matrix on the machined blank by adopting a chemical vapor infiltration method to obtain a density of 1.5-1.7 g/cm3A blank of (a);
or
Preparing a SiC matrix on the machined blank obtained in the fourth step in a dipping and cracking mode to obtain a blank after the second densification; the density of the blank after the second densification is 1.6-1.8 g/cm3；
Six-step chemical vapor deposition method for preparing SiC surface layer
Placing the blank obtained in the fifth step in a chemical vapor deposition furnace, and preparing a SiC surface layer through chemical vapor deposition to obtain a carbon-based composite material bone fracture plate;
seventhly, preparing the gelatin sustained-release microsphere coating containing the BMP active protein molecules
Oxidizing the carbon-based composite material bone fracture plate obtained in the step six by using concentrated acid, cleaning in an ultrasonic water solution, drying, cleaning by using deionized water until the cleaning solution is neutral, then soaking the carbon-based composite material bone fracture plate in a chitosan acetic acid solution containing BMP gelatin slow-release microspheres, performing self-assembly by using static electricity, repeatedly coating for many times by using a dipping and pulling method, drying, coating chitosan on the surface of the carbon-based composite material bone fracture plate, and subpackaging to obtain the bone induction carbon-based composite material bone fracture plate.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; in the step one, the continuous carbon fiber is 3-48K carbon fiber non-woven cloth or carbon cloth, and the surface density is 100-400 g/cm2(ii) a The short carbon fiber in the carbon fiber net tire is not less than 6K, the length is 10-80 mm, and the surface density of the net tire is 20-185 g/cm2(ii) a The interlayer density is 10-20 layers/10 mm; the needling density is 25-45 needles/cm2(ii) a The size around the carbon fiber preform is sheared according to bone fracture plate size +4~ 6mm, and the upper and lower two sides all are higher than the bone fracture plate 2~3mm behind the layer acupuncture is spread to thickness direction. Preferably, the continuous carbon fibers can be laid in a plane direction in a rotating mode at different angles for multiple times according to different designed shapes and thicknesses, and the laying angle is 0-180 degrees;
the invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; in the second step, the temperature of the high-temperature heat treatment is 600-800 ℃ and the time is 0.5-2 hours. And during high-temperature heat treatment, controlling the pressure in the furnace to be micro-positive pressure (namely slightly exceeding 0 scale of a vacuum pressure gauge). The protective gas is preferably an inert gas. The high-temperature heat treatment can remove organic glue and other impurities coated on the surface in a bundle form in the preparation process of the carbon fiber, and can relieve the stress generated by the carbon fiber preform in the needling process and the graphite cylinder pre-embedded at the position of the bolt hole.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; in the third step, the first step is that,
when preparing pyrolytic carbon by chemical vapor infiltration, the temperature is controlled to be more than or equal to 1000 ℃ and the time is controlled to be more than or equal to 50 hours.
As a further preferred scheme, the invention relates to a preparation method of the bone induction carbon-based composite material bone fracture plate; step three, placing the spare blank subjected to heat treatment in the step two into a deposition furnace; isotropic pyrolytic carbon densification is carried out on the carbon fiber by adopting a thermal gradient chemical vapor infiltration method; when the thermal gradient chemical vapor infiltration is carried out, the carbon source gas is hydrocarbon or natural gas with the carbon atom number less than or equal to 3; preferably, the carbon-containing gas is a hydrocarbon gas such as methane, propylene, propane, natural gas, etc., the diluent gas is nitrogen, hydrogen or a mixed gas thereof, the ratio of the carbon-containing gas to the diluent gas is 1: 1-3, the time is 50-150 hours, and the temperature is 1000-1200 ℃. As a further preferable condition, the flow rate of the carbon source gas during deposition is 10 to 30L/min. The gas pressure in the furnace is less than or equal to 1.2 kPa.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; step five, placing the rough-processed low-density blank obtained in the step four into a deposition furnace, and preparing pyrolytic carbon by adopting an isothermal chemical vapor infiltration method until the density of the blank is 1.5-1.7 g/cm3(ii) a When the pyrolytic carbon is prepared by adopting a chemical vapor infiltration method, the time is controlled to be more than or equal to 200 hours, and the temperature is controlled to be more than or equal to 1100 ℃.
As a preferred scheme, the invention relates to a preparation method of a bone induction carbon-based composite material bone fracture plate; in the fifth step, when the isothermal chemical vapor infiltration method is adopted to prepare pyrolytic carbon, the carbon source is hydrocarbon or natural gas with the carbon atom number less than or equal to 3; preferably, hydrocarbon gas such as methane, propylene, propane, natural gas and the like is selected as diluent gas, nitrogen, hydrogen or mixed gas thereof is selected as diluent gas, the ratio of the carbon source gas to the diluent gas is 1: 1-3, the deposition time is 200-300 hours, and the deposition temperature is 1100-1300 ℃. As a further preferable condition, the flow rate of the carbon source gas during deposition is 28 to 50L/min. As a further preferable condition, the pressure of the gas in the furnace is 1.5KPa or less.
As a preferred scheme, the bone induction carbon-based composite material provided by the inventionA preparation method of the material bone fracture plate; in the fifth step, the machined blank obtained in the fourth step can be placed into a mixed solution prepared from polycarbosilane and divinylbenzene for dipping, then crosslinking curing and cracking are carried out under a protective atmosphere to generate a SiC matrix, and the dipping, crosslinking curing and cracking processes are repeated until the density of the blank is 1.6-1.8 g/cm3(ii) a The mass ratio of polycarbosilane to divinylbenzene in the mixed solution is 1: 0.2 to 0.4; the temperature of crosslinking and curing is 120-160 ℃; the cracking temperature is 1200-1500 ℃. The protective gas is selected from one of nitrogen and argon.
As a preferred scheme, the invention relates to a preparation method of a bone induction carbon-based composite material bone fracture plate; in the sixth step, when the SiC surface layer is prepared by chemical vapor deposition, the SiC precursor is trichloromethylsilane (CH)3SiCl3MTS) is used as the deposition system MTS-H2-Ar deposition system, H2With simultaneous adjustment of H as a diluent gas2MTS ratio, H in the deposition system2And MTS in a molar ratio of H2: MTS is 8-10: 1, the Ar flow is 150-200 ml/min; the deposition temperature is 1000-1100 ℃, the pressure is 0.0001-1 kPa, and the deposition time is 50-200 hours. In the sixth step, the high purity H is used in industrial application2MTS was taken into the reactor by bubbling with high purity Ar as a diluent gas as a carrier gas.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; in the seventh step, the gelatin sustained release microspheres containing BMP active protein molecules are prepared by the following scheme:
placing a gelatin solution in a water bath for preheating, dropwise adding the preheated gelatin solution into liquid paraffin while stirring, continuously stirring uniformly after dropwise adding, then quickly transferring into an ice-water bath for treatment, then adding Phosphate Buffer Solution (PBS) of bone morphogenetic protein, then adding a cross-linking agent for cross-linking, and washing with a washing solution after cross-linking to obtain light yellow microspheres; and then continuously solidifying for a period of time in a low-temperature environment, finally fully washing with a washing solution again, sieving and subpackaging. The preheating temperature in the water bath is controlled to be 40-60 ℃, and the preheating time is 7-15 min; the temperature of the ice-water bath is controlled below 5 ℃, and the treatment time in the ice-water bath is controlled within 15-25 min. The concentration of the gelatin solution is 0.1-0.3 g/ml, and the liquid paraffin contains 1-5% of Span-80 (Span 80) in mass fraction; the cross-linking agent is glutaraldehyde, and the cross-linking reaction time is 1-3 h; the washing liquid is an acetone-water mixed solution, and the continuous curing time is 12-36 hours at the low temperature of 0-5 ℃. The concentration of the bone morphogenetic protein in the phosphate buffer solution of the bone morphogenetic protein is 100-300 mug/ml.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; and seventhly, in the chitosan acetic acid solution containing the BMP gelatin slow-release microspheres, the concentration of the BMP gelatin slow-release microspheres is 5-10 g/L.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; and (3) when the carbon-based composite material bone fracture plate obtained in the sixth step is oxidized by using concentrated acid, the used concentrated acid is preferably a mixed solution of 67 wt% concentrated nitric acid or 100ml/L concentrated sulfuric acid and 200g/L ammonium persulfate, and the temperature is controlled to be 60-70 ℃ during oxidation for 1-1.5 hours.
The invention relates to a preparation method of a bone induction carbon-based composite bone fracture plate; oxidizing the obtained carbon-based composite material bone fracture plate with concentrated acid to generate oxygen-containing groups such as-OH and-COOH groups on the surface of the bone fracture plate, then soaking the bone fracture plate in a chitosan acetic acid solution containing BMP gelatin slow-release microspheres, performing electrostatic self-assembly, repeatedly coating the bone fracture plate for multiple times by adopting a dipping and pulling method, drying, coating chitosan on the surface of the carbon-based composite material bone fracture plate, and then subpackaging to obtain the bone induction carbon-based composite material bone fracture plate.
The advantages and positive effects are as follows:
the invention applies the carbon-based composite material containing SiC to the bone fracture plate for the first time at home and abroad. The carbon-based composite material bone fracture plate prepared by the manufacturing technology has high strength and elasticity modulus equivalent to that of a bone, solves the problem that a patient is fractured after healing possibly suffered by the existing metal bone fracture plate and the dilemma of influence of a magnetic field of the metal bone fracture plate in clinic, can carry out X-ray, CT and MRI examination without restriction, and improves diagnosis and treatment accuracy.
The product of the invention has good biocompatibility. The coating material gelatin adopted by the invention is a natural high molecular material, is a protein obtained by collagen fracture, has the protein content of more than 82 percent, and has the molecular weight of tens of thousands to hundreds of thousands. Gelatin inherits the excellent biological functions of collagen, for example, gelatin has good biocompatibility and is non-toxic, and as an excellent medical biomaterial, gelatin is degradable, and degradation products are easily absorbed without generating side effects, and simultaneously, nutrition is provided for wounds to generate curative effects, and the like. But also can improve the distribution of BMP in the microsphere and improve the slow release effect of BMP (for example, the slow release rate of BMP is controlled in a reasonable range).
The preparation method has controllability. The emulsion crosslinking method is adopted to prepare the microspheres, and the particle size of the microspheres can be simply and easily regulated and controlled by changing the water-oil ratio. Compared with direct BMP injection, the method skillfully designs the SiC layer, well solves the problem of carbon particle shedding by utilizing the synergistic effect of proper SiC and pyrolytic carbon, utilizes concentrated acid to treat SiC to ensure proper corrosion and activation of SiC, provides necessary conditions for loading BMP as much as possible, and can further enhance the slow release effect of the BMP by the SiC layer treated by the concentrated acid; further, the BMP can be released in vivo more continuously and slowly, the decomposition of the BMP is reduced, the action time of the BMP is prolonged, the utilization rate of the active ingredient BMP is improved, the medical cost can be effectively reduced, and the economic burden of a patient is relieved.
Drawings
Fig. 1 is a schematic diagram of an osteoinductive carbon-based composite bone plate prepared in example 1.
Detailed Description
The invention is further illustrated by the following figures and examples.
Example 1:
preparing an osteoinductive carbon-based composite material bone fracture plate according to the following steps;
(1) preparing a prefabricated body:
sequentially laminating continuous carbon fibers and a carbon fiber net tireThen, needling in the axial direction, introducing longitudinal carbon fibers, and needling a prefabricated blank according to the required appearance of the bone fracture plate; the density of the prefabricated blank is 0.4-0.55 g/cm3(ii) a In the needling process, graphite cylinders are pre-embedded at bolt holes of the bone fracture plate; in the step (1), the continuous carbon fiber is 12K carbon fiber non-woven cloth or carbon cloth, and the surface density is 400g/cm2(ii) a The short carbon fiber in the carbon fiber net tire is 24K, the length is 80mm, and the surface density of the net tire is 180g/cm2(ii) a The interlayer density is 10 layers/10 mm; the needling density is 45 needles/cm2(ii) a The size around the carbon fiber preform is sheared according to bone fracture plate size +4~ 6mm, and the upper and lower two sides all are higher than the bone fracture plate 2~3mm behind the layer acupuncture is spread to thickness direction.
(2) High-temperature heat treatment:
carrying out high-temperature heat treatment on the prefabricated blank obtained in the step (1) in a nitrogen atmosphere; the temperature of the high-temperature heat treatment is 800 ℃;
(3) first densification
Placing the heat-treated prefabricated blank obtained in the step (2) into a deposition furnace; preparing pyrolytic carbon by a thermal gradient chemical vapor infiltration method; obtaining a density of 1.0g/cm3The porous blank of (a); when preparing pyrolytic carbon by a chemical vapor infiltration method, controlling the temperature to 1180 ℃ and the time to 80 hours; during thermal gradient chemical vapor infiltration, the carbon source gas is propylene gas, the diluent gas is hydrogen gas, the ratio of the carbon source gas to the diluent gas is 1: 3, and the flow rate of the carbon source gas is 30L/min during deposition; the furnace gas pressure was 1.2 kPa.
(4) Machining
Unloading the graphite cylinders pre-buried in the prefabricated blank, performing rough machining on the low-density blank obtained in the step (3), removing burrs and adhesive substances on the surface of the blank, machining the peripheral size to the product size, and machining the bolt connecting holes into through holes;
(5) second densification
Dipping the rough-processed low-density blank obtained in the step (4) in a mixed solution prepared from polycarbosilane and divinylbenzene, performing crosslinking curing and cracking in a protective atmosphere to generate a SiC matrix, and repeating dipping, crosslinking curing and crackingDecomposing until the blank density is 1.80g/cm3(ii) a The mass ratio of polycarbosilane to divinylbenzene in the mixed solution is 1: 0.4; the temperature for crosslinking and curing is 160 ℃; the temperature of cracking was 1450 ℃;
(6) preparing SiC layer by chemical vapor deposition
And (3) taking trichloromethylsilane (MTS) as a precursor, and performing SiC surface packing on the blank obtained in the step (5) by adopting a chemical vapor deposition method to obtain the carbon-based composite material bone fracture plate. Using MTS-H2-Ar deposition system, high purity H2As carrier gas, high-purity Ar as diluent gas, and introducing MTS into the reactor by bubbling, H2And MTS in a molar ratio of H2: MTS-8: 1, the deposition temperature is 1100 ℃ at the Ar flow rate of 200ml/min, the pressure is 1kPa, and the deposition time is 80 hours;
(7) preparing gelatin microspheres loaded with BMP:
preparing 0.1g/ml gelatin solution, preheating the gelatin solution in a water bath at 40 ℃ for 15min, dropwise adding the preheated gelatin solution into liquid paraffin while stirring, continuously stirring uniformly after dropwise adding, then quickly transferring the gelatin solution into an ice water bath for treatment for 15min, then adding Phosphate Buffer Solution (PBS) of bone morphogenetic protein, then adding a cross-linking agent (glutaraldehyde) for cross-linking for 1 hour, and washing with a washing solution after cross-linking to obtain light yellow microspheres; curing at 4 deg.C for 12 hr, washing with washing liquid, sieving, and packaging. The liquid paraffin contains 1.5 percent of Span-80 (Span 80) by mass; the washing solution is acetone-water mixed solution. The concentration of bone morphogenetic protein in the PBS solution of the bone morphogenetic protein is 100 mug/ml.
(8) Preparing gelatin slow-release microsphere coating containing BMP active protein molecule
Dispersing the gelatin sustained-release microspheres containing BMP obtained in the step (7) in an acetic acid solution of chitosan to obtain a mixed solution; in the mixed solution, the concentration of the BMP gelatin slow-release microspheres is 5 g/L.
Oxidizing the carbon-based composite material bone fracture plate obtained in the step (6) with concentrated nitric acid at 60 ℃ for 1.5 hours to generate-OH and-COOH groups on the surface of the bone fracture plate, then soaking the bone fracture plate in a chitosan acetic acid solution containing BMP gelatin slow-release microspheres, performing self-assembly by using static electricity, repeatedly coating the bone fracture plate by using a dipping and pulling method for multiple times, drying, coating chitosan on the surface of the carbon-based composite material bone fracture plate, and then subpackaging to obtain the bone induction carbon-based composite material bone fracture plate.
The density of the bone induction carbon-based composite material bone fracture plate is 1.95g/cm3(ii) a The mass of the functional layer containing the BMP active protein accounts for 0.5% of the total mass of the bone fracture plate (the test method comprises the steps of weighing the mass of the bone fracture plate after the concentrated acid is oxidized and washed and dried, and counting the mass as A, and weighing the mass of the bone induction carbon-based composite material bone fracture plate as B, wherein the value obtained by (B-A)/B x 100% is the mass of the functional layer containing the BMP active protein accounts for the total mass of the bone fracture plate).
The mass of the SiC layer accounts for 7.2% of the total mass of the bone fracture plate. The calculation method comprises the following steps: weighing the mass of the sample obtained after the secondary densification, and calculating the mass as C; weighing the bone induction carbon-based composite material bone fracture plate by a mass meter B; weighing the bone fracture plate, and weighing the mass A of the bone fracture plate after the concentrated acid is oxidized, washed and dried; the value obtained by (A-C)/B100% is the mass of the SiC layer in percentage of the total mass of the bone plate.
The bending, compression and shear strengths of the human bone and carbon-based composite bone plate materials were tested on an Instron 3369 electronic universal material testing machine. The bending strength test piece size is (length multiplied by width multiplied by height, the same below) 55mm multiplied by 10mm multiplied by 4mm, and a three-point bending method is adopted; compressive Strength test specimen size of
Figure BDA0001405874640000122
The size of a shear strength test sample is 36mm multiplied by 10mm multiplied by 6mm, and the loading directions are all vertical to the fiber laying direction of the non-woven cloth. The modulus of elasticity was measured on an MS-HT modulus of elasticity machine with test sample dimensions of 100mm by 10mm by 5 mm.
The determination of the drug release rate of the bone induction carbon-based composite material bone fracture plate is completed according to a BMP standard test method. After loading BMP on the microspheres by a physical adsorption method, detecting the drug release rate of the drug-loaded microspheres in an in vitro PBS buffer solution, taking the supernatant of the system at the time points of 1h, 2h, 4h, 8h, 12h, 24h, 3d, 7d and 15d for freezing and storing, after sampling is finished, adding a standard product and a sample into a 96-well plate according to the detection method of a BMP Elisa kit, finally measuring the absorbance at 450nm according to the detection steps of the kit to obtain a standard curve of the BMP, converting the content of the BMP in the sample according to the standard curve, and further calculating the cumulative drug release rate of the BMP within a certain time. The cumulative drug release rate of the bone fracture plate made of the osteoinductive carbon-based composite material in 15 days is 34 percent.
TABLE 1 mechanical Properties of human bone and carbon-based composite bone fracture plate
Figure BDA0001405874640000121
Example 2:
preparing an osteoinductive carbon-based composite material bone fracture plate according to the following steps;
(1) preparing a prefabricated body:
sequentially laminating continuous carbon fibers and a carbon fiber net tire, then needling in the axial direction, introducing longitudinal carbon fibers, and needling a prefabricated blank according to the required appearance of the bone fracture plate; the density of the prefabricated blank is 0.4-0.55 g/cm3(ii) a In the needling process, graphite cylinders are pre-embedded at bolt holes of the bone fracture plate; in the step (1), the continuous carbon fiber is 12K carbon fiber non-woven cloth or carbon cloth, and the surface density is 200g/cm2(ii) a The short carbon fiber in the carbon fiber net tire is 6K, the length is 20mm, and the surface density of the net tire is 100g/cm2(ii) a The interlayer density is 20 layers/10 mm; the needling density is 45 needles/cm2(ii) a The size around the carbon fiber preform is sheared according to bone fracture plate size +4~ 6mm, and the upper and lower two sides all are higher than the bone fracture plate 2~3mm behind the layer acupuncture is spread to thickness direction.
(2) High-temperature heat treatment:
carrying out high-temperature heat treatment on the prefabricated blank obtained in the step (1) in an argon atmosphere; the temperature of the high-temperature heat treatment is 600 ℃;
(3) first densification
Placing the heat-treated prefabricated blank obtained in the step (2) into a deposition furnace; preparing pyrolytic carbon by a thermal gradient chemical vapor infiltration method; a density of 0.9g/cm was obtained3The porous blank of (a); chemical gasWhen preparing pyrolytic carbon by a phase permeation method, controlling the temperature to be 1000 ℃ and the time to be 150 hours; during thermal gradient chemical vapor infiltration, the carbon source gas is propylene gas, the diluent gas is hydrogen gas, the ratio of the carbon source gas to the diluent gas is 1: 1, and the flow rate of the carbon source gas is 20L/min during deposition; the furnace gas pressure was 1.0 kPa.
(4) Machining
Unloading the graphite cylinders pre-buried in the prefabricated blank, performing rough machining on the low-density blank obtained in the step (3), removing burrs and adhesive substances on the surface of the blank, machining the peripheral size to the product size, and machining the bolt connecting holes into through holes;
(5) second densification
Preparing the pyrolytic carbon matrix from the rough-processed low-density blank body obtained in the step (4) by adopting a thermal gradient chemical vapor infiltration method, and continuously densifying to obtain the pyrolytic carbon matrix with the density of 1.65g/cm3A blank of (a); controlling the temperature to be 1100 ℃ and the time to be 300 hours; the carbon source gas is propylene gas, the diluent gas is hydrogen gas, the ratio of the carbon source gas to the diluent gas is 1: 3, and the flow rate of the carbon source gas is 40L/min during deposition; the furnace gas pressure was 1.0 kPa.
(6) Preparing SiC layer by chemical vapor deposition
And (3) taking trichloromethylsilane (MTS) as a precursor, and performing SiC surface packing on the blank obtained in the step (5) by adopting a chemical vapor deposition method to obtain the carbon-based composite material bone fracture plate. Using MTS-H2-Ar deposition system, high purity H2As carrier gas, high-purity Ar as diluent gas, and introducing MTS into the reactor by bubbling, H2And MTS in a molar ratio of H2: MTS 10: 1, the Ar flow rate is 150ml/min, the deposition temperature is 1000 ℃, the pressure is 0.1kPa, and the deposition time is 150 hours;
(7) preparing gelatin microspheres loaded with BMP:
preparing 0.3g/ml gelatin solution, preheating the gelatin solution in a water bath at 60 ℃ for 7min, dropwise adding the preheated gelatin solution into liquid paraffin while stirring, continuously stirring uniformly after dropwise adding, then quickly transferring the gelatin solution into an ice water bath for treatment for 20min, then adding Phosphate Buffer Solution (PBS) of bone morphogenetic protein, then adding a cross-linking agent (glutaraldehyde) for cross-linking for 2 hours, and washing with a washing solution after cross-linking to obtain light yellow microspheres; and then continuously solidifying for 24 hours, finally fully washing with a washing solution again, sieving and subpackaging. The liquid paraffin contains 5% of Span-80 (Span 80) by mass fraction; the washing solution is acetone-water mixed solution. The concentration of bone morphogenetic protein in the PBS solution of the bone morphogenetic protein is 300 mug/ml.
(8) Preparing gelatin slow-release microsphere coating containing BMP active protein molecule
Dispersing the gelatin sustained-release microspheres containing BMP obtained in the step (7) in an acetic acid solution of chitosan to obtain a mixed solution; in the mixed solution, the concentration of the BMP gelatin slow-release microspheres is 10 g/L.
Oxidizing the carbon-based composite material bone fracture plate obtained in the step (6) with concentrated sulfuric acid to generate-OH and-COOH groups on the surface of the bone fracture plate, then soaking the bone fracture plate in a chitosan acetic acid solution containing BMP gelatin slow-release microspheres, performing electrostatic self-assembly, repeatedly coating the bone fracture plate for multiple times by adopting a dipping and pulling method, drying, coating chitosan on the surface of the carbon-based composite material bone fracture plate, and then subpackaging to obtain the bone induction carbon-based composite material bone fracture plate.
The density of the bone induction carbon-based composite material bone fracture plate is 1.82g/cm3(ii) a The functional layer containing BMP active protein accounts for 1.0% of the total bone fracture plate (the test method comprises weighing concentrated acid, washing, and drying to obtain bone fracture plate A2Weighing the bone induction carbon-based composite material bone fracture plate by a mass meter B2，(B2-A2)/B2The value obtained is 100% in mass of the functional layer containing the BMP active proteins in percentage of the total mass of the bone plate).
The mass of the SiC layer accounts for 8.34% of the total mass of the bone fracture plate. The calculation method comprises the following steps: weighing the mass of the sample obtained after the secondary densification, and calculating the mass as D; the mass meter for weighing the bone induction carbon-based composite bone fracture plate is B2(ii) a Weighing the mass of the bone fracture plate after the concentrated acid is oxidized, washed and dried, and the mass is A2；(A2-D)/B2The value obtained is the percentage of the mass of the SiC layer to the total mass of the bone plate。
The bending, compression and shear strength of the bone plate material made of the carbon-based composite material is tested on an Instron 3369 electronic universal material testing machine. The bending strength test piece size is (length multiplied by width multiplied by height, the same below) 55mm multiplied by 10mm multiplied by 4mm, and a three-point bending method is adopted; compressive Strength test specimen size of
Figure BDA0001405874640000151
The size of a shear strength test sample is 36mm multiplied by 10mm multiplied by 6mm, and the loading directions are all vertical to the fiber laying direction of the non-woven cloth. The modulus of elasticity was measured on an MS-HT modulus of elasticity machine with test sample dimensions of 100mm by 10mm by 5 mm.
The determination of the drug release rate of the bone induction carbon-based composite material bone fracture plate is completed according to a BMP standard test method, and the 15-day cumulative drug release rate is 37 percent.
In the invention, the cumulative drug release rate of 34-37% in 15 days is favorable for the bone repair of human body.
TABLE 2 mechanical Properties of the bone plate made of carbon-based composite material
Figure BDA0001405874640000161
Comparative example 1
Other operations and procedures were consistent with example 1, except that: step (6) is omitted
The mechanical properties of the carbon-based composite material bone plate material are shown in table 3, and the cumulative drug release rate of the bone induction carbon-based composite material bone plate material in 15 days is 68%.
TABLE 3 mechanical Properties of the bone plate made of carbon-based composite materials
Figure BDA0001405874640000162
Comparative example 2
Other operations and procedures were consistent with example 2, except that: the step of concentrated acid oxidation in the step (6) and the step (8) is omitted;
the mechanical properties of the carbon-based composite material bone plate material are shown in table 4, and the cumulative drug release rate of the bone induction carbon-based composite material bone plate material in 15 days is 78%.
TABLE 4 mechanical Properties of the bone plate made of carbon-based composite materials
Figure BDA0001405874640000163

Claims (7)

1. An osteoinductive carbon-based composite bone fracture plate; the method is characterized in that: the bone fracture plate comprises carbon fibers, a pyrolytic carbon matrix, a SiC surface layer and a functional layer containing BMP active protein; the pyrolytic carbon matrix layer is uniformly coated on the carbon fiber; the functional layer containing the BMP active protein is inlaid and/or coated on the SiC surface layer; the SiC surface layer is positioned between the functional layer containing the BMP active protein and the pyrolytic carbon matrix; the density of the bone induction carbon-based composite bone fracture plate is 1.8-2.0 g/cm3(ii) a The mass of the functional layer containing the BMP active protein accounts for 0.5-1.0% of the total mass of the bone fracture plate;
the mass of the SiC surface layer accounts for 6-20% of the total mass of the bone fracture plate;
the bone induction carbon-based composite material bone fracture plate is prepared by the following steps:
step one preparation of preforms
Sequentially laminating continuous carbon fibers and a carbon fiber net tire, then needling in the axial direction, introducing longitudinal carbon fibers, and needling a prefabricated blank according to the required appearance of the bone fracture plate; the density of the prefabricated blank is 0.4-0.55 g/cm3(ii) a In the needling process, graphite cylinders are pre-embedded at bolt holes of the bone fracture plate;
step two high temperature heat treatment
Carrying out high-temperature heat treatment on the prefabricated blank obtained in the step one under the protective atmosphere; the temperature of the high-temperature heat treatment is more than or equal to 600 ℃;
step three first densification
Placing the prefabricated blank obtained in the second step after heat treatment in a deposition furnace; preparing pyrolytic carbon by a thermal gradient chemical vapor infiltration method; the obtained density is 0.8-1.0 g/cm3The porous blank of (a);
step four machining
Unloading the graphite cylinders pre-buried in the prefabricated blank, roughly processing the porous blank obtained in the step three, removing burrs and adhesive substances on the surface of the blank, processing the peripheral size to a set size, and processing the bolt connecting holes into through holes; obtaining a machining blank;
step five, second densification
Preparing pyrolytic carbon on a machined blank by adopting a chemical vapor infiltration method to obtain the pyrolytic carbon with the density of 1.5-1.7 g/cm3A blank of (a);
or
Preparing a SiC matrix on the machined blank obtained in the fourth step in a dipping and cracking mode to obtain a blank after the second densification; the density of the blank after the second densification is 1.6-1.8 g/cm3；
Six-step chemical vapor deposition method for preparing SiC layer
Placing the blank obtained in the fifth step into a chemical vapor deposition furnace, and preparing a SiC surface layer through chemical vapor deposition to obtain a carbon-based composite material bone fracture plate;
seventhly, preparing the gelatin sustained-release microsphere coating containing the BMP active protein molecules
Oxidizing the carbon-based composite material bone fracture plate obtained in the step six by using concentrated acid, washing the bone fracture plate by using deionized water until the cleaning solution is neutral, then soaking the bone fracture plate in a chitosan acetic acid solution containing BMP gelatin slow-release microspheres, performing electrostatic self-assembly, repeatedly coating the bone fracture plate for multiple times by using a dipping and pulling method, drying the bone fracture plate, coating chitosan on the surface of the carbon-based composite material bone fracture plate, and subpackaging the bone fracture plate to obtain the bone induction carbon-based composite material bone fracture plate; when the carbon-based composite material bone fracture plate is oxidized by using concentrated acid, the used concentrated acid is preferably a mixed solution of 67 wt% concentrated nitric acid or 100ml/L concentrated sulfuric acid and 200g/L ammonium persulfate, and the temperature is controlled to be 60-70 ℃ during oxidation for 1-1.5 hours.
2. An osteoinductive carbon-based composite bone plate according to claim 1; the method is characterized in that: the bone fracture plate comprises carbon fibers, a pyrolytic carbon matrix, a SiC surface layer and a functional layer containing BMP active protein; the pyrolytic carbon matrix layer is uniformly coated on the carbon fiber; filling the pores with the SiC matrix and coating the SiC matrix on the pyrolytic carbon layer to obtain a bone fracture plate blank; the SiC surface layer is coated on the surface of the bone plate blank; the functional layer containing the BMP active protein is inlaid and/or coated on the SiC surface layer.
3. An osteoinductive carbon-based composite bone plate according to claim 1; the method is characterized in that:
in the step one, the continuous carbon fiber is 3-48K carbon fiber non-woven cloth or carbon cloth, and the surface density is 100-400 g/cm2(ii) a The short carbon fiber in the carbon fiber net tire is not less than 6K, the length is 10-80 mm, and the surface density of the net tire is 20-185 g/cm2(ii) a The interlayer density is 10-20 layers/10 mm; the needling density is 25-45 needles/cm2(ii) a The periphery of the carbon fiber prefabricated body is cut according to the size of the bone fracture plate plus 4-6 mm, and the upper surface and the lower surface of the carbon fiber prefabricated body are 2-3 mm higher than the bone fracture plate after the layering in the thickness direction is needled;
step three, placing the spare blank subjected to heat treatment in the step two into a deposition furnace; isotropic pyrolytic carbon densification is carried out on the carbon fiber by adopting a thermal gradient chemical vapor infiltration method; when the thermal gradient chemical vapor infiltration is carried out, the carbon source gas is hydrocarbon or natural gas with the carbon atom number less than or equal to 3; the diluent gas is nitrogen, hydrogen or the mixture thereof, the ratio of the carbon source gas to the diluent gas is 1: 1-3, the time is 50-150 hours, and the temperature is 1000-1200 ℃; during deposition, the flow rate of the carbon source gas is 10-30L/min; the gas pressure in the furnace is less than or equal to 1.2kPa, the deposition temperature is controlled to be greater than or equal to 1000 ℃, and the time is controlled to be greater than or equal to 50 hours.
4. An osteoinductive carbon-based composite bone plate according to claim 1; the method is characterized in that: in the fifth step, the machined blank obtained in the fourth step is placed into a mixed solution prepared from polycarbosilane and divinylbenzene for dipping, then crosslinking curing and cracking are carried out under the protective atmosphere to generate a SiC matrix, and the dipping, crosslinking curing and cracking processes are repeated until the density of the blank is 1.6-1.8 g/cm3(ii) a The mass ratio of polycarbosilane to divinylbenzene in the mixed solution is 1: 0.2 to 0.4; the temperature of crosslinking and curing is 120-160 ℃; the cracking temperature is 1200-1500 ℃; the securityThe shielding gas is selected from one of nitrogen and argon.
5. An osteoinductive carbon-based composite bone plate according to claim 1; the method is characterized in that: in the sixth step, when the SiC surface coating is prepared by chemical vapor deposition, the SiC precursor is MTS, and the deposition system is MTS-H2-Ar deposition system with high purity H2Taking high-purity Ar as a diluent gas as a carrier gas, and carrying MTS into a reactor in a bubbling mode to deposit H in a system2And MTS in a molar ratio of H2: MTS is 8-10: 1, the Ar flow is 150-200 ml/min; during deposition, the deposition temperature is 1000-1100 ℃, the pressure is less than or equal to 1kPa, and the deposition time is 50-200 hours; the MTS is trichloromethylsilane.
6. An osteoinductive carbon-based composite bone plate according to claim 1; it is characterized in that; in the seventh step, the gelatin sustained release microspheres containing BMP active protein molecules are prepared by the following scheme:
placing a gelatin solution in a water bath for preheating, dropwise adding the preheated gelatin solution into liquid paraffin while stirring, continuously stirring uniformly after dropwise adding, then quickly transferring into an ice-water bath for treatment, adding a phosphate buffer solution of bone morphogenetic protein, then adding a cross-linking agent for cross-linking, and washing with a washing solution after cross-linking to obtain light yellow microspheres; then continuously solidifying for a period of time in a low-temperature environment of 0-5 ℃, finally fully washing with a washing liquid again, sieving and subpackaging; the preheating temperature in the water bath is controlled to be 40-60 ℃, and the preheating time is 7-15 min; the temperature of the ice-water bath is controlled below 5 ℃, and the treatment time in the ice-water bath is controlled within 15-25 min; the concentration of the gelatin solution is 0.1-0.3 g/ml, and the liquid paraffin contains 1-5% of Span-80 by mass fraction; the cross-linking agent is glutaraldehyde, and the cross-linking reaction time is 1-3 h; the washing liquid is an acetone-water mixed solution, and the continuous curing time is 12-36 hours at the low temperature of 0-5 ℃; the concentration of the bone morphogenetic protein in the phosphate buffer solution of the bone morphogenetic protein is 100-300 mug/ml.
7. An osteoinductive carbon-based composite bone plate according to claim 1; it is characterized in that; and seventhly, in the chitosan acetic acid solution containing the BMP gelatin slow-release microspheres, the concentration of the BMP gelatin slow-release microspheres is 5-10 g/L.
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