CN108421088B - Mineralized collagen-based medium-strength artificial bone repair material and preparation method thereof - Google Patents
Mineralized collagen-based medium-strength artificial bone repair material and preparation method thereof Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- 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
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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- 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
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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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
The invention relates to a mineralized collagen-based medium-strength artificial bone repair material and a preparation method thereof. The method comprises the steps of preparing a polymer/mineralized collagen composite material, preparing hard polymer/mineralized collagen composite material particles and preparing the mineralized collagen-based medium-strength artificial bone repair material. The method can obtain the bone repair material with certain supporting strength and certain porosity, and the material can be used in parts needing certain bearing, such as tibial plateau, Evans heel osteotomy and Cotton wedge-shaped opening osteotomy.
Description
Technical Field
The invention relates to the technical field of bone materials, in particular to a mineralized collagen-based medium-strength artificial bone repair material and a preparation method thereof.
Background
Bone tissue is the largest and most vulnerable tissue organ of the human body, and millions of patients with bone tissue defects need to be treated by surgery every year. The loss of bone organ or tissue defect caused by osteoporosis, trauma, tumor and infection is one of the problems which troubles the healthy life of human beings. The shape and function of the defect site are usually recovered clinically through bone graft repair and reconstruction surgery, and the bone graft has become the largest graft in demand next to blood transfusion and has a trend of increasing year by year.
Currently, the implant materials for treating bone defects can be roughly classified into autogenous bone, allogenic bone, artificial bone, etc. Autologous bone grafting is the most clinically used method at present, but is a treatment means of 'treating injury with injury' at the expense of bone tissues at healthy parts, can cause new injury to bone supplying areas, and has limited autologous bone sources. Although allogeneic or xenogeneic bone transplantation overcomes the defects of 'limited source and secondary trauma' of autologous bone transplantation, immunological rejection reaction after transplantation exists, and potential risks of disease transmission also exist. In order to overcome various problems of autologous bone, allogeneic bone and xenogeneic bone transplantation, people have been making efforts to hope to prepare an ideal bone repair material by an artificial method.
The artificial bone repair material is divided into non-degradable material and degradable material with good biocompatibility, but the existing degradable bone repair material has low strength generally or has no proper pore diameter and porosity to meet the crawling substitution of bone cells so as to achieve the aim of bone growth.
The mineralized collagen bone repair material is a bone repair material with good biocompatibility, and the mineralized collagen is a bionic bone repair material which is designed by a bionic natural bone extracellular matrix and has a hierarchical structure. The mineralized ossein repair material is similar to natural bone in both microstructure and components, has good biocompatibility and bone induction repair capacity, is an excellent bone repair material, and has the defects of low strength (generally 1-2 MPa) of the mineralized ossein repair material and limitation of the application range.
The applicant develops a mineralized collagen-based artificial bone repair material earlier, the strength of the mineralized collagen-based artificial bone repair material can be improved to 65-150 MPa, and the mineralized collagen-based artificial bone repair material with high strength can be used as a bone repair material for a bearing part. But because of high hardness and high elastic modulus, the material cannot be applied to tibial plateaus, Evans heel osteotomies and Cotton wedge-shaped opening osteotomies. Moreover, the bone repair material prepared by the method has low porosity and is not suitable for the growth and creeping substitution of bone cells.
Thereafter, the applicant developed an artificial bone repair material with high porosity, and the porosity of the bone repair material can reach 95% at most by optimizing the preparation process. However, the applicant finds that the method only simply compounds the high polymer material and the mineralized collagen into the bone repair material, and although the bone repair material also has certain strength, the strength is generally lower, and the method cannot be applied to tibial plateau, Evans heel osteotomy and Cotton wedge-shaped opening osteotomy.
In clinical use, a bone repair material with certain supporting strength, certain porosity and good biocompatibility is urgently needed.
Disclosure of Invention
Technical problem to be solved
Aiming at the problems, the invention provides a mineralized collagen-based medium-strength artificial bone repair material and a preparation method thereof.
(II) technical scheme
In order to solve the technical problems, the invention provides the following technical scheme:
a preparation method of a mineralized collagen-based medium-strength artificial bone repair material comprises the following steps:
(1) preparation of polymer/mineralized collagen composite: dissolving a high molecular polymer in an organic solvent to prepare a first high polymer solution with the concentration of 0.05-0.15 g/mL and a second high polymer solution with the concentration of 0.08-0.20 g/mL;
mixing mineralized collagen dry powder with a first high polymer solution, wherein the mass ratio of the mineralized collagen dry powder to a high polymer in the first high polymer solution is 1: 3-3: 1, and preparing into a first polymer/mineralized collagen mixed solution;
carrying out freeze-drying treatment on the first polymer/mineralized collagen mixed solution to obtain a freeze-dried product;
removing residual organic solvent in the freeze-dried product by an ultrasonic extraction mode, and drying the freeze-dried product to obtain a polymer/mineralized collagen composite material;
(2) preparation of hard polymer/mineralized collagen composite particles: crushing the polymer/mineralized collagen composite material, screening the crushed material by using a 80-mesh sieve, and taking fine powder passing through the sieve as a preparation component;
sequentially carrying out primary pressing, high pressure, double pressing and pressure maintaining on the fine powder to obtain a mould pressing product;
ultrasonically cleaning and drying the mould pressing product, then crushing the mould pressing product into fine particles, and sieving and sorting the fine particles with the particle size of 0.1-0.8 mm to obtain hard polymer/mineralized collagen composite particles;
(3) preparing a mineralized collagen-based medium-strength artificial bone repair material: mixing the second high polymer solution and the hard polymer/mineralized collagen composite particles according to the mass ratio of 2: 1-4: 3, and filling the obtained mixture into a mold under normal pressure to obtain a prefabricated body;
and (3) carrying out freeze-drying treatment on the preform, removing residual organic solvent in a freeze-dried product in an ultrasonic extraction mode, carrying out vacuum drying, and then sterilizing the product in an irradiation mode to prepare the mineralized collagen-based medium-strength artificial bone repair material.
Preferably, in the step (1), the high molecular polymer is any one selected from poly-epsilon-caprolactone with viscosity of 1.0 to 3.0dl/g, polylactic acid with molecular weight of 10 to 30 ten thousand, and polylactic acid-glycolic acid copolymer with molecular weight of 10 to 30 ten thousand.
Preferably, in the step (1), the organic solvent is selected from any one of 1, 4-dioxane, chloroform, acetone and dimethyl sulfoxide or a mixed solvent of two.
Preferably, in step (1), the lyophilization process is performed as follows: pre-freezing the first polymer/mineralized collagen mixed solution under the conditions of normal pressure and-30 to-20 ℃, subliming the first polymer/mineralized collagen mixed solution under the conditions of vacuum and-10 to 0 ℃, and finally performing vacuum drying at the temperature of 0 to 50 ℃.
Preferably, in the step (2), the preliminary pressure, the high pressure, the double pressure and the holding pressure are sequentially performed as follows:
initial pressing: putting the fine powder into a mold, compacting, putting the mold on a press, and manually pressurizing until force cannot be applied;
high pressure: starting a motor or using a manual pressure lever until the pressure reaches 15-25 MPa;
double pressing: turning over the mold or removing the base, and performing bidirectional pressurization;
pressure maintaining: and after the double pressure is finished, keeping the pressure for 90-120 s.
Preferably, in step (3), the preform is subjected to a lyophilization process as follows: pre-freezing the prefabricated body under the condition of normal pressure and-30 to-20 ℃, subliming under the condition of vacuum and-10 to 0 ℃, and finally carrying out vacuum drying at 0 to 50 ℃.
Preferably, in the step (3), the reagent used for irradiation is a cobalt 60 sterilizing agent, and the dosage is 15-38 kGy.
Preferably, in the step (3), the preform has a shape of any one of a pellet, a cube, a rectangular parallelepiped, a cylinder, a trapezoidal block, and a wedge.
Preferably, the mineralized dry collagen powder is prepared by the following method:
s1, dissolving collagen in any one of hydrochloric acid, citric acid or acetic acid to prepare collagen acid solution with the concentration of 0.5-2 mg/mL;
s2, continuously stirring the collagen acid solution, and slowly dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01-0.16 mol per gram of collagen;
s3, continuously stirring the solution obtained in the step S2, and slowly dropwise adding a solution containing phosphate ions, wherein the molar ratio of the addition amount of the phosphate ions to the addition amount of the calcium ions is 1.3-2.0;
s4, continuously stirring the solution obtained in the step S3, slowly dripping a NaOH solution until the pH value of the mixed system is 6-8, beginning to precipitate when the pH value is 5-6, and generating a white suspension when the pH value is 7;
and S5, standing the mixed system obtained in the step S4 for 24-120 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain the mineralized collagen dry powder.
The mineralized collagen-based medium-strength artificial bone repair material is prepared by the preparation method, and preferably has the following characteristics:
the shape is any one of granular, cube, cuboid, cylindrical, trapezoidal block and wedge-shaped block;
the compressive strength is between 8 and 50 MPa;
the porosity is 40-80%;
the degradation time is 6-24 months.
(III) advantageous effects
The technical scheme of the invention has the following advantages:
the bone repair material is provided with a polymer material with good biocompatibility in a certain proportion, a support is provided for bone implantation, and meanwhile, the bone repair material has certain porosity, so that the material can meet the growing of cells while having certain strength, and the material is gradually degraded through creeping substitution of the cells, and simultaneously, new bones are gradually induced to form.
The strength of the material can reach 8 to 50MPa, the porosity is 40 to 80 percent, and the degradation time is six months to two years. Thus, the present invention provides a bone repair material having both a certain support strength and a certain porosity that can be used in areas requiring a certain amount of weight bearing, such as tibial plateau, Evans's calcaneal osteotomy, and Cotton's wedge opening osteotomy.
The preparation method provided by the invention can be used for designing the bone repair material with a corresponding shape according to indications, for example, a wedge-shaped block, a trapezoid-shaped block, a large particle, a small particle, a tooth shape or the shape with a fixing hole can be designed.
The invention prepares mineralized collagen dry powder, then prepares mineralized collagen high polymer composite material, prepares hard mineralized collagen high polymer particles, and rapidly bonds and compounds the hard mineralized collagen high polymer particles through high polymer solution, thus preparing the bone repair material with medium strength.
Drawings
FIG. 1 is a schematic flow diagram of the preparation process provided in example 1;
FIG. 2 is a structural diagram of a bone repair material prepared in example 1 in the shape of a trapezoidal block, in which a is a perspective view and b is a plan view;
FIG. 3 is a block diagram of a bone repair material in the shape of a wedge made in example 2, wherein a is a left side view, b is a front view, c is a top view, and d is a perspective view;
FIG. 4 is a block diagram of a bone repair material in the shape of a wedge made in example 3, wherein a is a left side view, b is a front view, c is a top view, and d is a perspective view;
FIG. 5 is a perspective view of a bone repair material having a cylindrical shape according to example 4;
FIG. 6 is a perspective view of a bone repair material having a cubic shape obtained in example 5.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The invention provides a preparation method of a mineralized collagen-based medium-strength artificial bone repair material, which comprises the following steps:
(1) preparation of Polymer/mineralized collagen composite
Dissolving a high molecular polymer in an organic solvent to prepare a first high polymer solution with a concentration of 0.05-0.15 g/mL (for example, 0.05g/mL, 0.08g/mL, 0.10g/mL, 0.12g/mL or 0.15g/mL) and a second high polymer solution with a concentration of 0.08-0.20 g/mL (for example, 0.08g/mL, 0.10g/mL, 0.15g/mL or 0.20 g/mL). The high molecular polymer can be any one of poly epsilon-caprolactone with the viscosity of 1.0-3.0 dl/g, polylactic acid with the molecular weight of 10-30 ten thousand and polylactic acid-glycolic acid copolymer with the molecular weight of 10-30 ten thousand. The first polymer solution and the second polymer solution may be prepared by selecting the same polymer or polymer composition, or by selecting different polymers or polymer compositions. The organic solvent may be selected from one or a mixture of two of 1, 4-dioxane, chloroform, acetone, and dimethyl sulfoxide.
Mixing the mineralized collagen dry powder with the first high polymer solution, wherein the mass ratio of the mineralized collagen dry powder to the high polymer in the first high polymer solution is 1: 3-3: 1 (for example, 1:3, 1:2, 1:1, 2:1 or 3:1), and preparing into a first polymer/mineralized collagen mixed solution.
The mineralized collagen dry powder used in this step can be prepared as follows:
s1, dissolving collagen in any one of hydrochloric acid, citric acid or acetic acid to prepare a collagen acid solution with a concentration of 0.5-2 mg/mL (for example, 0.5mg/mL, 1.0mg/mL, 1.5mg/mL or 2 mg/mL);
s2, continuously stirring the collagen acid solution, and slowly dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01-0.16 mol (for example, 0.01mol, 0.05mol, 0.08mol, 0.1mol, 0.12mol, 0.15mol or 0.16mol) of the calcium ions correspondingly added to each gram of collagen;
s3, continuously stirring the solution obtained in S2, and slowly dropping a solution containing phosphate ions, wherein the molar ratio of the amount of phosphate ions added to the amount of calcium ions added is 1.3 to 2.0 (for example, 1.3, 1.5, 1.6, 1.7, 1.9, 2.0);
s4, continuously stirring the solution obtained in the step S3, slowly dripping a NaOH solution until the pH value of the mixed system is 6-8, beginning to precipitate when the pH value is 5-6, and generating a white suspension when the pH value is 7;
and S5, standing the mixed system obtained in the step S4 for 24-120 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain the mineralized collagen dry powder.
And (3) carrying out freeze-drying treatment on the first polymer/mineralized collagen mixed solution to obtain a freeze-dried product.
Lyophilization may be performed as follows: the first polymer/mineralized collagen mixed solution is pre-frozen under the conditions of normal pressure, -30 to-20 ℃ (for example, -30 ℃ and, -25 ℃ and-20 ℃, specifically), is sublimated under the conditions of vacuum, -10 to 0 ℃ (for example, -10 ℃ and, -5 ℃ and 0 ℃, and is finally dried under the vacuum condition of 0 to 50 ℃ (for example, 0 ℃, 5 ℃, 10 ℃ and 15 ℃, 20 ℃, 30 ℃, 40 ℃ and 50 ℃).
Removing residual organic solvent in the freeze-dried product by an ultrasonic extraction mode, and drying the freeze-dried product to obtain a polymer/mineralized collagen composite material;
(2) preparation of hard polymer/mineralized collagen composite particles
Crushing the polymer/mineralized collagen composite material, sieving the crushed material by using a 80-mesh sieve, and taking fine powder passing through the sieve as a preparation component.
And (3) sequentially carrying out primary pressing, high pressure, double pressing and pressure maintaining on the fine powder to obtain a mould pressing product.
The initial pressure, the high pressure, the double pressure and the pressure maintaining are carried out in sequence as follows:
initial pressing: putting the fine powder into a mold, compacting, putting the mold on a press, and manually pressurizing until force cannot be applied;
high pressure: starting a motor or using a manual pressure lever until the pressure reaches 15-25 MPa (for example, 15MPa, 20MPa or 25 MPa);
double pressing: turning over the mold or removing the base, and performing bidirectional pressurization;
pressure maintaining: and after the double pressure is finished, keeping the pressure for 90-120 s (which can be 90s, 100s, 110s and 120 s).
Ultrasonically cleaning and drying the mould pressing product, then crushing the mould pressing product into fine particles, and sieving and sorting the fine particles with the particle size of 0.1-0.8 mm to obtain hard polymer/mineralized collagen composite particles;
(3) preparation of mineralized collagen-based medium-strength artificial bone repair material
And mixing the second high polymer solution and the hard polymer/mineralized collagen composite particles according to the mass ratio of 2: 1-4: 3 (for example, 2:1, 3:2 and 4:3), filling the obtained mixture under normal pressure, and designing a mold with a corresponding shape according to the indication to prepare a prefabricated body meeting the requirement. The shape of the prefabricated body can be designed into any one of granular shape, cube shape, cuboid shape, cylindrical shape, trapezoid block and wedge block.
And (3) carrying out freeze-drying treatment on the preform, removing residual organic solvent in a freeze-dried product in an ultrasonic extraction mode, carrying out vacuum drying, and then sterilizing the product in an irradiation mode to prepare the mineralized collagen-based medium-strength artificial bone repair material. In this step, the preform may be subjected to a lyophilization process as follows: the preform is prefrozen under normal pressure at-30 to-20 ℃ (for example, -30 ℃, -25 ℃, -20 ℃), then sublimed under vacuum at-10 to 0 ℃, for example, -10 ℃, -5 ℃, 0 ℃), and finally vacuum-dried at 0 to 50 ℃, for example, at 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃. The irradiation can adopt a cobalt 60 sterilizing agent, and the dosage is 15-38 kGy.
The invention provides a mineralized collagen-based medium-strength artificial bone repair material which is prepared by adopting the preparation method. Preferably, the repair material has the following characteristics:
the shape is any one of granular, cube, cuboid, cylindrical, trapezoidal block and wedge-shaped block;
the compressive strength is between 8 and 50 MPa;
the porosity is 40-80%;
the degradation time is 6-24 months.
The following are examples of the present invention.
Example 1
As shown in fig. 1, the preparation method comprises the following steps:
step 1, preparing mineralized collagen dry powder, which specifically comprises the following steps:
s1, dissolving collagen in hydrochloric acid to prepare an acid solution of the collagen, wherein the concentration of the collagen is 0.5 mg/mL;
s2, continuously stirring the solution obtained in the step S1, and slowly dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01mol per gram of collagen;
s3, continuously stirring the solution obtained in the step S2, and slowly dropwise adding a solution containing phosphate ions, wherein the molar ratio of the addition amount of the phosphate ions to the addition amount of the calcium ions in the step S2 is Ca/P (1.5);
s4, continuously stirring the solution obtained in the step S3, slowly dropwise adding a NaOH solution until the pH value of the mixed system is 6-8, beginning to precipitate when the pH value is 5-6, and generating a white suspension when the pH value is 7;
s5, standing the mixed system obtained in the step S4 for 24 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain mineralized collagen material dry powder for later use.
Step 2, preparing the polymer/mineralized collagen composite material, which specifically comprises the following steps:
swelling step: dissolving a high molecular polymer (poly-epsilon-caprolactone with the viscosity of 1.8dl/g is selected in the embodiment) in 1, 4-dioxane to form a No. 1 high polymer solution with the concentration of 0.05 g/mL;
adding mineralized collagen dry powder into No. 1 high polymer solution to prepare polymer/mineralized collagen mixed solution, wherein the mass ratio of the mineralized collagen dry powder to the high polymer is 1: 2;
pre-freezing the mixed solution of the polymer and the mineralized collagen at the temperature of minus 20 ℃ under normal pressure, sublimating the mixed solution at the temperature of 0 ℃ under the vacuum condition, and drying the mixed solution at the temperature of 50 ℃ in vacuum;
and removing residual organic solvent after freeze-drying by means of ultrasonic extraction and drying to obtain the polymer/mineralized collagen composite material.
Step 3, preparing hard polymer/mineralized collagen composite particles, which specifically comprises the following steps:
putting the prepared polymer/mineralized collagen composite material into a small-sized pulverizer, and pulverizing for 5-10 seconds to obtain fine powder; and sieving the crushed polymer/mineralized collagen composite material by using a stainless steel sieve, wherein the mesh number of the stainless steel sieve is 80 meshes (the particle size of the corresponding material is less than 200 mu m), and the powder passing through the stainless steel sieve is the powder required to be subjected to the next step.
And (3) a mould pressing process: filling the powder into a cylindrical die with the diameter of phi 25mm by a funnel, and compacting by a stainless steel pressure bar; a preliminary pressing procedure, namely placing the die filled with the materials on a press machine, and manually pressurizing until the force cannot be applied by hands; a high-pressure process, wherein a motor is started (or a pressure rod is pressed by a hand) until the set pressure of 25.0MPa is reached; a double-pressure process, namely stopping the machine after a pointer of a pressure gauge reaches a preset high pressure value, turning over the die or removing the base, and performing bidirectional pressurization; a pressure maintaining process, wherein after the double pressure is finished, the pressure is maintained for 90 seconds;
demolding after pressure maintaining, properly and simply cleaning the surface, ultrasonically cleaning and drying, and then putting the material into a small-sized pulverizer to pulverize for 3-5 times for 1-3 seconds each time to obtain fine particles; and (4) screening the particle size, screening the crushed material by using a stainless steel sleeve, and selecting particles with the particle size of 0.1-0.8 mm. Namely the prepared hard polymer/mineralized collagen composite particles.
Step 4, preparing the medium-strength mineralized collagen-based artificial bone repair material, which specifically comprises the following steps:
preparing No. 2 high polymer solution: the polymer (selected in this example, poly epsilon-caprolactone with viscosity of 1.8dl/g) was dissolved in 1, 4-dioxane to prepare a No. 2 polymer solution with a concentration of 0.08 g/mL.
The No. 2 high polymer solution and the hard polymer/mineralized collagen composite material particles are quickly stirred and mixed, the liquid-powder mixing ratio is 2:1 by mass,
the mold was filled under normal pressure to prepare a desired shape (the material prepared in this example was a trapezoidal block, as shown in FIG. 2).
Pre-freezing the product at-20 deg.C, sublimating at 0 deg.C under vacuum condition, and vacuum drying at 50 deg.C; removing residual organic solvent in the freeze-dried product by an ultrasonic extraction mode, and drying in vacuum;
demoulding, trimming and performing radiation sterilization (cobalt 60 sterilizing agent, the dosage is 15-38kGy) to obtain the mineralized collagen-based artificial bone repair material with medium strength.
The detection proves that the strength of the bone repair material is 32MPa, and the porosity is 55%.
Example 2
The preparation method is basically the same as that of example 1, except that:
preparing a No. 1 high polymer solution by adopting polylactic acid with the molecular weight of 10 ten thousand, wherein the mass volume concentration is 0.15 g/mL;
mixing mineralized collagen dry powder and No. 1 high polymer solution according to the mass ratio of 1: 1;
preparing a No. 2 high polymer solution with the concentration of 0.20g/mL by adopting polylactic acid with the molecular weight of 30 ten thousand;
the mixing ratio of the No. 2 high polymer solution to the hard polymer/mineralized collagen composite material particles is 4: 3.
The final bone repair material is in the shape of a wedge, as shown in fig. 3.
Different models can be made according to the needs, and the specific conditions of each model are shown in the following table.
The detection proves that the strength of the bone repair material is 38MPa, and the porosity is 45%.
Example 3
The preparation method is basically the same as that of example 1, except that:
preparing a No. 1 high polymer solution by adopting a polylactic acid-glycolic acid copolymer with the molecular weight of 10 ten thousand, wherein the mass volume concentration is 0.1 g/mL;
mixing mineralized collagen dry powder and No. 1 high polymer solution according to the mass ratio of 3: 1;
preparing No. 2 high polymer solution with the concentration of 0.15g/mL by adopting poly epsilon-caprolactone with the viscosity of 2.0 dl/g;
the mixing ratio of the No. 2 high polymer solution to the hard polymer/mineralized collagen composite material particles is 4: 2.5.
The final bone repair material is in the shape of a wedge, as shown in fig. 4.
Different models can be made according to the needs, and the specific conditions of each model are shown in the following table.
The detection proves that the strength of the bone repair material is 22MPa, and the porosity is 65%.
Example 4
The preparation method is basically the same as that of example 1, except that:
preparing a No. 1 high polymer solution by adopting a polylactic acid-glycolic acid copolymer with the molecular weight of 30 ten thousand, wherein the mass volume concentration is 0.15 g/mL;
mixing mineralized collagen dry powder and No. 1 high polymer solution according to the mass ratio of 2: 1;
preparing a No. 2 high polymer solution with the concentration of 0.20g/mL by adopting a polylactic acid-glycolic acid copolymer with the molecular weight of 30 ten thousand;
the mixing ratio of the No. 2 high polymer solution to the hard polymer/mineralized collagen composite material particles is 1.5: 1.
The final bone repair material is formed in a cylindrical shape as shown in fig. 5.
The detection shows that the strength of the bone repair material is 25MPa, and the porosity is 60%.
Example 5
The preparation method is basically the same as that of example 1, except that:
preparing a No. 1 high polymer solution with the concentration of 0.1g/mL by adopting polylactic acid with the molecular weight of 30 ten thousand;
mixing mineralized collagen dry powder and No. 1 high polymer solution according to the mass ratio of 1: 2;
preparing a No. 2 high polymer solution with the concentration of 0.1g/mL by adopting polylactic acid with the molecular weight of 20 ten thousand;
the mixing ratio of the No. 2 high polymer solution to the hard polymer/mineralized collagen composite material particles is 4: 3.
The final bone repair material is formed in a cubic shape as shown in fig. 6.
The detection proves that the strength of the bone repair material is 18MPa, and the porosity is 75%.
Example 6
The preparation method is basically the same as that of example 1, except that:
in the step 4, the mass ratio of the No. 2 high polymer solution to the hard polymer/mineralized collagen composite particles is 3: 2.
The detection shows that the strength of the prepared repair material is 35MPa, the porosity is 52 percent, and the strength is higher than that of the product of the example 1, but the porosity is reduced.
Comparative example 1
The preparation method is basically the same as that of example 1, except that:
in step 3, the particle size of the hard polymer/mineralized collagen composite particles is controlled to be less than 0.1mm (excluding 0.1mm) by crushing and screening. Because the particle size is too small to play the role of hard particles, the conditions that the mixture can not be completely infiltrated and the prepared material is dispersed and dispersed exist in the preparation process.
Comparative example 2
The preparation method is basically the same as that of example 1, except that:
in step 4, the mass ratio of the organic solvent to the high molecular polymer in the No. 2 high polymer solution is 1: 1. The experiment failed and the high polymer could not be dissolved completely.
Comparative example 3
The preparation method is basically the same as that of example 1, except that:
in step 4, the mass ratio of the organic solvent to the high molecular polymer in the No. 2 high polymer solution is 15: 1.
The strength of the comparative sample 5 was found to be 3MPa and the porosity was found to be 82%.
Comparative example 4
The preparation method is basically the same as that of example 1, except that:
step 1, preparing mineralized collagen dry powder, which specifically comprises the following steps:
s1, dissolving collagen in hydrochloric acid to prepare an acid solution of the collagen, wherein the concentration of the collagen is 0.05 mg/mL. Because the concentration of the collagen is too low, the yield of the mineralized collagen dry powder is low, the energy consumption is high, the precipitation phenomenon is not obvious, and even if the material can be prepared, the efficiency is too low in the actual production, and the time and the labor are wasted.
In summary, the present invention provides a bone repair material with a certain supporting strength and a certain porosity and a method for preparing the same, wherein the bone repair material can be used in the parts needing a certain weight bearing, such as tibial plateau, Evans heel osteotomy, and Cotton wedge-shaped opening osteotomy.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (8)
1. A preparation method of a mineralized collagen-based medium-strength artificial bone repair material is characterized by comprising the following steps:
(1) preparation of polymer/mineralized collagen composite: dissolving a high molecular polymer in an organic solvent to prepare a first high polymer solution with the concentration of 0.05-0.15 g/mL and a second high polymer solution with the concentration of 0.08-0.20 g/mL;
mixing mineralized collagen dry powder with a first high polymer solution, wherein the mass ratio of the mineralized collagen dry powder to a high polymer in the first high polymer solution is 1: 3-3: 1, and preparing into a first polymer/mineralized collagen mixed solution;
carrying out freeze-drying treatment on the first polymer/mineralized collagen mixed solution to obtain a freeze-dried product;
removing residual organic solvent in the freeze-dried product by an ultrasonic extraction mode, and drying the freeze-dried product to obtain a polymer/mineralized collagen composite material; the high molecular polymer is selected from any one of poly epsilon-caprolactone with the viscosity of 1.0-3.0 dl/g, polylactic acid with the molecular weight of 10-30 ten thousand and polylactic acid-glycolic acid copolymer with the molecular weight of 10-30 ten thousand;
(2) preparation of hard polymer/mineralized collagen composite particles: crushing the polymer/mineralized collagen composite material, screening the crushed material by using a 80-mesh sieve, and taking fine powder passing through the sieve as a preparation component;
sequentially carrying out primary pressing, high pressure, double pressing and pressure maintaining on the fine powder to obtain a mould pressing product;
ultrasonically cleaning and drying the mould pressing product, then crushing the mould pressing product into fine particles, and sieving and sorting the fine particles with the particle size of 0.1-0.8 mm to obtain hard polymer/mineralized collagen composite particles;
(3) preparing a mineralized collagen-based medium-strength artificial bone repair material: mixing the second high polymer solution and the hard polymer/mineralized collagen composite particles according to the mass ratio of 2: 1-4: 3, and filling the obtained mixture into a mold under normal pressure to obtain a prefabricated body;
freeze-drying the preform, removing residual organic solvent in a freeze-dried product by an ultrasonic extraction mode, drying in vacuum, and then sterilizing the product by an irradiation mode to prepare the mineralized collagen-based medium-strength artificial bone repair material; the repair material has the following characteristics: the shape of the block is any one of a cube, a cuboid, a cylinder, a trapezoid block and a wedge block; the compressive strength is between 8 and 50 MPa; the porosity is 40-80%; the degradation time is 6-24 months.
2. The method according to claim 1, wherein in the step (1), the organic solvent is selected from any one or a mixture of two of 1, 4-dioxane, chloroform, acetone and dimethyl sulfoxide.
3. The production method according to claim 1, wherein in the step (1), the lyophilization process is performed as follows: pre-freezing the first polymer/mineralized collagen mixed solution under the conditions of normal pressure and-30 to-20 ℃, subliming the first polymer/mineralized collagen mixed solution under the conditions of vacuum and-10 to 0 ℃, and finally performing vacuum drying at the temperature of 0 to 50 ℃.
4. The production method according to claim 1, wherein in the step (2), the preliminary pressure, the high pressure, the double pressure, and the holding pressure are sequentially performed as follows:
initial pressing: putting the fine powder into a mold, compacting, putting the mold on a press, and manually pressurizing until force cannot be applied;
high pressure: starting a motor or using a manual pressure lever until the pressure reaches 15-25 MPa;
double pressing: turning over the mold or removing the base, and performing bidirectional pressurization;
pressure maintaining: and after the double pressure is finished, keeping the pressure for 90-120 s.
5. The production method according to claim 1, wherein in the step (3), the preform is subjected to the freeze-drying process in the following manner: pre-freezing the prefabricated body under the condition of normal pressure and-30 to-20 ℃, subliming under the condition of vacuum and-10 to 0 ℃, and finally carrying out vacuum drying at 0 to 50 ℃.
6. The preparation method according to claim 1, wherein in the step (3), the agent used for irradiation is cobalt 60 sterilizing agent, and the dosage is 15-38 kGy.
7. The method according to any one of claims 1 to 6, wherein the mineralized dry collagen powder is prepared by the following method:
s1, dissolving collagen in any one of hydrochloric acid, citric acid or acetic acid to prepare collagen acid solution with the concentration of 0.5-2 mg/mL;
s2, continuously stirring the collagen acid solution, and slowly dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01-0.16 mol per gram of collagen;
s3, continuously stirring the solution obtained in the step S2, and slowly dropwise adding a solution containing phosphate ions, wherein the molar ratio of the addition amount of the phosphate ions to the addition amount of the calcium ions is 1.3-2.0;
s4, continuously stirring the solution obtained in the step S3, slowly dripping a NaOH solution until the pH value of the mixed system is 6-8, beginning to precipitate when the pH value is 5-6, and generating a white suspension when the pH value is 7;
and S5, standing the mixed system obtained in the step S4 for 24-120 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain the mineralized collagen dry powder.
8. A mineralized collagen-based medium-strength artificial bone repair material prepared by the preparation method according to any one of claims 1 to 7, wherein the repair material has the following characteristics:
the shape of the block is any one of a cube, a cuboid, a cylinder, a trapezoid block and a wedge block;
the compressive strength is between 8 and 50 MPa;
the porosity is 40-80%;
the degradation time is 6-24 months.
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| CN110101487B (en) * | 2019-05-14 | 2020-07-03 | 清华大学 | Multi-stage biomimetic mineralized collagen-based skull repairing implant and preparation method thereof |
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