CN108553691B - Injectable self-curing artificial bone repair material and preparation method thereof - Google Patents
Injectable self-curing 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
- A61L27/58—Materials at least partially resorbable by the body
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—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
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- 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
- A61L27/56—Porous materials, e.g. foams or sponges
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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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 an injectable self-curing artificial bone repair material and a preparation method thereof. The preparation method comprises the following steps: the preparation method comprises the steps of preparing biphase calcium phosphate porous particles, preparing mineralized collagen porous calcium phosphate composite material and mixing with calcium sulfate hemihydrate. The prepared artificial bone repair material has the following characteristics: (a) the mineralized collagen is uniformly distributed on the surface and pores of the biphase calcium phosphate porous particles, so that the mineralized collagen is uniformly combined with the porous calcium phosphate, and better biocompatibility is achieved; (b) the porous structure is beneficial to the growth and creeping substitution of bone tissues, and has certain supporting strength; (c) can be used as carrier of growth factor and various antibiotics for anti-inflammatory treatment; (d) developing under X-ray for inspection; (e) the degradable bone scaffold is degradable, secondary pain caused by taking out is avoided, and the degradation rate can be matched with the growth rate of new bones; (f) can be injected in situ and has excellent self-curing performance.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to an injectable self-curing 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. Loss of bone organs or tissue defects caused by osteoporosis, trauma, tumors, infections have become one of the problems that afflict the healthy lives of humans. 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 artificial bone repair material by an artificial method.
The artificial bone repair material is mostly in a regular shape prepared in advance, and is not fully utilized or incompletely filled when an irregular shape is filled, so that the artificial bone repair material capable of self-curing is needed, the filling of different shapes can be met, and the artificial bone repair material can self-cure in situ to ensure good filling.
When treating some infected patients, the used materials are not easy to load with antibiotics, and bone defects caused by tumor or cyst excision, trauma, infection, congenital diseases, operation and fracture nonunion often appear in clinical treatment. The presence of these defects leads to a change in the biomechanical environment of the lesion, to functional disuse or to infection, which adversely affects the life of the patient. Therefore, there is a need in the treatment to use bone substitutes to fill defects, restore the appearance, mechanical strength and function of the lesion, eliminate dead space, and reduce post-operative infection. Meanwhile, the material has good biocompatibility and osteoinductive capacity and can have a degradation speed matched with the growth of autologous bones.
Conventional bone cements have high strength, but generate high heat during setting, which can cause damage to surrounding healthy soft tissue. For example, PMMA bone cement is a non-degradable material and cannot form chemical bonds with host bone tissue, and its high thermal yield and release of methyl methacrylate monomers during curing also damage tissue and cells in the area.
The mineralized collagen is a bionic bone repair material which is designed by a bionic natural bone extracellular matrix and has a hierarchical structure, is similar to natural bone in terms of both microstructure and components, has good biocompatibility and bone induction repair capacity, and is an excellent bone repair material.
In the prior patent application document (application number 201210254608.8), an anti-infection mineralized collagen-calcium sulfate bone repair material prepared by mixing mineralized collagen, alpha-calcium sulfate hemihydrate, vancomycin and calcium sulfate dihydrate is developed, has good injectability, biocompatibility and self-curing performance, and can be degraded, slowly released by medicines, resist infection and promote adhesion and spreading of osteoblasts. However, the bone repair material has the following problems:
(a) only one antibiotic, vancomycin, can be loaded, but other kinds of antibiotics or growth factors cannot be loaded;
(b) for some patients with serious inflammation (such as inflammation caused by tumor or cyst excision, trauma, infection and the like), the immune response of the bone defect part is stronger, and the biocompatibility of the material is higher;
(c) the alpha-calcium sulfate hemihydrate has good biocompatibility, particularly good fluid injectability, in-situ self-curing property and plasticity, but the degradation speed is too high, the alpha-calcium sulfate hemihydrate is completely absorbed in 1-3 months, and the degradation speed is not matched with the growth speed of new bones.
The use of calcium phosphate salts in bone repair materials has been studied and is described in, for example, application documents 201210558900.9, 201310682213.2, 201110130874.5. However, the inventor finds that the degradation time of the calcium phosphate material is long or the calcium phosphate material cannot be degraded in research. When the calcium phosphate bone repair material is used for treatment, part of bone repair material of patients needs to be taken out through an operation, and secondary damage is easily caused to the patients.
In view of the above, we developed a novel injectable self-curable bone repair material and a method for preparing the same.
Disclosure of Invention
Technical problem to be solved
Aiming at the technical problems, the invention provides an injectable self-curing 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:
the preparation method of the injectable self-curing artificial bone repair material comprises the following steps:
(1) preparation of biphasic calcium phosphate porous particles: the preparation components comprise a first calcium salt, polyvinyl alcohol and PMMA microspheres, the mass ratio is (0.1-0.5) to 3:2, the first calcium salt is composed of hydroxyapatite and beta-calcium phosphate according to the mass ratio of 5: 1-1: 3, and the preparation method comprises the following steps:
(a) preparing a polyvinyl alcohol solution with the concentration of 0.2-0.5 g/mL;
(b) preparing a biphase phosphate suspension; adding hydroxyapatite and beta-calcium phosphate into a PBS solution to form a suspension;
(c) adding the polyvinyl alcohol solution into the biphase phosphate turbid liquid, stirring for 0.5-1 hour, then adding PMMA microspheres, and stirring for 0.5-1 hour to obtain a sintering base liquid;
(d) placing the sintering base liquid in sintering equipment for sintering to obtain a sintering material;
the sintering comprises the following stages:
the first stage is as follows: the heating rate is 5-10 ℃/min, the target temperature is 400-800 ℃, and the constant temperature time is 300-350 min;
and a second stage: the heating rate is 5-10 ℃/min, the target temperature is 1000-1200 ℃, and the constant temperature time is 180-200 min;
and a third stage: stopping heating the sintering equipment, and naturally cooling to room temperature;
(e) pulverizing the sintered material;
(f) screening;
(2) preparing a mineralized collagen porous calcium phosphate composite material: adding the biphase calcium phosphate porous particles into a collagen acid solution with the concentration of 1-5 mg/mL, stirring and mixing for 2-3 hours to prepare a suspension with the concentration of 10-30 wt%;
continuously stirring the suspension, and dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01-0.15 mol per gram of collagen; dropwise adding a solution containing phosphate ions, wherein the molar ratio of the phosphate ions to the calcium ions is 0.8-1.8; continuously stirring, dropwise adding a NaOH solution until the pH value of the mixed system is 7-8, beginning to precipitate when the pH value reaches 5-6, and generating a white turbid liquid when the pH value reaches 7; standing the obtained mixed system for 24-96 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain a mineralized collagen porous calcium phosphate composite material with the mineralized collagen content of 2-25 wt%;
(3) mixing: mixing the mineralized collagen porous calcium phosphate composite material and the alpha-semi-hydrated calcium sulfate powder according to the mass ratio of 7: 3-2: 8, and drying and sterilizing the mixture to obtain the injectable self-curing artificial bone repair material.
Preferably: in the step (1), the PMMA microspheres adopt any one or two of particles with the particle size of 50-800 micrometers; preferably, the PMMA microspheres with the particle size of 50-200 microns and the PMMA microspheres with the particle size of 400-600 microns are a mixture formed according to the mass ratio of 2: 8-8: 2.
Preferably: in the step (1), the preparation component further comprises a second calcium salt added in the step (b), wherein the second calcium salt is selected from any one or more of alpha-tricalcium phosphate, calcium hydrophosphate dihydrate, calcium hydrophosphate and tetracalcium phosphate, and the using amount of the second calcium salt accounts for 1-10% of the total mass of the calcium salt.
Preferably: in the step (2), the solvent used for preparing the collagen acid solution is selected from any one of hydrochloric acid, citric acid and acetic acid.
Preferably: in the step (3), the alpha-calcium sulfate hemihydrate powder is prepared as follows:
adding calcium sulfate dihydrate, sodium citrate, aluminum sulfate and water into a reaction container according to the mass ratio of 1:0.0025:0.0025:5.67, sealing and stirring, and reacting for 6 hours at the temperature of 120 ℃; after the reaction is finished, carrying out suction filtration on the reaction liquid while the reaction liquid is hot, washing the filter cake for 3-5 times by using deionized boiling water after the suction filtration, and then putting the filter cake into a drying oven for drying for 12-24 hours at 100 ℃ to prepare calcium sulfate hemihydrate;
grinding the calcium sulfate hemihydrate into powder, and sieving with a 100-mesh sieve to obtain the alpha-calcium sulfate hemihydrate powder.
Preferably: in the step (3), the mineralized collagen porous calcium phosphate composite material and the alpha-calcium sulfate hemihydrate powder are mixed according to the mass ratio of 5: 5-3: 7.
Preferably: in the step (3), the mixture further comprises a coagulant, wherein the coagulant is selected from any one of calcium sulfate dihydrate, potassium sulfate and potassium chloride, and the mass of the coagulant accounts for 5-20 wt% of the total mass of the mixture.
Preferably: in the step (3), the mixture further comprises a plasticizer, wherein the plasticizer is selected from any one of hydroxymethyl cellulose, hydroxypropyl methyl cellulose and chitosan, and the mass of the plasticizer accounts for 1-15 wt% of the total mass of the mixture.
Preferably: in the step (3), the sterilization is carried out by adopting an irradiation mode, the used reagent is a cobalt 60 sterilizing agent, and the dosage is 15-35 kGy.
The injectable self-curing artificial bone repair material is prepared by adopting the preparation method.
(III) advantageous effects
The technical scheme of the invention has the following advantages:
according to the invention, through a special sintering process, the biphase calcium phosphate porous particles are prepared, and mineralized collagen is prepared on the surface and in the gaps of the porous calcium phosphate, so that the mineralized collagen is uniformly combined with the porous calcium phosphate, and the collagen is uniformly mineralized in the gaps and on the surface of the biphase calcium phosphate porous particles, but not simply mixed, so that the material has good biocompatibility and certain supporting strength; the alpha-calcium sulfate hemihydrate is introduced into the system, and the proportion of the alpha-calcium sulfate hemihydrate is more scientific and reasonable, so that the material has self-curing performance, the requirement of injection self-curing in clinic is met, and the material has no temperature change in the curing process and no damage to surrounding tissues. In conclusion, the preparation method provided by the invention combines the advantages of mineralized collagen, calcium phosphate salt and alpha-calcium sulfate hemihydrate, overcomes the defects of various materials, prepares the artificial bone repair material with the characteristics of drug loading, plasticity, developability, injectability, degradability and the like, and meets different clinical requirements.
The artificial bone repair material prepared by the invention is a porous composite material, is beneficial to the growth and creeping substitution of bone tissues, has certain supporting strength, is self-cured, can be molded at will, can be loaded with antibiotics and growth factors, is developed under X-ray, and is beneficial to examination.
The artificial bone repair material prepared by the invention can be degraded, secondary pain caused by taking out can be avoided, the degradation rate is matched with the growth rate of new bones, and the degradation time can be adjusted by adjusting the proportion of a plurality of components.
Drawings
FIG. 1 is a surface adhesion behavior of BMSCs cells in the artificial bone repair material prepared in example 1, observed by using a scanning electron microscope;
FIG. 2 is a result of a cytotoxicity test of the artificial bone repair material prepared in example 1;
FIG. 3 shows the results of animal experimental tissue sections of the artificial bone repair material prepared in example 1.
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 preparation method of the injectable self-curing artificial bone repair material comprises the following steps:
(1) preparation of biphasic calcium phosphate porous particles: the preparation components comprise a first calcium salt, polyvinyl alcohol and PMMA microspheres, the mass ratio is (0.1-0.5): 3:2, and the first calcium salt is composed of hydroxyapatite and beta-calcium phosphate according to the mass ratio of 5: 1-1: 3;
the preparation method comprises the following steps:
(a) preparing a polyvinyl alcohol solution with the concentration of 0.2-0.5 g/mL;
(b) preparing a biphase phosphate suspension; adding hydroxyapatite and beta-calcium phosphate into a PBS solution to form a suspension;
(c) adding the polyvinyl alcohol solution into the biphase phosphate turbid liquid, stirring for 0.5-1 hour, then adding PMMA microspheres, and stirring for 0.5-1 hour to obtain a sintering base liquid;
(d) placing the sintering base liquid in sintering equipment for sintering to obtain a sintering material;
the sintering comprises the following stages:
the first stage is as follows: the heating rate is 5-10 ℃/min, the target temperature is 400-800 ℃, and the constant temperature time is 300-350 min;
and a second stage: the heating rate is 5-10 ℃/min, the target temperature is 1000-1200 ℃, and the constant temperature time is 180-200 min;
and a third stage: stopping heating the sintering equipment, and naturally cooling to room temperature;
(e) pulverizing the sintered material;
(f) and (6) screening.
The invention selects a biphase calcium phosphate composite formula, preferably a hydroxyapatite and beta-TCP (namely beta-calcium phosphate) composite biphase. In the selected biphase calcium phosphate material, a second calcium salt can be added, wherein the calcium salt is selected from one or more calcium salts of alpha-tricalcium phosphate, calcium hydrophosphate dihydrate, calcium hydrophosphate and tetracalcium phosphate, and the dosage of the calcium salt accounts for 1-10% of the total mass of the calcium salt.
The invention adopts PMMA microspheres (polymethyl methacrylate microspheres) as pore-forming agent. In some embodiments, the PMMA microspheres used are any one or two of PMMA microspheres with the particle size of 50-800 micrometers, and further preferably, a mixture of polymethyl methacrylate microspheres with the particle size of 50-200 micrometers and polymethyl methacrylate microspheres with the particle size of 400-600 micrometers is adopted according to the mass ratio of 2: 8-8: 2.
(2) Preparing a mineralized collagen porous calcium phosphate composite material: adding the biphase calcium phosphate porous particles into a collagen acid solution (when the collagen acid solution is prepared, a solvent can be any one of hydrochloric acid, nitric acid and acetic acid), wherein the concentration of the collagen acid solution is 1-5 mg/mL, and stirring and mixing for 2-3 hours to prepare a suspension liquid with the concentration of 10-30 wt%;
continuously stirring the suspension, and dropwise adding (in order to obtain a better reaction effect, the dropwise adding speed is not too fast, and the dropwise adding is preferably slow) a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01-0.15 mol per gram of collagen; dropwise adding (in order to obtain a better reaction effect, the dropwise adding speed is not too fast, and the dropwise adding is slow) a solution containing phosphate ions, wherein the molar ratio of the phosphate ions to the calcium ions is 0.8-1.8; continuously stirring, dropwise adding (in order to obtain a better reaction effect, the dropwise adding speed is not too fast, and the dropwise adding is preferably slow) NaOH solution until the pH value of the mixed system is 7-8, when the pH value reaches 5-6, the mixed system begins to precipitate, and when the pH value reaches 7, the mixed system generates white turbid liquid; and standing the obtained mixed system for 24-96 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain the mineralized collagen porous calcium phosphate composite material with the mineralized collagen content of 2-25 wt%.
The mineralized collagen is precipitated and arranged on the surfaces and in the gaps of the biphase calcium phosphate porous particles, and can be distributed more uniformly, so that the artificial bone repair material has better bioactivity.
(3) Mixing: mixing the mineralized collagen porous calcium phosphate composite material and the alpha-semi-hydrated calcium sulfate powder according to the mass ratio of 7: 3-2: 8, preferably according to the mass ratio of 5: 5-3: 7, drying and sterilizing the mixture, and thus obtaining the injectable self-curing artificial bone repair material. The alpha-calcium sulfate hemihydrate powder can be prepared as follows: adding calcium sulfate dihydrate, sodium citrate, aluminum sulfate and water into a reaction container according to the mass ratio of 1:0.0025:0.0025:5.67, sealing and stirring, and reacting for 6 hours at the temperature of 120 ℃; after the reaction is finished, carrying out suction filtration on the reaction liquid while the reaction liquid is hot, washing the filter cake for 3-5 times by using deionized boiling water after the suction filtration, and then putting the filter cake into a drying oven for drying for 12-24 hours at 100 ℃ to prepare calcium sulfate hemihydrate; grinding the calcium sulfate hemihydrate into powder, and sieving with a 100-mesh sieve to obtain the alpha-calcium sulfate hemihydrate powder.
In some embodiments, the sterilization may be performed by irradiation with a cobalt 60 sterilant at a dose of 15-35 kGy.
In addition, the mixture also comprises a coagulant, and the artificial bone repair material containing the coagulant is prepared. The coagulant can be selected from any one of calcium sulfate dihydrate, potassium sulfate and potassium chloride, and the dosage of the coagulant can be controlled within the range of 5-20 wt% (the mass of the coagulant accounts for 5-20% of the total mass of the mixture). The coagulation time of the prepared artificial bone repair material can be adjusted within 5-60 minutes, and the use requirements of different clinical operations are met.
In addition, the mixture also comprises a plastic agent, and the artificial bone repair material containing the plastic agent is prepared. The used shaping agent can be used for adjusting shaping and improving the collapse resistance, and is preferably selected from any one of hydroxymethyl cellulose, hydroxypropyl methyl cellulose and chitosan, and the using amount is controlled to be 1-15 wt% (the mass of the shaping agent accounts for 1-15% of the total mass of the mixture).
The artificial bone repair material prepared by the method has the following characteristics:
(a) the mineralized collagen is uniformly distributed on the surface and pores of the biphase calcium phosphate porous particles, so that the mineralized collagen is uniformly combined with the porous calcium phosphate, and the artificial bone repair material has better biocompatibility.
(b) The artificial bone repair material has a porous structure, is beneficial to growth and creeping substitution of bone tissues, and has certain supporting strength.
(c) The artificial bone repairing material can also be used as a carrier of growth factors and various antibiotics for anti-inflammatory treatment.
(d) The artificial bone repair material is developed under X-ray, which is beneficial to observation in and after operation.
(e) The artificial bone repair material can be degraded, so that secondary pain caused by taking out can be avoided, and the degradation rate can be matched with the growth rate of new bones.
(f) The artificial bone repair material can be injected in situ and has excellent self-curing performance.
The following are examples of the present invention.
Example 1
S1 preparation of alpha-calcium sulfate hemihydrate powder by hydrothermal method
Mixing CaSO4·2H2Adding O into a reaction kettle, and respectively taking CaSO4·2H2Adding sodium citrate and aluminum sulfate with the O mass of 0.25 percent into a reaction kettle, and then adding CaSO4·2H2Deionized water with the mass of 5.67 times of that of O is used for sealing the reaction kettle and stirring at the temperature of 120 ℃ for 6 hours; after the reaction is finished, carrying out suction filtration on the reaction solution while the reaction solution is hot, washing the filter cake for 5 times by using deionized boiling water after the suction filtration, and keeping the temperature of the filtrate and the washing liquid above 90 ℃ in the whole process; putting the pumped and dried filter cake into a drying oven to be dried for 12 hours at the temperature of 100 ℃ to prepare the alpha-calcium sulfate hemihydrate; grinding by a mortar, and sieving by a 100-mesh sieve to prepare the alpha-semi-hydrated calcium sulfate powder with uniform particle size.
S2 preparation of biphasic calcium phosphate porous particles
Preparing a mixture of a first calcium salt, polyvinyl alcohol and PMMA microspheres (a mixture of PMMA microspheres with the particle size of 100 micrometers and PMMA microspheres with the particle size of 500 micrometers in a mass ratio of 1:1), wherein the mass ratio is 0.4:3:2, and the first calcium salt is composed of hydroxyapatite and beta-calcium phosphate in a mass ratio of 1: 3;
the preparation method comprises the following steps:
(a) preparing a polyvinyl alcohol solution with the concentration of 0.2 g/mL;
(b) preparing a biphase phosphate suspension; adding hydroxyapatite and beta-calcium phosphate into a PBS solution to form a suspension;
(c) adding the polyvinyl alcohol solution into the biphase phosphate suspension, stirring for 0.8 hour, then adding PMMA microspheres, and stirring for 0.8 hour to obtain a sintering base solution;
(d) placing the sintering base liquid in sintering equipment for sintering to obtain a sintering material;
the sintering comprises the following stages:
the first stage is as follows: the heating rate is 10 ℃/min, the target temperature is 800 ℃, and the constant temperature time is 300 min;
and a second stage: the heating rate is 10 ℃/min, the target temperature is 1200 ℃, and the constant temperature time is 180 min;
and a third stage: stopping heating the sintering equipment, and naturally cooling to room temperature;
(e) pulverizing the sintered material;
(f) and (6) screening.
S3 preparation of mineralized collagen porous calcium phosphate composite material
Dissolving collagen in hydrochloric acid to prepare a collagen acid solution, wherein the concentration of the collagen is 1 mg/mL; adding biphasic porous calcium phosphate particles thereto, and mixing with stirring for 2 hours to form a suspension having a concentration of 10 wt% (the concentration representing the mass of biphasic porous calcium phosphate particles in the suspension as a percentage of the mass of the suspension);
continuously stirring the suspension solution, and slowly dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01mol per gram of collagen; slowly dropwise adding a solution containing phosphate ions, wherein the molar ratio of the phosphate ions to the calcium ions is Ca/P (1.5);
continuously stirring, slowly dropwise adding a NaOH solution until the pH value of the mixed system reaches 7-8, when the pH value of the system reaches 5-6, beginning precipitation of the mixed system, and when the pH value reaches 7, enabling the mixed system to generate a white turbid liquid;
and standing the obtained mixed system for 24 hours, separating out precipitates, washing away impurity ions, freeze-drying, and grinding to obtain the mineralized collagen porous calcium phosphate composite material.
The mineralized collagen is deposited and arranged on the surface and in the gaps of the porous calcium phosphate, and can be distributed more uniformly, so that the whole material has good bioactivity, and the content of the mineralized collagen is 4%.
S4, mixing
The mineralized collagen porous calcium phosphate composite material and the alpha-calcium sulfate hemihydrate powder are mixed according to the mass ratio of 5:5, the mixture is dried and subjected to radiation sterilization (the used reagent is a cobalt 60 sterilizing agent, and the dosage is 15kGy), and then the injectable self-curing bone repair material is obtained, the setting time is 30 minutes, and the degradation time is one year and half.
The early adhesion behavior of BMSCs cells (namely bone marrow mesenchymal stem cells) on the surface of the material is observed by a scanning electron microscope, the scanning electron microscope can display the surface appearance of the material and the whole contour of the adhered cells by processing the composite surface of the material and the cells, has stereoscopic impression, can finely observe the surface structures of the pseudopodium of the material, the secretion of matrix particles and the like, and can objectively evaluate the influence of the surface modified material on the morphological change of osteoblasts. As shown in figure 1, the bone repair material prepared by the invention has good biocompatibility and can promote the adhesion of cells.
Fig. 2 shows the results of the cytotoxicity experiments of the bone repair material. As can be seen in FIG. 2, the cells co-cultured with the bone repair material have normal morphology, good adherence, no cell lysis or apoptosis, and can be judged as 0-grade cytotoxic reaction.
FIG. 3 shows the results of experimental tissue sections of 12 weeks after surgery. As can be seen from figure 3, the material has good bone repair capacity, can finish the repair of bone defect, can see that the defect area has new bone trabeculae, realizes the orderly arrangement of the bone trabeculae, the bone graft bed has a large amount of new bones growing into the transplanted bones in a finger shape, has rich cell components, can see the material which is not completely degraded, and provides longer support for the maturation of bone tissues.
Example 2
The preparation method is basically the same as that of example 1, except that:
in S2:
PMMA microspheres with the particle size of 100 microns are used as pore-forming agents.
In S3:
the concentration of the collagen acid solution is 5mg/mL, and the concentration of the suspension is 20 wt%;
correspondingly adding 0.05mol of calcium ions into each gram of collagen, wherein the molar ratio of the phosphate ions to the calcium ions is 1.8;
the content of mineralized collagen in the obtained mineralized collagen porous calcium phosphate composite material is 10%.
In S4:
mixing the mineralized collagen porous calcium phosphate composite material and alpha-calcium sulfate hemihydrate powder according to the mass ratio of 3:7, wherein the setting time is 20 minutes, and the degradation time is 1 year.
Example 3
The preparation method is basically the same as that of example 1, except that:
in S2:
PMMA microspheres with the particle size of 800 microns are used as pore-forming agents.
In S3:
the concentration of the collagen acid solution is 3mg/mL, and the concentration of the suspension is 30 wt%;
correspondingly adding 0.15mol of calcium ions into each gram of collagen;
the content of mineralized collagen in the obtained mineralized collagen porous calcium phosphate composite material is 15%.
In S4:
mixing the mineralized collagen porous calcium phosphate composite material and the alpha-semi-hydrated calcium sulfate powder according to the mass ratio of 7:3, wherein the setting time is 60 minutes, and the degradation time is two years.
Example 4
The preparation method is basically the same as that of example 1, except that:
in S2:
PMMA microspheres with the particle size of 50 microns and PMMA microspheres with the particle size of 400 microns (mass ratio is 1:1) are used as pore-forming agents.
In S3:
the concentration of the collagen acid solution is 5mg/mL, and the concentration of the suspension is 30 wt%;
correspondingly adding 0.1mol of calcium ions into each gram of collagen;
the content of mineralized collagen in the obtained mineralized collagen porous calcium phosphate composite material is 3%.
In S4:
mixing the mineralized collagen porous calcium phosphate composite material and the alpha-calcium sulfate hemihydrate powder according to the mass ratio of 2:8, wherein the setting time is 15 minutes, and the degradation time is nine months.
Example 5
The preparation method is basically the same as that of example 4, except that:
in S4, calcium sulfate dihydrate is added in an amount of 10 wt% of the total mass of the mixture, and the prepared composite material contains the calcium sulfate dihydrate and a coagulant is added, so that the setting time can be shortened to 10 minutes.
Example 6
The preparation method is basically the same as that of example 5, except that:
chitosan is also added into S4, the addition amount is 10 wt% of the total mass of the mixture, and the prepared composite material contains chitosan.
Comparative example 1
The preparation method is basically the same as that of example 1, except that: in S2, only hydroxyapatite is used as a preparation component and is mixed with PMMA microspheres to form a sintering material.
Comparative example 2
The preparation method is basically the same as that of example 1, except that: in S2, the pore former used had a particle size of 10 μm.
Comparative example 3
The preparation method is basically the same as that of example 1, except that: in S2, the pore former used had a particle size of 1000. mu.m.
Comparative example 4
The preparation method is basically the same as that of example 1, except that: in S2, the sintering is performed as follows: the sinter was heated directly to 1000 ℃ and sintered at this temperature for the same time as in example 1.
Comparative example 5
The preparation method is basically the same as that of example 1, except that: s3 proceeds as follows:
dissolving collagen in hydrochloric acid to prepare a collagen acid solution, wherein the concentration of the collagen acid solution is 1 mg/mL;
continuously stirring the suspension solution, and slowly dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01mol per gram of collagen; slowly dropwise adding a solution containing phosphate ions, wherein the molar ratio of the phosphate ions to the calcium ions is Ca/P (1.5);
continuously stirring, slowly dropwise adding a NaOH solution until the pH value of the mixed system reaches 7-8, when the pH value of the system reaches 5-6, beginning precipitation of the mixed system, and when the pH value reaches 7, enabling the mixed system to generate a white turbid liquid;
standing the obtained mixed system for 24 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain mineralized collagen;
and mixing the biphase calcium phosphate porous particles and the mineralized collagen according to the mass ratio of 1:0.4 to obtain the mineralized collagen porous calcium phosphate composite material.
Comparative example 6
The preparation method is basically the same as that of example 1, except that: in S4, the mineralized collagen porous calcium phosphate composite and the alpha-calcium sulfate hemihydrate powder are mixed according to a ratio of 1: 0.1 mass ratio.
The properties of the bone repair materials prepared in the respective comparative examples were measured, and the test results are shown in table 1.
TABLE 1
From the test results of comparative example 1, comparative example 2, comparative example 3 and comparative example 4, it can be seen that the mixing of the components, the particle size of the pore-forming agent and the sintering conditions all affect the performance of the bone repair material when the porous calcium phosphate particles are sintered. Comparative example 5 the biocompatibility of the bone repair material prepared by separately preparing mineralized collagen and mixing the biphasic calcium phosphate porous particles prepared in the previous step is significantly inferior to that of the present invention. From the test results of the comparative example 6, it can be seen that the mixing ratio of the mineralized collagen porous calcium phosphate composite material and the alpha-calcium sulfate hemihydrate powder also has a great influence on the performance of the bone repair material.
In conclusion, the invention prepares the biphase calcium phosphate porous particles by a special sintering process, and prepares the mineralized collagen on the surface and in the gaps of the porous calcium phosphate, so that the mineralized collagen is uniformly combined with the porous calcium phosphate, and the material has good biocompatibility and certain supporting strength; the alpha-calcium sulfate hemihydrate is introduced into the system, and the proportion of the alpha-calcium sulfate hemihydrate is more scientific and reasonable, so that the material has self-curing performance, the requirement of injection self-curing in clinic is met, and the material has no temperature change in the curing process and no damage to surrounding tissues. In conclusion, the preparation method provided by the invention combines the advantages of mineralized collagen, calcium phosphate salt and alpha-calcium sulfate hemihydrate, overcomes the defects of various materials, prepares the bone repair material with the characteristics of drug loading, plasticity, developability, injectability, degradability and the like, and meets different clinical requirements.
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 (11)
1. The preparation method of the injectable self-curing artificial bone repair material is characterized by comprising the following steps: the preparation method comprises the following steps:
(1) preparation of biphasic calcium phosphate porous particles: the preparation components comprise a first calcium salt, polyvinyl alcohol and PMMA microspheres, the mass ratio is (0.1-0.5): 3:2, and the first calcium salt is composed of hydroxyapatite and beta-calcium phosphate according to the mass ratio of 5: 1-1: 3;
the preparation method comprises the following steps:
(a) preparing a polyvinyl alcohol solution with the concentration of 0.2-0.5 g/mL;
(b) preparing a biphase phosphate suspension; adding hydroxyapatite and beta-calcium phosphate into a PBS solution to form a suspension;
(c) adding the polyvinyl alcohol solution into the biphase phosphate turbid liquid, stirring for 0.5-1 hour, then adding PMMA microspheres, and stirring for 0.5-1 hour to obtain a sintering base liquid;
(d) placing the sintering base liquid in sintering equipment for sintering to obtain a sintering material;
the sintering comprises the following stages:
the first stage is as follows: the heating rate is 5-10 ℃/min, the target temperature is 400-800 ℃, and the constant temperature time is 300-350 min;
and a second stage: the heating rate is 5-10 ℃/min, the target temperature is 1000-1200 ℃, and the constant temperature time is 180-200 min;
and a third stage: stopping heating the sintering equipment, and naturally cooling to room temperature;
(e) pulverizing the sintered material;
(f) screening;
(2) preparing a mineralized collagen porous calcium phosphate composite material: adding the biphase calcium phosphate porous particles into a collagen acid solution with the concentration of 1-5 mg/mL, stirring and mixing for 2-3 hours to prepare a suspension with the concentration of 10-30 wt%;
continuously stirring the suspension, and dropwise adding a solution containing calcium ions, wherein the addition amount of the calcium ions is 0.01-0.15 mol per gram of collagen; dropwise adding a solution containing phosphate ions, wherein the molar ratio of the phosphate ions to the calcium ions is Ca/P = 0.8-1.8; continuously stirring, dropwise adding a NaOH solution until the pH value of the mixed system is 7-8, beginning to precipitate when the pH value reaches 5-6, and generating a white turbid liquid when the pH value reaches 7; standing the obtained mixed system for 24-96 hours, separating out precipitates, washing away impurity ions, then carrying out freeze drying, and grinding to obtain a mineralized collagen porous calcium phosphate composite material with the mineralized collagen content of 2-25 wt%;
(3) mixing: mixing the mineralized collagen porous calcium phosphate composite material and the alpha-semi-hydrated calcium sulfate powder according to the mass ratio of 7: 3-2: 8, and drying and sterilizing the mixture to obtain the injectable self-curing artificial bone repair material.
2. The method of claim 1, wherein: in the step (1), the PMMA microspheres adopt any one or two of particles with the particle size of 50-800 micrometers.
3. The method of claim 2, wherein: the PMMA microspheres are a mixture of PMMA microspheres with the particle size of 50-200 micrometers and PMMA microspheres with the particle size of 400-600 micrometers according to the mass ratio of 2: 8-8: 2.
4. The method of claim 1, wherein: in the step (1), the preparation component further comprises a second calcium salt added in the step (b), wherein the second calcium salt is selected from any one or more of alpha-tricalcium phosphate, calcium hydrophosphate dihydrate, calcium hydrophosphate and tetracalcium phosphate, and the using amount of the second calcium salt accounts for 1-10% of the total mass of the calcium salt.
5. The method of claim 1, wherein: in the step (2), the solvent used for preparing the collagen acid solution is selected from any one of hydrochloric acid, citric acid and acetic acid.
6. The method of claim 1, wherein: in the step (3), the alpha-calcium sulfate hemihydrate powder is prepared as follows:
adding calcium sulfate dihydrate, sodium citrate, aluminum sulfate and water into a reaction container according to the mass ratio of 1:0.0025:0.0025:5.67, sealing and stirring, and reacting for 6 hours at the temperature of 120 ℃; after the reaction is finished, carrying out suction filtration on the reaction liquid while the reaction liquid is hot, washing the filter cake for 3-5 times by using deionized boiling water after the suction filtration, and then putting the filter cake into a drying oven for drying for 12-24 hours at 100 ℃ to prepare calcium sulfate hemihydrate;
grinding the calcium sulfate hemihydrate into powder, and sieving with a 100-mesh sieve to obtain the alpha-calcium sulfate hemihydrate powder.
7. The method of claim 1, wherein: in the step (3), the mineralized collagen porous calcium phosphate composite material and the alpha-calcium sulfate hemihydrate powder are mixed according to the mass ratio of 5: 5-3: 7.
8. The method of claim 1, wherein: in the step (3), the mixture further comprises a coagulant, wherein the coagulant is selected from any one of calcium sulfate dihydrate, potassium sulfate and potassium chloride, and the mass of the coagulant accounts for 5-20 wt% of the total mass of the mixture.
9. The method of claim 1, wherein: in the step (3), the mixture further comprises a plasticizer, wherein the plasticizer is selected from any one of hydroxymethyl cellulose, hydroxypropyl methyl cellulose and chitosan, and the mass of the plasticizer accounts for 1-15 wt% of the total mass of the mixture.
10. The method of claim 1, wherein: in the step (3), the sterilization is carried out by adopting an irradiation mode, the used reagent is a cobalt 60 sterilizing agent, and the dosage is 15-35 kGy.
11. The injectable self-curing artificial bone repair material is characterized in that: prepared by the preparation method of any one of claims 1 to 10.
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