CN108324997B

CN108324997B - Carbon-carbon composite bone fracture plate with BMP slow release coating and preparation method thereof

Info

Publication number: CN108324997B
Application number: CN201810196422.9A
Authority: CN
Inventors: 肖涛; 刘立宏; 李专; 蔡锦云
Original assignee: Central South University
Current assignee: Central South University
Priority date: 2018-03-09
Filing date: 2018-03-09
Publication date: 2020-09-22
Anticipated expiration: 2038-03-09
Also published as: CN108324997A

Abstract

The invention discloses a carbon-carbon composite bone fracture plate with a BMP slow release coating and a preparation method thereof, and the carbon-carbon composite bone fracture plate comprises a carbon-carbon composite base material formed by sequentially and alternately laminating 0-degree non-woven fabric, a carbon fiber net tire and 90-degree non-woven fabric; filling needled carbon fibers between the carbon-carbon composite material substrate layers; the surface of the carbon-carbon composite material base material is coated with a pyrolytic carbon layer; and a BMP slow release coating is compounded on the surface of the pyrolytic carbon layer. The carbon-carbon composite bone fracture plate with the BMP slow release coating has good biocompatibility, the mechanical property is close to that of human bones, and the carbon-carbon composite bone fracture plate does not interfere or block medical examination.

Description

Carbon-carbon composite bone fracture plate with BMP slow release coating and preparation method thereof

Technical Field

The invention relates to the technical field of biomedical materials, in particular to a carbon-carbon composite bone fracture plate with a BMP (BMP) slow release coating and a preparation method thereof.

Background

Most of the traditional bone fracture plates are made of metal materials, mainly stainless steel and titanium alloy. However, the bone plate made of metal mainly has the following problems in clinical application: (1) stress shielding exists, and blood circulation at the fracture part is easy to damage; (2) the electrochemical reaction corrosion is easy to generate in vivo; (3) can not directly promote the healing of the fracture, and is easy to cause postoperative complications such as delayed healing or nonhealing, fracture of the bone fracture plate, loosening and falling of screws, rejection reaction and the like; (4) the X-ray, CT and MRI examination results of patients are often seriously affected by the metal bone fracture plate, so that the examination results are inaccurate.

Patent document CN1296013C discloses a carbon fiber reinforced peek composite bone plate, which is obtained by mixing and granulating carbon fiber particles and peek, and then performing injection molding, and since injection molding is used, continuous carbon fibers with a length of more than 2cm cannot be used, and a continuous spreading structure cannot be obtained, the reinforcing effect of the carbon fibers does not fully play a role.

Therefore, there is a need to develop a bone plate with good biocompatibility, better mechanical properties to fit human bones, and no influence on the examination results of patients, so as to replace the existing bone plate.

Disclosure of Invention

The present invention has been made in view of the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a carbon-carbon composite bone plate having a BMP (bone morphogenetic protein) sustained-release coating layer, which has good biocompatibility, mechanical properties close to those of human bones, and does not interfere with or block medical examinations, and a method for preparing the same.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

a carbon-carbon composite bone fracture plate with a BMP slow release coating,

comprises a carbon-carbon composite material base material formed by sequentially and alternately laminating 0-degree non-woven fabrics, carbon fiber net tires and 90-degree non-woven fabrics;

filling needled carbon fibers between the carbon-carbon composite material substrate layers;

the surface of the carbon-carbon composite material base material is coated with a pyrolytic carbon layer; and is

And a BMP slow release coating is compounded on the surface of the pyrolytic carbon layer.

Preferably, the BMP slow release coating is a gelatin slow release microsphere coating containing BMP active protein molecules.

More preferably, in the BMP slow release coating, the particle size of the BMP slow release microspheres is 10-100 μm, the encapsulation rate is more than or equal to 80%, and the drug loading rate is 20-50 μ g/mg.

Preferably, the filling amount of the needle-punched carbon fibers is 10 to 15 percent of the mass of the carbon-carbon composite material base material, and the diameter of the needle-punched carbon fibers is 5 to 7 microns.

Preferably, the pyrolytic carbon layer is multilayer, the thickness of each layer of pyrolytic carbon is 2-5 mm, and the total coating amount of the pyrolytic carbon is 5-10% of the mass of the carbon-carbon composite material base material.

Preferably, the elastic modulus of the bone fracture plate is 10 GPa-30 GPa, the compressive strength is more than or equal to 200MPa, the bending strength is more than or equal to 220MPa, the shear strength is more than or equal to 16MPa, the tensile strength is 110 MPa-130 MPa, and the elongation is less than or equal to 2%.

The invention relates to a preparation method of a carbon-carbon composite bone fracture plate with a BMP slow release coating, which comprises the following steps:

(1) cutting the 0-degree non-woven fabric, the carbon fiber net tire and the 90-degree non-woven fabric according to the design size, sequentially and alternately laminating the cut 0-degree non-woven fabric, the carbon fiber net tire and the 90-degree non-woven fabric, and filling needling carbon fibers between layers to serve as a reinforcing phase;

(2) placing the alternately laminated product obtained in the step (1) on a heating table for preheating, coating pyrolytic carbon on the alternately laminated product, extruding and discharging interlayer gas, then placing the product in a preforming mold, and preforming according to the shape designed by the preforming mold;

(3) putting the product preformed in the step (2) into a preheating oven for preheating, then taking out the product and putting the product into a forming die for hot press forming to obtain a carbon-carbon composite material;

(4) cooling the die subjected to hot press molding in the step (3), taking out a product, cleaning and drying the product, and then performing CNC (computer numerical control) processing according to a design drawing of the bone fracture plate to obtain a carbon-carbon composite bone fracture plate prefabricated body;

(5) preparing gelatin sustained-release microspheres containing BMP active protein molecules by an emulsification crosslinking curing method;

(6) modifying chitosan on the surface of the carbon-carbon composite bone fracture plate prefabricated body obtained in the step (4) by an electrostatic self-assembly method;

(7) and (3) compounding the gelatin slow-release microspheres containing BMP active protein molecules obtained in the step (5) on the surface of the carbon-carbon composite material bone fracture plate preform modified with chitosan obtained in the step (6) by adopting a dipping and pulling method to obtain the carbon-carbon composite material bone fracture plate with the BMP slow-release coating.

In the above preparation method, preferably, in the step (5), the gelatin sustained release microspheres containing BMP active protein molecules are specifically prepared by the following method:

(5.1) preparing a gelatin solution, preheating the gelatin solution in a water bath, 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 cross-linking agent for cross-linking, and washing with a washing solution after cross-linking to obtain light yellow microspheres; then the mixture is placed in a low-temperature environment for continuous solidification for a period of time, and finally the mixture is fully washed again by using a washing solution, sieved and subpackaged to obtain blank gelatin microspheres;

(5.2) mixing the blank gelatin microspheres obtained in the step (5.1) as raw materials with a sodium alginate solution to prepare gelatin/sodium alginate blank core-shell structure slow-release microspheres;

and (5.3) adding the gelatin/sodium alginate hollow core-shell structure slow-release microspheres prepared in the step (5.2) into a PBS buffer solution of bone morphogenetic protein, and fully shaking to obtain the gelatin-sodium alginate core-shell structure slow-release microspheres loaded with BMP.

In the preparation method, preferably, in the step (3), the preheating temperature is 45-75 ℃, and the preheating time is 40-60 min.

In the above preparation method, preferably, in the step (3), the hot press molding temperature is 100 to 250 ℃, the pressing time is 60 to 120min, and the external pressure is 100kg/cm²～120kg/cm²。

In the preparation method, preferably, in the step (3), the volume content of the carbon fiber in the carbon-carbon composite material is more than or equal to 35%.

In the preparation method, preferably, in the step (3), the density of the carbon-carbon composite material is more than or equal to 1.75g/cm³。

In the preparation method, preferably, in the step (4), the cooling temperature in the cooling operation is 35-45 ℃, the cooling time is 5-10 min, and the cooling external pressure is 110kg/cm²～120kg/cm²。

In the above preparation method, preferably, in the step (4), the drying temperature is 155 to 165 ℃.

Compared with the prior art, the invention has the advantages that: the carbon-carbon composite bone fracture plate is characterized in that 0-degree non-woven fabric, carbon fiber net tires and 90-degree non-woven fabric are sequentially and alternately laminated to form a matrix of a carbon-carbon composite material, needling carbon fibers are filled among layers to serve as a reinforcing phase, pyrolytic carbon is coated on products, the carbon-carbon composite material is prepared through preforming and hot press molding, then the carbon-carbon composite material is processed into a bone fracture plate preform, and a BMP slow release coating is compounded on the bone fracture plate preform to obtain the carbon-carbon composite bone fracture plate with the BMP slow release coating. The obtained bone fracture plate has good biocompatibility and fatigue property, the mechanical property of the bone fracture plate is close to that of human bones, and the bone fracture plate does not interfere or block MRI, CT, X-ray examination and the like.

Drawings

Fig. 1 is a photograph showing a comparison of the morphology of a human bone and a carbon-carbon composite material obtained in example 1 of the present invention after compression, wherein the left image in fig. 1 is a human bone and the right image is a carbon-carbon composite material.

Fig. 2 is a photograph of a carbon-carbon composite bone plate obtained in example 1 of the present invention.

Fig. 3 is a microscopic morphology (SEM) of a human bone and the carbon-carbon composite bone plate obtained in example 1 of the present invention.

Fig. 4 is an SEM image of a carbon-carbon composite that was not soaked in simulated body fluid.

Fig. 5 is an SEM image of the carbon-carbon composite after 70 days of immersion in a simulated body fluid.

Fig. 6 is an interpolated energy spectrum of fig. 5.

FIG. 7 is a graph showing the residual bending strength after fatigue of the carbon-carbon composite material obtained in example 1 of the present invention.

FIG. 8 is an SEM image of hollow gelatin microspheres of example 1 of the present invention.

Fig. 9 is an SEM image of the gelatin-sodium alginate core-shell structure sustained release microsphere in example 1 of the present invention.

FIG. 10 is the in vitro release curve of gentamicin sulfate loaded BMP slow release coating in example 1 of the present invention.

Detailed Description

In order to facilitate an understanding of the invention, the invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of the invention is not limited to the specific embodiments below.

Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.

Example 1:

cutting 0-degree non-woven fabric, carbon fiber net tire and 90-degree non-woven fabric into the size of a designed block, sequentially and alternately laminating the cut 0-degree non-woven fabric, carbon fiber net tire and 90-degree non-woven fabric according to the design requirement of a mechanical structure, and filling needled carbon fibers between layers to serve as a reinforcing phase.

And placing the alternately laminated product on a heating table for preheating, coating two layers of pyrolytic carbon on the alternately laminated product, wherein the thickness of each layer of pyrolytic carbon is 3mm, the total coating amount of the pyrolytic carbon on the product is 5% of the product mass, extruding and discharging interlayer gas, smoothly pressing, placing the product in a pre-forming die, and pre-forming according to the shape designed by the pre-forming die.

Preheating the pre-formed product in a preheating oven at 45 deg.C for 40min, taking out, placing into a forming mold, closing the mold, and hot-press forming at 100 deg.C for 60min under 100kg/cm external pressure²Obtaining the carbon-carbon composite material, wherein the volume content of the carbon fiber in the carbon-carbon composite material is 38 percent, and the density of the carbon-carbon composite material is 1.85g/cm³。

Cooling the hot-pressed mold in a cooling table at 35 deg.C for 5min under external pressure of 110kg/cm²And then sending the bone fracture plate into a demoulding table, opening the mould to take out a product, cleaning and drying the product at the drying temperature of 155 ℃, and then carrying out CNC machining according to the design drawing of the bone fracture plate to obtain the carbon-carbon composite material bone fracture plate preform.

Preparing a gelatin solution, preheating in a water bath, 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 cross-linking agent for cross-linking, and washing with a washing solution after cross-linking to obtain light yellow microspheres; then the mixture is placed in a low-temperature environment for continuous solidification for a period of time, and finally the mixture is fully washed again by using a washing solution, sieved and subpackaged to obtain blank gelatin microspheres; taking blank gelatin microspheres as a raw material, and mixing the blank gelatin microspheres with a sodium alginate solution to prepare gelatin/sodium alginate blank core-shell structure slow-release microspheres; adding the gelatin/sodium alginate hollow core-shell structure slow-release microspheres into a PBS buffer solution of bone morphogenetic protein, and fully oscillating to obtain the BMP-loaded gelatin-sodium alginate core-shell structure slow-release microspheres.

Modifying chitosan on the surface of the obtained carbon-carbon composite bone fracture plate preform by an electrostatic self-assembly method; and compounding the obtained gelatin sustained-release microspheres containing BMP active protein molecules on the surface of the carbon-carbon composite bone fracture plate preform modified with chitosan by adopting a dipping and pulling method to obtain the carbon-carbon composite bone fracture plate with the BMP sustained-release coating.

A photograph showing a comparison of the morphology of a human bone and the resulting carbon-carbon composite material after compression is shown in FIG. 1 (the left image in FIG. 1 is a human bone, and the right image is a carbon-carbon composite material). A photograph of the resulting carbon-carbon composite bone plate is shown in fig. 2.

The microscopic morphology of the human bone and the carbon-carbon composite bone plate obtained in this example is shown in fig. 3. As can be seen from FIG. 3, the human bone (b in FIG. 3) and the bone plate (d in FIG. 3) of the present embodiment are porous structures, which can provide smooth passage for cell adhesion and bone tissue growth, and can enhance the interface bonding degree between the implant and the bone tissue.

The biocompatibility of the material was studied by simulating a body fluid immersion experiment. The SEM image of the carbon-carbon composite material without soaking the simulated body fluid is shown in fig. 4, the SEM image of the carbon-carbon composite material after soaking the simulated body fluid for 70 days is shown in fig. 5, and fig. 6 is the interpolated energy spectrum of fig. 5. The analysis of energy spectrum data shows that a layer of sediment is deposited on the surface of the carbon-carbon composite material after the carbon-carbon composite material is soaked in simulated body fluid, the sediment consists of Ca, P and O elements, wherein the atomic ratio of calcium to phosphorus is 1.6, which indicates that bone-like apatite is generated on the surface of the carbon-carbon composite material, and the obtained carbon-carbon composite material can promote the healing of bones.

The fatigue properties of the obtained carbon-carbon composite materials were studied, and the curves of the carbon-carbon composite materials after loading of 60%, 70%, 80%, and 90% stress fatigue were shown in fig. 7. As can be seen from fig. 7, when the stress level during fatigue is low (60% and 70%), the residual bending strength is equal to or slightly higher than the static bending strength, and it can be seen from the graph that the curves at these two stress levels show longer displacement of the sample residual bending strength-displacement curve, reflecting that the sample is plastic after fatigue; after fatigue loading at higher stress levels (80% and 90%), the residual bending strength of the test specimen is significantly higher than the static bending strength, e.g., the bending strength of the test specimen can be increased by 42.94% at 90% stress level. However, as the strength increases, the plasticity of the material decreases, and the material fails suddenly. In addition, after high stress level loading, fine steps appear on the curve, i.e. the bearing surfaces of the material, which are the main cause of the improvement of the residual bending strength. As can be seen from fig. 7, the carbon-carbon composite material has good fatigue properties.

Fig. 8 is an SEM picture of blank gelatin microspheres, fig. 9 is an SEM picture of gelatin-sodium alginate core-shell structure sustained release microspheres, and fig. 10 is an in vitro release curve of gentamicin sulfate loaded BMP sustained release coating, wherein the lower curve is core-shell structure drug loaded gelatin/sodium alginate microspheres, and the upper curve is non-core-shell structure gelatin drug loaded microspheres. As can be seen from fig. 10, the drug-loaded gelatin/sodium alginate microspheres with core-shell structures have better drug slow-release performance than gelatin drug-loaded microspheres without core-shell structures, have no burst release phenomenon, and effectively prolong the drug release time.

The mechanical properties of the obtained carbon-carbon composite bone fracture plate were tested, and the mechanical property parameters of the carbon-carbon composite bone fracture plate are shown in table 1.

Example 2:

And placing the obtained alternately laminated product on a heating table for preheating, coating two layers of pyrolytic carbon on the alternately laminated product, wherein the thickness of each layer of pyrolytic carbon is 2mm, the total coating amount of the pyrolytic carbon on the product is 6% of the product quality, extruding and discharging interlayer gas, pressing smoothly, then placing the product in a pre-forming die, and pre-forming according to the shape designed by the pre-forming die.

Preheating the pre-formed product in a preheating oven at 55 deg.C for 50min, taking out, placing into a forming mold, closing the mold, and hot-press forming at 150 deg.C for 80min under external pressure of 105kg/cm²Obtaining the carbon-carbon composite material, wherein the volume content of the carbon fiber in the carbon-carbon composite material is 40 percent, and the density of the carbon-carbon composite material is 1.90g/cm³。

Cooling the hot-pressed mold in a cooling table at 38 deg.C for 6min under 112kg/cm external pressure²And then sending the bone fracture plate into a demoulding table, opening the mould to take out a product, cleaning and drying the product at the drying temperature of 158 ℃, and then carrying out CNC machining according to the design drawing of the bone fracture plate to obtain the carbon-carbon composite material bone fracture plate preform.

Example 3:

And placing the obtained alternately laminated product on a heating table for preheating, coating two layers of pyrolytic carbon on the alternately laminated product, wherein the thickness of each layer of pyrolytic carbon is 4mm, the total coating amount of the pyrolytic carbon on the product is 8% of the product mass, extruding and discharging interlayer gas, smoothly pressing, then placing the product in a pre-forming die, and pre-forming according to the shape designed by the pre-forming die.

Preheating the pre-formed product in a preheating oven at 65 deg.C for 55min, taking out, placing into a forming mold, closing the mold, and hot-press forming at 200 deg.C for 100min under external pressure of 110kg/cm²Obtaining the carbon-carbon composite material, wherein the volume content of the carbon fiber in the carbon-carbon composite material is 42 percent, and the density of the carbon-carbon composite material is 1.95g/cm³。

Cooling the hot-pressed mold in a cooling table at 40 deg.C for 8min under external pressure of 115kg/cm²Then fed into a demolding tableAnd opening the die to take out the product, cleaning and drying the product at 160 ℃, and then performing CNC (computer numerical control) processing according to the design drawing of the bone fracture plate to obtain the carbon-carbon composite bone fracture plate preform.

Example 4:

And placing the alternately laminated product on a heating table for preheating, coating two layers of pyrolytic carbon on the alternately laminated product, wherein the thickness of each layer of pyrolytic carbon is 5mm, the total coating amount of the pyrolytic carbon on the product is 10% of the product mass, extruding and discharging interlayer gas, smoothly pressing, placing the product in a pre-forming die, and pre-forming according to the shape designed by the pre-forming die.

Preheating the preformed product in a preheating oven at 75 deg.C for 60min, taking out, placing into a forming mold, closing the mold, and hot-press forming at 250 deg.C for 120min under 120kg/cm external pressure²Obtaining the carbon-carbon composite material, wherein the volume content of the carbon fiber in the carbon-carbon composite material is 45 percent, and the density of the carbon-carbon composite material is 1.98g/cm³。

Cooling the hot-pressed mold in a cooling table at 45 deg.C for 10min under cooling external pressure of 120kg/cm²And then the blank is sent into a demoulding table, the mould is opened to take out a product, the product is cleaned and dried at the drying temperature of 165 ℃, and then CNC processing is carried out according to the design drawing of the bone fracture plate to obtain the carbon-carbon composite material bone fracture plate preform.

TABLE 1 comparative data of mechanical properties of bone plates of examples and of the currently available bone plate materials with human bone

Bone-knitting plate material	Tensile strength MPa	Elastic modulus GPa	Elongation percentage%
				Example 1	112-135	11-31	1.5
Example 2	98-138	9-29	1.4
				Example 3	88-140	8-30	1.5
Example 4	102-125	10-28	1.3
				Human bone	80-150	1-30	1.5
317 stainless steel	670-710	192-230	12
				Titanium alloy	770-810	95-129	10
Co-Cr-Mo alloy	428-470	190-230	18
				C/nylon	230-270	6-14	5.4

As can be seen from table 1, the tensile strength, elastic modulus and elongation of the carbon-carbon composite bone fracture plate with BMP slow release coatings obtained in examples 1 to 4 of the present invention are close to those of human bones, while the mechanical properties of 317 stainless steel, titanium alloy, Co-Cr-Mo alloy and C/nylon composite materials have a large difference from those of human bones.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A preparation method of a carbon-carbon composite bone fracture plate with a BMP slow release coating is characterized by comprising the following steps:

the carbon-carbon composite bone fracture plate comprises a carbon-carbon composite base material formed by sequentially and alternately laminating 0-degree non-woven fabrics, carbon fiber net tires and 90-degree non-woven fabrics;

Compounding a BMP slow release coating on the surface of the pyrolytic carbon layer; a silicon carbide layer is not arranged between the pyrolytic carbon layer and the BMP slow release coating;

the filling amount of the needled carbon fibers is 10-15% of the mass of the carbon-carbon composite material base material, and the diameter of the needled carbon fibers is 5-7 mu m;

the pyrolytic carbon layer is multilayer, the thickness of each layer of pyrolytic carbon is 2-5 mm, and the total coating amount of the pyrolytic carbon is 5-10% of the mass of the carbon-carbon composite material base material;

the BMP slow release coating is a gelatin slow release microsphere coating containing BMP active protein molecules; in the BMP slow release coating, the particle size of the BMP slow release microspheres is 10-100 μm, the encapsulation rate is more than or equal to 80%, and the drug loading rate is 20-50 μ g/mg; the elastic modulus of the bone fracture plate is 10 GPa-30 GPa, the compressive strength is more than or equal to 200MPa, the bending strength is more than or equal to 220MPa, the shear strength is more than or equal to 16MPa, the tensile strength is 110 MPa-130 MPa, and the elongation is less than or equal to 2%; the preparation method comprises the following steps:

(7) compounding the gelatin slow-release microspheres containing BMP active protein molecules obtained in the step (5) on the surface of the carbon-carbon composite material bone fracture plate preform modified with chitosan obtained in the step (6) by adopting a dipping and pulling method to obtain the carbon-carbon composite material bone fracture plate with the BMP slow-release coating;

in the step (5), the gelatin sustained-release microspheres containing BMP active protein molecules are prepared by the following method:

(5.3) adding the gelatin/sodium alginate hollow core-shell structure slow-release microspheres prepared in the step (5.2) into a PBS buffer solution of bone morphogenetic protein, and fully oscillating to obtain gelatin-sodium alginate core-shell structure slow-release microspheres loaded with BMP;

in the step (3), the preheating temperature is 45-75 ℃, and the preheating time is 40-60 min;

in the step (3), the hot-press molding temperature is 100-250 ℃, the pressurizing time is 60-120 min, and the external pressure is 100kg/cm²～120kg/cm²；

In the step (3), the volume content of the carbon fiber in the carbon-carbon composite material is more than or equal to 35 percent, and the density of the carbon-carbon composite material is more than or equal to 1.75g/cm³；

In the step (4), the cooling temperature in the cooling operation is 35-45 ℃, the cooling time is 5-10 min, and the cooling external pressure is 110kg/cm²～120kg/cm²；

In the step (4), the drying temperature is 155-165 ℃.