CN1270783C - Degradable nanometer composite material for biological and medical use - Google Patents

Abstract

The invention discloses a degradable biomedical nanocomposite material and a preparation method thereof. The biodegradation rate of the composite material is adjusted through different Ca/P ratios in the inorganic phase, different crystallization states and different inorganic phase composite ratios. compound, so that the biodegradation rate of the entire composite material can be adjusted; the composition of the inorganic phase is one of amorphous calcium phosphate, α-phase tricalcium phosphate, β-phase tricalcium phosphate, apatite and calcium hydrogen phosphate or It consists of two phases; the preparation method uses solvent solution-casting or solution-non-solvent precipitation to uniformly disperse the calcium phosphate powder in the degradable polymer matrix by selecting an organic solvent, so that the composite material can achieve nano-scale composite and more fully play performance of composite materials. In addition, porous nanocomposites can be obtained by particle filtration. The nanocomposite material prepared by the invention can be widely used in the fields of biomedical materials such as bone screws, bone joint plates and bone tissue engineering.

Description

Degradable biomedical nanocomposite material and preparation method thereof

Technical field

The invention relates to a degradable biomedical nanocomposite material and a preparation method thereof, belonging to the technical field of preparation of biomedical substitute materials.

Background technique

Due to diseases or trauma, hard tissues such as human bones or teeth are damaged or lost, and a large number of artificial synthetic substitute materials are needed for repair and treatment. At present, hard tissue replacement materials mainly include three types of materials: metals, ceramics, and polymers. They each have their own characteristics.

Metal materials have high strength and are easy to process. However, the price is expensive, and it does not match the bone stress, which will cause bone tissue resorption, and the metal ions produced by physiological corrosion will have adverse reactions to the tissue, and such materials need a second operation to remove after the tissue heals.

Calcium phosphate material is a widely used ceramic material because of its chemical composition similar to the inorganic phase in bone, good biological activity and osteoconductivity. However, its poor mechanical properties limit the scope of application of calcium phosphate, which is mainly used in non-load-bearing fields (such as filling of bone loss and bone cement, etc.).

There are two main types of polymer materials: non-biodegradable materials and biodegradable materials. The former such as polyethylene, polypropylene, polytetrafluoroethylene and polymethyl methacrylate. These materials have good mechanical properties and biocompatibility, but they are not bioactive and cannot be degraded, requiring secondary surgery to remove them. The latter, such as α-polyester polymers, has good mechanical properties and biocompatibility, and its biggest feature is that it can degrade after being implanted in the human body. As the tissue heals, the implant slowly degrades. , The implant degrades completely, so no secondary surgery is required. However, this type of degradable material also has many shortcomings: after the material is implanted in the body, X-rays do not develop, and the implantation cannot be effectively detected; as the degradation time increases, the mechanical properties of this type of material decrease too quickly; during the degradation process The acidic substances produced in the blood can cause a sterile inflammatory response in the tissue.

The biodegradation rate of the calcium phosphate material is adjustable. The degradation rates of calcium phosphate with different Ca/P ratios and crystallinity are different, and their order from large to small is: α-TCP>β-TCP>HA, amorphous calcium phosphate>low crystallinity calcium phosphate>high crystallinity of calcium phosphate. The degradation rate of calcium phosphate can be adjusted if calcium phosphate in different crystal phases is compounded together.

Therefore, from the perspective of bone tissue structure, calcium phosphate is added to degradable polymers to prepare organic-inorganic composite materials similar to bone tissue structure. Filling calcium phosphate into polymers to prepare degradable biomedical biocomposites has incomparable advantages over a single component: (1) In terms of mechanical properties, it can improve the lack of mechanical properties of calcium phosphate itself and improve the toughness of the material; 2) In terms of biological activity, adding different amounts of calcium phosphate can enhance the biological properties of polymer materials; (3) In terms of biodegradation, the acidic substances produced by the polymer after adding calcium phosphate can be effectively inhibited, by adjusting the calcium phosphate The crystal phase and crystal phase composition or the composition ratio of polymer monomers and copolymer monomers or the composition ratio of calcium phosphate and polymer can adjust the biodegradation rate of composite materials; (3) in medical testing, adding phosphoric acid After adding calcium, the implant can be developed by X-ray, which makes it easier to detect the implantation; in addition, the acidic substance produced by the polymer can promote the degradation of calcium phosphate, which is more conducive to the healing of bone tissue.

Chinese patent (CN1403167) and U.S. patent (US5981619) disclosed that calcium phosphate was added to the polymer to obtain a composite material with better mechanical properties. However, there are still differences between the structure of these composite materials and the structure of bone tissue: the main reason is that the particle size of calcium phosphate is relatively large (the calcium phosphate in bones is tens of nanometers, while their calcium phosphate is 1-100 μm). The degradation performance of the material is not good enough, and the dispersion of inorganic substances in the polymer matrix is not uniform enough. The above invention cannot effectively adjust the degradation rate of the composite material to meet the requirements of different implantation sites on the degradation rate of the implant. In addition, the emergence and development of bone tissue engineering also put forward the requirement of adjustable biodegradation rate for porous scaffold materials.

Contents of Invention

The object of the present invention is to provide a degradable biomedical nanocomposite material with fine calcium phosphate particles uniformly dispersed in a polymer matrix and a preparation method thereof.

The degradable biomedical nanocomposite material of the present invention is a composite film or composite powder composed of calcium phosphate and a degradable polymer or a composite material for preparing biomedical substitutes, wherein the content (mass percentage) of calcium phosphate is 5-50 %, the content (mass percentage) of the degradable polymer is 95-50%.

The preparation method of degradable biomedical nano composite material of the present invention has:

plan 1

The preparation method comprises the following steps:

1) Disperse calcium phosphate in an organic solvent under the action of an ultrasonic wave or a mechanical emulsifier, and the content of calcium phosphate in the organic solvent (by mass/volume percentage) is 0.1% to 10%;

2) Dissolve the degradable polymer in the calcium phosphate-organic solvent mixed solution at 10°C to 60°C, and form a uniform mixed solution through the action of ultrasonic waves or mechanical emulsifiers. The mass/volume concentration of the polymer solution is 1%. ~10%.

3) The uniformly mixed solution is cast into a calcium phosphate/degradable polymer composite film by a conventional solution casting method, or a calcium phosphate/degradable polymer composite powder is precipitated by a conventional non-solvent precipitation method, and then dried.

For further preparation, the obtained composite film or composite powder can be made into a composite material for preparing biomedical substitutes by thermocompression molding or injection molding. The thermocompression molding steps are as follows: put the above composite film or composite powder into the mold , the filling amount is 70% of the mold, pre-press at room temperature with a pressure of 0.5MPa-40MPa, then hold the pressure for 5-30 minutes at a temperature of 80-190°C and a pressure of 0.5-100MPa, and cool take out the product;

The injection molding steps are as follows: the above-mentioned composite powder or composite film is crushed at low temperature, added to an injection molding machine for hot injection molding, and the molding conditions are as follows: injection pressure is 0.1MPa-5Mpa, and temperature is 100°C-250°C.

The bending strength of the biodegradable biomedical nanocomposite prepared in scheme 1 is 80-250 MPa, and the bending modulus is 1-10 Gpa.

Scenario 2

The preparation method comprises the following steps:

1) Add calcium phosphate and pore-forming agent to the organic solvent under the action of ultrasonic wave or mechanical emulsifier, the content of calcium phosphate in the organic solvent (by mass/volume percentage) is 0.1%～10%;

2) Dissolve the degradable polymer in the above mixed solution at 10°C-60°C, and form a uniform mixed solution through the action of ultrasonic waves or mechanical emulsifiers. The mass/volume concentration of the polymer solution is 1%-10% .

3) The uniformly mixed solution is cast into a calcium phosphate/degradable polymer composite film by a conventional solution casting method, or a calcium phosphate/degradable polymer composite powder is precipitated by a conventional non-solvent precipitation method, and then dried.

For further preparation, the obtained composite film or composite powder can be made into a composite material for the preparation of biomedical substitutes by hot pressing. The steps of hot pressing are as follows: put the above composite film or composite powder into the mold, and 70% of the mould, pre-press at room temperature with a pressure of 0.5-40MPa, then hold the pressure for 5-30 minutes at a temperature of 80-190°C and a pressure of 0.5-100MPa, cool and take out the product, and Soak in a constant temperature water bath at 37°C, and dissolve the pore-forming agent at an oscillation frequency of 100 times/h to obtain a porous composite material.

The degradable biomedical nano-composite material prepared in scheme 2 has a pore size of 10 μm to 200 μm, a porosity of 75% to 95%, and a compressive strength of 0.5 MPa to 3 MPa.

In the present invention, the calcium phosphate includes: amorphous calcium phosphate or α-phase tricalcium phosphate or β-phase tricalcium phosphate or apatite or calcium hydrogen phosphate or apatite/α-phase tricalcium phosphate composite powder or apatite Stone/β-phase tricalcium phosphate composite powder or α-phase tricalcium phosphate composite powder/β-phase tricalcium phosphate composite powder, wherein the apatite is fluorine-containing hydroxyapatite or carbonate-containing apatite. The particles of these powders are evenly distributed, and the size is generally about 40nm to 500nm. The content of each phase in the calcium phosphate composite powder can be adjusted from 0 to 100%, and the degradation rate of calcium phosphate can be adjusted by changing the Ca/P ratio. The crystal phase or crystal phase composition of calcium phosphate is adjusted.

In the present invention, the degradable polymer includes: polylactic acid or polyglycolic acid or polyhydroxybutyric acid or polycaprolactone or polydioxanone or polyanhydride or polyester or their monomers Copolymers, wherein the polylactic acid is poly-L-lactic acid or poly-(D,L)-lactic acid or poly-L-(D,L)-lactic acid. The degradation rate of a polymer can be adjusted by changing the composition and ratio of monomers in the polymer.

In the preparation process of the present invention, the organic solvent may be dichloromethane or chloroform or tetrahydrofuran or dimethylformamide or dimethyl sulfoxide or dioxane. Pore-forming agent can use sodium chloride or sugar. The non-solvent is methanol or ethanol.

The preparation technology adopted by the invention is simple and feasible, simple to operate, low in cost and easy to industrialize. The preparation method uniformly disperses the calcium phosphate powder in the degradable polymer matrix by selecting an organic solvent and adopting solvent solution-casting or solution-non-solvent precipitation, so that the composite material can be composited at the nanometer level, and the performance of the composite material can be fully exerted. In addition, porous nanocomposites can be obtained by particle filtration. The biodegradation rate of the biomedical nanocomposite material of the present invention can be effectively adjusted by changing the composition of calcium phosphate or polymer or the composition ratio of calcium phosphate and polymer, so as to meet the requirements of different tissue engineering. The acidic substance produced by the material polymer can promote the degradation of calcium phosphate, which is more conducive to the healing of bone tissue. Its mechanical properties match those of bone. The invention can be widely used in the fields of biomedical materials such as bone screws, bone plates and bone tissue engineering.

Detailed ways

The degradable biomedical nanocomposite material of the present invention is made up of calcium phosphate and degradable polymer, wherein the content (mass percentage) of calcium phosphate is 5～50%, the content (mass percentage) of degradable polymer is 95～50% %.

When using Scheme 1 to prepare degradable biomedical nanocomposites, calcium phosphate is first added to the organic solvent to form a uniform calcium phosphate suspension under the action of ultrasonic waves or mechanical emulsifiers, and then the polymer is mixed at 10°C to 60°C. Add it into the calcium phosphate suspension solution, and after the polymer is completely dissolved under magnetic stirring, ultrasonic or mechanical emulsifier acts for 10-30 minutes, and then cast into a calcium phosphate/degradable polymer film or add a large amount of ethanol or methanol to precipitate out Calcium phosphate/degradable polymer composite powder. Then dry the powder or film at 40-60°C for 24 hours, and then vacuum-dry at 40-60°C for 48 hours until the quality of the dried product no longer decreases, take out the calcium phosphate/degradable polymer film or powder and put it in Refrigerate at 5°C in a desiccator for later use.

There are two ways of thermoforming calcium phosphate/degradable polymer film or powder: thermo-compression molding and thermo-injection molding. Hot molding route: Put the above-mentioned composite film or composite powder into a special mold, the filling amount is 70% of the mold, first pre-press at room temperature with a pressure of 0.5MPa ~ 40MPa, and then at a temperature of 80 ~ 190 ℃, under the condition of 0.5-100MPa pressure, hold the pressure for 5-30 minutes, cool down and take out the product, and then process it into the desired shape of bone screw, bone plate and other samples on the lathe. The samples were sterilized by ethylene oxide or gamma-rays and then sealed and refrigerated for later use.

Hot injection molding route: The above-mentioned composite powder or composite film is crushed at low temperature, and added to the injection molding machine for hot injection molding. The molding conditions are as follows: the injection pressure is 0.1MPa-5MPa and the temperature is 100°C-250°C. The injection mold is a bone screw bone plate mold of the required special shape and the like. The samples obtained by injection molding can be trimmed and sterilized with ethylene oxide or γ-rays to obtain the required bone screws, bone plates, etc., and the samples are sealed and refrigerated for future use.

Porous degradable biomedical nanocomposites can be prepared by adopting Scheme 2. First, calcium phosphate and pore-forming agent (sodium chloride or sugar) are added to an organic solvent to form a uniform suspension solution under the action of ultrasonic waves or mechanical emulsifiers. , and then add the polymer to the calcium phosphate suspension solution, magnetic stirring until the polymer is completely dissolved, ultrasonic or mechanical emulsifier for 10 to 30 minutes, then cast into a film or add a large amount of ethanol or methanol to precipitate calcium phosphate/ Degradable polymer composite powder. Then dry the powder or film at 40-60°C for 24 hours, and then vacuum-dry at 40-60°C for 48 hours until the quality of the dried product is no longer reduced, take out the calcium phosphate/degradable polymer film or powder and put it in Refrigerate at 5°C in a desiccator for later use.

Put the above-mentioned film or powder into a special mold, the filling amount is 70% of the mold, first pre-press at room temperature with a pressure of 0.5-40MPa, and then pre-press at a temperature of 80-190°C and a pressure of 0.5-100MPa Under certain conditions, hold the pressure for 5-30 minutes, cool and take out the product, then soak it in a constant temperature water tank at 37°C, and dissolve the pore-forming agent at an oscillation frequency of 100 times/h. The soaking time is 72 hours. Water once, change the water every 6 hours in the last 36 hours, and change it every 8 hours thereafter. The calcium phosphate/degradable polymer porous nanocomposite material with a pore size of 10 μm to 200 μm obtained after filtering out the pore-forming agent.

Further illustrate the present invention below in conjunction with embodiment

Example 1

Add 0.4g of apatite/β-phase tricalcium phosphate composite powder into 200ml of tetrahydrofuran, ultrasonically oscillate for 15 minutes, add 3.6g of polylactic acid, dissolve it under magnetic stirring at 50°C, ultrasonicate it, and cast it on a 38mm-diameter Form a film in the mold, after drying at 40°C for 24 hours, put it into a vacuum drying oven and dry it under vacuum until the quality of the film is constant. The calcium/PLA composite was refrigerated in a desiccator.

Example 2

Add 0.2g of α-phase tricalcium phosphate powder into 200ml of dimethylformamide, ultrasonically oscillate for 15 minutes, then add 3.8g of polycaprolactone, dissolve it under magnetic stirring at 50°C, ultrasonicate it, and cast it on a 38mm-diameter Form a film in a mold, dry it at 160°C for 24 hours, then put it into a vacuum drying oven and dry it under vacuum until the quality of the film is constant. The fat composite material was placed in a desiccator and refrigerated.

Example 3

Add 0.8g of α-phase tricalcium phosphate composite powder/β-phase tricalcium phosphate composite powder into 200ml of dimethyl sulfoxide, ultrasonically oscillate for 15 minutes, then add 3.2g of polylactic acid, magnetically stir and dissolve at 50°C and then ultrasonically After treatment, cast it into a mold with a diameter of 38mm to form a film. After drying at 160°C for 24 hours, put it in a vacuum drying oven and dry it in vacuum until the quality of the film is constant. The obtained α-phase tricalcium phosphate composite powder/β The calcium phosphate/polylactic acid composite material with a tricalcium phosphate composite powder content of 20 wt% is placed in a desiccator for refrigeration.

Example 4

Add 0.8g of apatite/α-phase tricalcium phosphate composite powder and sodium chloride with a particle size of 200-300μm into 200ml of tetrahydrofuran, and after ultrasonic vibration for 15 minutes, add 3.2g of polylactic acid and dissolve it under magnetic stirring at 50°C After ultrasonic treatment, cast it into a mold with a diameter of 38mm to form a film. After drying for 24 hours at 40°C, put it into a vacuum drying oven and dry it in vacuum until the quality of the film is constant. The obtained calcium phosphate content is 20wt%. Calcium Phosphate/Sodium Chloride/Polylactic Acid Composite. The above-mentioned composite material was pre-pressed at room temperature with a pressure of 30 MPa, and then held at a temperature of 180°C and a pressure of 40 MPa for 5 minutes, cooled, and the product was taken out. The product is soaked in a constant temperature water tank at 37°C at an oscillation frequency of 100 times/h. The soaking time is 72 hours. The water is changed every hour for the first 12 hours, the water is changed every 6 hours for the next 36 hours, and every 8 hours thereafter. After filtering out sodium chloride, a porous degradable calcium phosphate/degradable polymer composite material with a pore size of about 200 μm, a porosity of 90%, and a compressive strength of 2 MPa was obtained.

Example 5

Put the composite material obtained in Example 1 into a special mold, and the filling amount is 70% of the mold. First, it is pre-pressed at room temperature with a pressure of 30 MPa, and then at a temperature of 180 ° C and a pressure of 40 MPa. Hold the pressure for 5 minutes, cool down, take out the product, and then process it into samples such as bone screws and bone plates of the desired shape on a lathe. The samples were sterilized by ethylene oxide or gamma-rays and then sealed and refrigerated for later use.

Example 6

The composite material obtained in Example 1 was pulverized at low temperature and added to an injection molding machine for hot injection molding. The molding conditions are shown in Table 1. The injection mold is a bone screw bone plate mold of the required special shape. The samples obtained by injection molding can be trimmed and sterilized with ethylene oxide or γ-rays to obtain the required bone screws, bone plates, etc., and the samples are sealed and refrigerated for future use.

Table 1 Injection molding process conditions of calcium phosphate/polylactic acid nanocomposites Work area temperature The first heating zone The second heating zone The third heating zone outlet temperature Injection pressure mold temperature 45°C 200℃ 215°C 220°C 200℃ 0.15MPa room temperature

Claims (10)

1. The preparation method of degradable biomedical nano composite material is characterized in that comprising the following steps: 1) Disperse calcium phosphate in an organic solvent under the action of an ultrasonic wave or a mechanical emulsifier, and the content of calcium phosphate in the organic solvent is 0.1% to 10% by mass/volume; 2) Dissolve the degradable polymer in the calcium phosphate-organic solvent mixed solution at 10°C to 60°C, and form a uniform mixed solution through the action of ultrasonic waves or mechanical emulsifiers. The mass/volume concentration of the polymer solution is 1%. ~10%; 3) The uniformly mixed solution is cast into a calcium phosphate/degradable polymer composite film by a conventional solution casting method, or a calcium phosphate/degradable polymer composite powder is precipitated by a conventional non-solvent precipitation method, and then dried. 2. according to the described preparation method of claim 1, it is characterized in that organic solvent is methylene dichloride or chloroform or tetrahydrofuran or dimethylformamide or dimethyl sulfoxide or dioxane. 3. according to the preparation method of degradable biomedical nano-composite material described in claim 1, it is characterized in that also comprising adopting thermocompression molding or injection molding to make composite film or composite powder of gained for preparing biomedical substitute material, the steps of hot press molding are as follows: put the above-mentioned composite film or composite powder into the mold, the filling amount is 70% of the mold, firstly pre-press at room temperature with a pressure of 0.5MPa-40MPa, and then pre-press at a temperature of 80 Under the conditions of ~190°C and pressure of 0.5~100MPa, hold the pressure for 5~30 minutes, cool and take out the product; The injection molding steps are as follows: the above-mentioned composite powder or composite film is crushed at low temperature, added to an injection molding machine for hot injection molding, and the molding conditions are as follows: injection pressure is 0.1MPa-5Mpa, and temperature is 100°C-250°C. 4. according to the preparation method of degradable biomedical nanocomposite material described in claim 1, it is characterized in that described calcium phosphate is amorphous calcium phosphate or alpha phase tricalcium phosphate or beta phase tricalcium phosphate or apatite or Calcium hydrogen phosphate or apatite/α-phase tricalcium phosphate composite powder or apatite/β-phase tricalcium phosphate composite powder or α-phase tricalcium phosphate composite powder/β-phase tricalcium phosphate composite powder, wherein apatite is Fluorohydroxyapatite or carbonate-containing apatite. 5. according to the preparation method of degradable biomedical nanocomposite material described in claim 1, it is characterized in that described degradable polymer is polylactic acid or polyglycolic acid or polyhydroxybutyric acid or polycaprolactone or polyparaffin Dioxanone or polyanhydrides or polyorthoesters or copolymers of their monomers, wherein the polylactic acid is poly-L-lactic acid or poly-(D,L)-lactic acid or poly-L-(D,L) - Lactic acid. 6. The preparation method of degradable biomedical nanocomposite material, it is characterized in that comprising the following steps: 1) adding calcium phosphate and pore forming agent into the organic solvent, the content of calcium phosphate in the organic solvent is 0.1%-10% by mass/volume percentage; 2) Dissolving the degradable polymer in the above mixed solution to form a uniform mixed solution, the mass/volume concentration of the polymer solution is 1% to 10%; 3) The uniformly mixed solution is cast into a calcium phosphate/degradable polymer composite film by a conventional solution casting method, or a calcium phosphate/degradable polymer composite powder is precipitated by a conventional non-solvent precipitation method, and then dried. 7. The preparation method according to claim 6, characterized in that the organic solvent is chloroform or tetrahydrofuran or dimethylformamide or dimethyl sulfoxide or dioxane; the pore-forming agent is sodium chloride or sugar. 8. according to the preparation method of degradable biomedical nanocomposite material described in claim 6, it is characterized in that also comprising the composite film of gained or composite powder adopting thermocompression molding to make the composite material for preparing biomedical substitute, heating The compression molding steps are as follows: put the above-mentioned composite film or composite powder into the mold, and the filling amount is 70% of the mold. Under the condition of 0.5-100MPa, hold the pressure for 5-30 minutes, cool and take out the product, soak it in a constant temperature water bath at 37°C, and dissolve the pore-forming agent at an oscillation frequency of 100 times/h to obtain a porous composite material. 9. according to the preparation method of degradable biomedical nanocomposite material described in claim 6, it is characterized in that described calcium phosphate is amorphous calcium phosphate or alpha phase tricalcium phosphate or beta phase tricalcium phosphate or apatite or Calcium hydrogen phosphate or apatite/α-phase tricalcium phosphate composite powder or apatite/β-phase tricalcium phosphate composite powder or α-phase tricalcium phosphate composite powder/β-phase tricalcium phosphate composite powder, wherein apatite is Fluorohydroxyapatite or carbonate-containing apatite. 10. according to the preparation method of degradable biomedical nanocomposite material described in claim 6, it is characterized in that described degradable polymer is polylactic acid or polyglycolic acid or polyhydroxybutyric acid or polycaprolactone or polyparaffin Dioxanone or polyanhydrides or polyorthoesters or copolymers of their monomers, wherein the polylactic acid is poly-L-lactic acid or poly-(D,L)-lactic acid or poly-L-(D,L) - Lactic acid.