CN102008753B - Organic-inorganic composite gel material for bone repair and preparation method thereof - Google Patents

Abstract

The invention relates to an organic-inorganic composite gel material for bone repair and a preparation method thereof. In the material, the organic material is composed of synthetic polymer or natural polymer, and the inorganic material is composed of SiO ₂ , CaO, P ₂ O ₅ , the mole fractions of the three inorganic materials are: 50-80%, 10-40%, and 1-10% respectively; the mass ratio of the organic material to the inorganic material is: 0.1-1:1. This method interpenetrates biocompatible and biodegradable polymer chains into the SiO ₂ inorganic network structure to form a semi-interpenetrating structure, which not only achieves a good blend of the two at the molecular level, but also improves the quality of the material. The mechanical properties of the material improve the bioactivity of the material and have important development potential in the field of bone defect repair.

Description

An organic-inorganic composite gel material for bone repair and its preparation method

technical field

The invention belongs to the field of polymer materials, and more specifically relates to an organic-inorganic composite gel material for bone repair and a preparation method thereof.

Background technique

Bones are the scaffolding of the human body, responsible for supporting, protecting, bearing, hematopoietic, storing calcium, and metabolizing functions. They are important tissues and organs of the human body. Although bone tissue has a certain ability to regenerate and self-repair, clinically, large-scale bone defects caused by tumors, trauma, infection, and congenital dysplasia, as well as osteoporosis caused by the increase in life expectancy, exceed the capacity of bone tissue. Self-healing ability requires surgical bone grafting. Currently, there are many bone graft substitutes used clinically, mainly including autologous bone, allogeneic bone and xenograft bone. Autologous bone is the best way to treat bone defects because of its good osteoinductivity, osteoconductivity, and biocompatibility, but its source is very limited, and the donor area will cause many complications, such as damage to the donor area, pain , infection and hematoma. For allogeneic and xenogeneic bone grafts, there are risks of immune reactions and disease carriage. Therefore, most bone repairs require the use of artificial materials with the same functions as autologous bone.

等，具有优良的生物活性和生物相容性，能够在材料界面与人体骨形成化学键合，从而诱导更迅速的骨修复与再生。但是这类材料的脆性大、弹性模量低、断裂韧性和机械强度较低，且降解速度与新生骨组织的生长速度不匹配，这些缺点在一定程度上限制了其应用范围。相比之下，高分子材料具有较高的拉伸强度、抗弯强度和弹性，在力学性能上能够弥补无机材料的缺陷。其中，合成高分子材料，如PLA、PGA、PEG、PCL等，具有很好的生物可降解性和组织相容性，天然高分子材料，如丝素蛋白、壳聚糖、胶原蛋白、海藻酸钠等，已被许多研究证明具有良好的细胞相容性和低的抗原性，且降解产物安全，可作为细胞外基质被人体吸收。但由于高分子材料缺乏无机材料所具备的优良的生物活性，在植入体内后无法与机体骨组织形成良好的化学键合，因此，将高分子材料与无机材料进行复合，制备一种兼具无机材料生物活性和高分子材料弹性及生物降解性的复合材料，使其应用于医疗修复领域，具有重要的研究价值和深远的社会经济意义。 With the rapid development of material science and tissue engineering, the use of synthetic bone substitute materials to repair bone defects has become the research focus of materials science and medicine. Typical materials studied in the early stage include metallic materials and inorganic materials, which are classified as the first generation of bioinert materials and the second generation of bioactive materials according to the classification standard of Hench LL. Although in the early clinical applications, metal materials became the preferred bone implant materials due to their good mechanical strength and fatigue resistance, but due to the toxicity of heavy metal ions, the materials are easily corroded, and the gap between the implanted bone and the autologous bone There is a stress shielding effect, which is easy to cause osteoporosis and is not conducive to the realization of bone repair. The second generation of bioceramics and bioglass materials, including hydroxyapatite, β-calcium phosphate, alumina ceramics and Bioglass

etc., have excellent bioactivity and biocompatibility, and can form chemical bonds with human bone at the material interface, thereby inducing more rapid bone repair and regeneration. However, such materials have high brittleness, low elastic modulus, low fracture toughness and mechanical strength, and the degradation rate does not match the growth rate of new bone tissue. These shortcomings limit their application to a certain extent. In contrast, polymer materials have high tensile strength, flexural strength and elasticity, and can make up for the defects of inorganic materials in terms of mechanical properties. Among them, synthetic polymer materials, such as PLA, PGA, PEG, PCL, etc., have good biodegradability and tissue compatibility, natural polymer materials, such as silk fibroin, chitosan, collagen, alginic acid Sodium, etc., have been proved by many studies to have good cytocompatibility and low antigenicity, and the degradation products are safe and can be absorbed by the human body as extracellular matrix. However, because polymer materials lack the excellent biological activity of inorganic materials, they cannot form a good chemical bond with the body's bone tissue after implantation. Therefore, polymer materials and inorganic materials are combined to prepare an inorganic The composite material of material bioactivity and polymer material elasticity and biodegradability makes it used in the field of medical repair, which has important research value and far-reaching social and economic significance.

SiO ₂ -P ₂ O ₅ -Na ₂ O-CaO bioglass 45S5 prepared by melting method by Hench LL et al. and SiO ₂ -CaO-P ₂ O ₅ bioglass 70S30C, 58S prepared by sol-gel method later All have good biological activity, and can quickly form a chemical bond with the bone tissue of the body after being implanted in the body. These materials have been well applied in dental restoration. However, since the material needs to be heated to 600°C or above during the preparation process, the material is relatively brittle and cannot be used for the repair of load-bearing bones. However, the high temperature limits its recombination with organic polymers. Therefore, previous research reports on bioglass and organic polymer composites mostly use the method of physical blending. Polymer materials cannot be uniformly blended with inorganic materials at the molecular level. There are limited improvements to the properties of the material.

Contents of the invention

In order to solve the above problems, the present invention provides an organic-inorganic composite gel material for bone repair and its preparation method. The composite material will have biocompatible and biodegradable polymer chains interspersed with SiO ₂ In the inorganic network structure, the semi-interpenetrating structure is formed, which not only realizes the good blending of the two at the molecular level, but also improves the mechanical properties of the material and the biological activity of the material, which has important development potential in the field of bone defect repair .

The present invention is implemented through the following technical solutions:

An organic-inorganic composite gel material for bone repair, the organic material in the composite material is composed of synthetic polymers or natural polymers, the composition of inorganic materials is SiO ₂ , CaO, P ₂ O ₅ , and the composition of inorganic materials The mole fractions of the three are: 50-80%, 10-40%, and 1-10% respectively; the mass ratio of organic materials to inorganic materials is: 0.1~1:1.

The synthetic macromolecule in described organic material can be any one or several in polylactide, polyglutamic acid, polyethylene glycol, polycaproic acid amide; Described natural macromolecule can be chitosan, Any one or more of collagen, silk fibroin, and sodium alginate.

The porosity of the composite gel material is 50-95%, and it has a connected pore structure with a pore diameter of 1-500 nm.

The elastic modulus of the composite gel material is 100-2000 MPa.

A method for preparing an organic-inorganic composite gel material for bone repair is to prepare the composite material in one step using a sol-gel process, so that the organic polymer chains are interspersed in the inorganic SiO ₂ network structure, so that the organic and inorganic components realize Homogeneous blending at the molecular level, where the temperature during preparation does not exceed 100 °C.

The concrete steps of described preparation method are:

1) The SiO ₂ precursor orthosilicate ethyl ester, the CaO precursor calcium chloride and the P ₂ O ₅ precursor triethyl phosphate according to the molar fraction of 50-80%, 10-40%, 1- 10% mixing, wherein the solvent of ethyl orthosilicate is water, the cosolvent is ethanol, the hydrolysis catalyst is a strong acid solution with a mass concentration of 5-10%, and the amount of the catalyst added is to adjust the pH of the solution to 1-3, stirring uniform;

2) During the hydrolysis process, add an organic polymer aqueous solution with a mass concentration of 1-20%, so that the mass ratio of the organic component to the inorganic component is 0.1-1:1, and add 0.15-0.25mL catalyst to promote the _SiO2 network Structure formation, thus forming an organic-inorganic composite system;

3) React the organic-inorganic composite system after adding the catalyst in step 2) for 5-6 minutes, pour it into a polystyrene mold, realize the gelation and aging process at room temperature, and dry it below 100°C to form The porous composite gel material.

The catalyst in step 2) is hydrofluoric acid.

Compared with the existing methods for preparing bone repair materials, the technical solution described in this patent has the advantages of preparing composite gel materials:

The selected organic polymer has good biocompatibility, and the ternary inorganic component has good biological activity, and the combination of the two will achieve a synergistic effect on its performance;

1) The room temperature sol-gel method is used to prepare composite materials in one step, so that the one-dimensional polymer chains are interspersed in the three-dimensional inorganic network of SiO ₂ , and the organic and inorganic components are uniformly blended at the molecular level, which improves the composite material. Uniformity;

2) The temperature of the entire material preparation process does not exceed 100°C, which fully ensures the activity of the organic polymer chain and creates good conditions for loading drugs in the material in the later stage;

3) The processing performance of the material is good. Since the composite system is poured into the mold when it is close to the gel point, the fluidity of the system is good, so the material can be manufactured into various shapes as required;

4) The composite gel material has good biological activity. When soaked in simulated body fluid, it can rapidly grow hydroxyapatite, which is beneficial to the formation and conduction of new bone;

5) The composite gel material has good cytocompatibility, and mouse osteoblast MC3T3 can proliferate rapidly in the material extract.

Description of drawings

Figure 1 is the surface morphology of the composite gel after soaking in SBF;

Figure 2 is the elemental analysis spectrum of the composite gel surface substances.

Detailed ways

An organic-inorganic composite gel material for bone repair, the organic material in the composite material is composed of synthetic polymers or natural polymers, the composition of inorganic materials is SiO ₂ , CaO, P ₂ O ₅ , and the composition of inorganic materials The mole fractions of the three are: 50-80%, 10-40%, and 1-10% respectively; the mass ratio of organic materials to inorganic materials is: 0.1~1:1.

The synthetic macromolecule in described organic material can be any one or several in polylactide, polyglutamic acid, polyethylene glycol, polycaproic acid amide; Described natural macromolecule can be chitosan, Any one or more of collagen, silk fibroin, and sodium alginate.

The porosity of the composite gel material is 50-95%, and it has a connected pore structure with a pore diameter of 1-500 nm.

The elastic modulus of the composite gel material is 100-2000 MPa.

A method for preparing an organic-inorganic composite gel material for bone repair is to prepare the composite material in one step using a sol-gel process, so that the organic polymer chains are interspersed in the inorganic SiO ₂ network structure, so that the organic and inorganic components realize Homogeneous blending at the molecular level, where the temperature during preparation does not exceed 100 °C.

The concrete steps of described preparation method are:

1) The SiO ₂ precursor orthosilicate ethyl ester, the CaO precursor calcium chloride and the P ₂ O ₅ precursor triethyl phosphate according to the molar fraction of 50-80%, 10-40%, 1- 10% mixing, wherein the solvent of ethyl orthosilicate is water, the cosolvent is ethanol, the hydrolysis catalyst is a strong acid solution with a mass concentration of 5-10%, and the amount of the catalyst added is to adjust the pH of the solution to 1-3, stirring uniform;

2) During the hydrolysis process, add an organic polymer aqueous solution with a mass concentration of 1-20%, so that the mass ratio of the organic component to the inorganic component is 0.1-1:1, and add 0.15-0.25mL catalyst to promote the _SiO2 network Structure formation, thus forming an organic-inorganic composite system;

3) React the organic-inorganic composite system after adding the catalyst in step 2) for 5-6 minutes, pour it into a polystyrene mold, realize the gelation and aging process at room temperature, and dry it below 100°C to form The porous composite gel material.

The catalyst in step 2) is hydrofluoric acid.

Example 1

Stir 12.3ml tetraethyl orthosilicate, 4ml distilled water and 6ml ethanol at room temperature, add hydrochloric acid with a mass concentration of 5% to adjust the pH of the system to about 2. Stir evenly, add 1.2 g of calcium chloride and 0.5 ml of triethyl phosphate into the system, and dissolve completely. Add 5 ml of an aqueous solution of polyglutamic acid with a mass concentration of 10% to the system so that the mass ratio of polyglutamic acid to the ternary inorganic component is 0.12:1. After stirring and mixing, add 0.15 mL of hydrofluoric acid dropwise To promote the polycondensation process, pour the composite system into the mold when it is close to the gel point. After aging at room temperature for about 1 week, freeze in a freeze dryer at -50 °C for 24-48 h, then vacuum-dry for 4-6 h to remove residual solvents and obtain the desired porous gel material.

Example 2

Stir 12.3 ml tetraethyl orthosilicate, 4 ml distilled water and 6 ml ethanol at room temperature, add 10% hydrochloric acid to adjust the pH of the system to about 2. After stirring for a period of time, add 3.6 g of calcium chloride and 1.25 ml of triethyl phosphate into the system and dissolve them completely. Add 7 ml of an aqueous solution of polycapropropionamide and polylactide with a mass concentration of 20% to the system so that the mass ratio of the organic component to the ternary inorganic component is 0.25:1. After stirring and mixing, add 0.25 mL of hydrogen dropwise Fluoric acid promotes the polycondensation process, and when it is close to the gel point, the composite system is poured into a mold for molding. After aging and drying at room temperature for about 30 days, the desired porous gel material was obtained.

Example 3

Stir 12.3 ml tetraethyl orthosilicate, 4 ml distilled water and 6 ml ethanol at room temperature, add 7% hydrochloric acid to adjust the pH of the system to about 2. After stirring for a period of time, add 1.2 g of calcium chloride and 0.5 ml of triethyl phosphate into the system and dissolve them completely. Add 10 ml of an aqueous solution of silk fibroin with a mass concentration of 10% to the system so that the mass ratio of silk fibroin to ternary inorganic components is 1:1. After stirring and mixing, add 0.20 mL of hydrofluoric acid dropwise to promote the polycondensation process , when it is close to the gel point, pour the composite system into the mold for molding. After aging at room temperature for 1 week, it was placed in an oven at 40 °C to continue drying to obtain the desired porous gel material.

Example 4

Stir 12.3 ml tetraethyl orthosilicate, 4 ml distilled water and 6 ml ethanol at room temperature, add a small amount of dilute hydrochloric acid to adjust the pH of the system to about 2. After stirring for a period of time, add 3.6 g of calcium chloride and 1.25 ml of triethyl phosphate into the system and dissolve them completely. Add 7 mL of aqueous solutions of chitosan and collagen with a mass concentration of 20% to the system so that the mass ratio of the organic component to the ternary inorganic component is 0.25:1. After stirring and mixing, add a few drops of hydrofluoric acid A small amount of catalyst promotes the polycondensation process, and when it is close to the gel point, the composite system is poured into a mold for molding. After aging and drying at room temperature for about 30 days, it was dried in an oven at 80 °C for about 3 days to remove the residual solvent and obtain the desired porous gel material.

Example 5

An organic-inorganic composite gel material for bone repair, the composition of the organic material is polylactide, and the composition of the inorganic material is SiO ₂ , CaO, P ₂ O ₅ , wherein the mole fractions of the three inorganic materials are: 50%, 40%, 10%; the mass ratio of organic material to inorganic material is: 0.625:1. The porosity of the composite gel material is 50-95%, and it has a connected pore structure with a pore diameter of 1-500 nm.

The elastic modulus of the composite gel material is 100-2000 Mpa.

The preparation method of the organic-inorganic composite gel material adopts the sol-gel process to prepare the composite material in one step, so that the organic polymer chains are interspersed in the inorganic _SiO2 network structure, so that the organic and inorganic components can be uniformly blended at the molecular level, Wherein the temperature during the preparation process does not exceed 100°C.

The concrete steps of described preparation method are:

1) Mix the SiO ₂ precursor orthosilicate ethyl ester, the CaO precursor calcium chloride and the P ₂ O ₅ precursor triethyl phosphate (TEP) in the stated ratio, and the tetraethyl orthosilicate solvent is Water, cosolvent is ethanol, and hydrolysis catalyst is the sulfuric acid solution that mass concentration is 10%, and the addition amount of catalyst is to adjust the pH of solution to 3;

2) During the hydrolysis process, add an organic polymer aqueous solution with a mass concentration of 1%, so that the mass ratio of the organic component to the inorganic component is 0.625:1, and add 0.20mL of catalyst to promote the formation of the SiO ₂ network structure, thereby forming Organic-inorganic composite system;

3) React the organic-inorganic composite system after adding the catalyst in step 2) for 5 minutes, pour it into a polystyrene mold, realize the gelation and aging process at room temperature, and dry it below 100°C to form the porous composite gel material.

Example 6

An organic-inorganic composite gel material for bone repair. The organic material is composed of natural polymers, and the inorganic materials are composed of SiO ₂ , CaO, and P ₂ O ₅ . The mole fractions of the three inorganic materials are: 79%, 20%, 1%; the mass ratio of organic material to inorganic material is: 0.3:1.

The natural polymers in the organic material are collagen and sodium alginate.

The porosity of the composite gel material is 50-95%, and it has a connected pore structure with a pore diameter of 1-500 nm.

The elastic modulus of the composite gel material is 100-2000 Mpa.

The concrete steps of described preparation method are:

1) Mix the SiO ₂ precursor orthosilicate ethyl ester, the CaO precursor calcium chloride and the P ₂ O ₅ precursor triethyl phosphate (TEP) in the stated ratio, and the tetraethyl orthosilicate solvent is Water, cosolvent is ethanol, and hydrolysis catalyst is 20% nitric acid solution, and the addition amount of catalyst is to adjust the pH of solution to 1;

2) During the hydrolysis process, add an organic polymer aqueous solution with a mass concentration of 15%, so that the mass ratio of the organic component to the inorganic component is 0.3:1, and add 0.15mL of catalyst to promote the formation of the SiO ₂ network structure, thereby forming Organic-inorganic composite system;

3) React the organic-inorganic composite system after adding the catalyst in step 2) for 6 minutes, pour it into a polystyrene mold, realize the gelation and aging process at room temperature, and dry it below 100°C to form the porous composite gel material.

The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims (2)

1. An organic-inorganic composite gel material for bone repair, characterized in that: the composition of the organic material in the composite gel material is a synthetic macromolecule or a natural macromolecule, and the composition of the inorganic material is SiO ₂ , CaO , P ₂ O ₅ , wherein the mole fractions of the inorganic materials are: 50-80%, 10-40%, and 1-10% respectively; the mass ratio of the organic materials to the inorganic materials is: 0.1-1:1; The synthetic macromolecules in the organic material are any one or more of polylactide, polyglutamic acid, and polyethylene glycol; the natural macromolecules are chitosan, collagen, silk fibroin, Any one or more of sodium alginate; The porosity of the composite gel material is 50-95%, and the connected pore structure with a pore diameter of 1-500 nm; The elastic modulus of the composite gel material is 100-2000 MPa. 2. A method for preparing an organic-inorganic composite gel material for bone repair as claimed in claim 1, characterized in that: the preparation method adopts a sol-gel process to prepare the composite material in one step, so that the organic polymer The chains are interspersed in the inorganic SiO ₂ network structure, so that the organic and inorganic components can be uniformly blended at the molecular level, and the temperature during the preparation process does not exceed 100 ° C; The concrete steps of described preparation method are: 1) The SiO ₂ precursor orthosilicate ethyl ester, the CaO precursor calcium chloride and the P ₂ O ₅ precursor triethyl phosphate according to the molar fraction of 50-80%, 10-40%, 1- 10% mixing, wherein the solvent of ethyl orthosilicate is water, the cosolvent is ethanol, the hydrolysis catalyst is a strong acid solution with a mass concentration of 5-10%, and the amount of the catalyst added is to adjust the pH of the solution to 1-3, stirring uniform; 2) During the hydrolysis process, add an organic polymer aqueous solution with a mass concentration of 1-20%, so that the mass ratio of the organic component to the inorganic component is 0.1-1:1, and add 0.15-0.25mL catalyst to promote the _SiO2 network Structure formation, thus forming an organic-inorganic composite system; 3) React the organic-inorganic composite system after adding the catalyst in step 2) for 5-6 minutes, pour it into a polystyrene mold, realize the gelation and aging process at room temperature, and dry it below 100°C to form The porous composite gel material; The catalyst in step 2) is hydrofluoric acid.

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