CN108530851B - Bioactive composite material and preparation method and application thereof - Google Patents

Bioactive composite material and preparation method and application thereof Download PDF

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CN108530851B
CN108530851B CN201710122217.3A CN201710122217A CN108530851B CN 108530851 B CN108530851 B CN 108530851B CN 201710122217 A CN201710122217 A CN 201710122217A CN 108530851 B CN108530851 B CN 108530851B
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prepolymer
coupling agent
silane coupling
composite material
citric acid
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CN108530851A (en
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邱东
任辉辉
张忠民
赵慧宇
李爱玲
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Huakui Technology Taizhou Co ltd
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Institute of Chemistry CAS
University of Chinese Academy of Sciences
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Abstract

The invention relates to a bioactive composite material, a preparation method and application thereof, wherein the composite material is prepared by compounding poly (glycol ester citrate) with bioactive glass, or further modifying the poly (glycol ester citrate) by using a silane coupling agent, and has good bioactivity, osteoconductivity, biocompatibility and controllable biodegradability, and simultaneously the mechanical property is greatly improved, and the preparation method is simple in process and easy to produce.

Description

Bioactive composite material and preparation method and application thereof
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a bioactive composite material and a preparation method and application thereof.
Background
With the increasing aging trend of the population, the incidence of bone defects caused by trauma, diseases, aging, bone tumors and the like is increasing year by year, and the bone defects become one of the main problems facing human health. The clinical repairing and replacing materials for bone defect mainly include autogenous bone, allogenic bone and synthetic bone repairing material. Autologous bone is the most ideal bone repair material, but the source of autologous bone is limited, and secondary operation is required for patients, so that the pain of the patients is increased; the allogeneic bone has the problems of disease transmission, immunological rejection reaction and the like. Accordingly, there is an increasing demand for synthetic bone repair and replacement materials.
In recent years, poly (diol citrates), PDC), a novel synthetic material, has attracted much attention due to its excellent biocompatibility, controllable biodegradability, and simple synthetic route. However, PDC is a soft polymer material, has very low mechanical properties (young's modulus <2MPa) and no bioactivity, which limits the application of PDC in the field of bone repair.
Bioactive Glass (BG) is a bone repair material with good bioactivity, osteoconductivity and biocompatibility. In a body fluid environment, Hydroxyapatite (HA) similar to bone tissue components can be formed on the surface of the material, so that firm chemical bonding is formed between the bone tissue and the material, and new bone tissue formation is induced; in addition, the ions, particularly Si and Ca ions, precipitated therefrom stimulate bone cells at the gene level to promote bone tissue repair. According to the relevant literature, BG is reported to promote bone tissue repair more effectively than other inorganic ceramic particles, such as HA and tricalcium phosphate (TCP). However, BG is brittle and its inherent brittleness makes it difficult to process, limiting its range of clinical applications. The BG particles and the PDC are compounded into the composite material, so that the defects of the BG particles and the PDC can be overcome, and the composite material with excellent performance of the BG particles and the PDC can be prepared. However, in the recently developed PDC/BG composite material, the BG content is low (the BG content is less than or equal to 30 wt.%) and the interaction between BG and PDC is not strong, so that the obtained composite material still shows strong elastomer property, has low mechanical property and poor biological activity, and is not suitable for repairing bone tissue defects.
Disclosure of Invention
The invention aims to provide a novel bioactive composite material and a preparation method thereof. The composite material has good bioactivity, osteoconductivity, biocompatibility and controllable biodegradability, and greatly improved mechanical properties, and has wide application prospect. The preparation method has simple process and is easy to produce.
According to one aspect of the present invention, there is provided a method of preparing a bioactive composite material, comprising the steps of:
(1) preparation of poly (citric acid glycol ester) prepolymer (PDC prepolymer for short)
Carrying out condensation polymerization reaction on citric acid and diol or polyol to obtain a PDC prepolymer;
(2) preparation of bioactive composite materials
Mixing the PDC prepolymer obtained in the step (1) with bioactive glass, uniformly stirring, and performing thermocuring molding to obtain a bioactive composite material;
wherein the weight ratio of the PDC prepolymer to the bioactive glass is 25: 75-65: 35, and preferably 30: 70-50: 50. Preferably, the bioactive composite material is a citrate-based bioactive composite material.
According to the present invention, preferably, in step (1): the diol or the polyol is selected from 1, 8-octanediol, xylitol, polyethylene glycol or a mixture of two or three of the 1, 8-octanediol, the xylitol and the polyethylene glycol in any proportion, and the molecular weight of the polyethylene glycol is further preferably 150-600; the molar ratio of the citric acid to the glycol or the polyol is 1 (0.8-1.2); the condensation polymerization reaction is carried out at 140-160 ℃; the reaction time is 10min to 2h, and preferably 30 to 60 min. According to the invention, the thermosetting molding is preferably carried out at 50 to 120 ℃.
According to another aspect of the present invention, there is provided a method for preparing a bioactive composite material, comprising the steps of:
(1) preparation of poly (citric acid glycol ester) prepolymer (PDC prepolymer for short)
Carrying out condensation polymerization reaction on citric acid and diol or polyol to obtain a PDC prepolymer;
(2) preparation of silane coupling agent modified PDC prepolymer (PDC-Si prepolymer for short)
Adding the PDC prepolymer into a silane coupling agent solution for reaction to obtain a PDC-Si prepolymer;
(3) preparation of bioactive composite materials
And (3) mixing the PDC-Si prepolymer obtained in the step (2) with bioactive glass, uniformly stirring, and performing thermocuring molding to obtain the bioactive composite material. Preferably, the bioactive composite material is a silane coupling agent modified citric acid based bioactive composite material.
According to the present invention, preferably, in step (1): the diol or the polyol is selected from 1, 8-octanediol, xylitol, polyethylene glycol or a mixture of two or three of the 1, 8-octanediol, the xylitol and the polyethylene glycol in any proportion, and the molecular weight of the polyethylene glycol is further preferably 150-600; the molar ratio of the citric acid to the glycol or the polyol is 1 (0.8-1.2); the condensation polymerization reaction is carried out at 140-160 ℃; the reaction time is 10min to 2h, and preferably 30 to 60 min.
According to the present invention, preferably, in step (2): the silane coupling agent is KH560 or KH 550; the molar ratio of the PDC prepolymer to the silane coupling agent in terms of citric acid is greater than 1:0 and less than or equal to 1:1, preferably 1 (0.1-1), more preferably 1 (0.2-0.8), and most preferably 1 (0.3-0.5); the solvent of the silane coupling agent solution is ethanol, acetone, dioxane, dimethylformamide or the like, and ethanol is more preferable.
According to the present invention, preferably, in step (3): the weight ratio of the PDC-Si prepolymer to the bioactive glass is 25: 75-70: 30, and the preferable weight ratio is 30: 70-50: 50; the thermosetting molding is carried out at 50-120 ℃.
It will be appreciated by those skilled in the art that bioactive glasses of various compositions and particle sizes useful in the art may be used in the present invention. Preferably, the bioactive glass consists of: x (SiO)2)·y(CaO)·m(P2O5)·n(Na2O), wherein the range of x, y, m, n (mol.%): x is 45-80 mol.%, y is 15-40 mol.%, m is 0-11 mol.%, and n is 0-25 mol.%. Preferably, the bioactive glass has a particle size of 38 μm or less.
According to another aspect of the present invention, the present invention further provides a bioactive composite material prepared by the method of the present invention.
According to another aspect of the invention, the invention further provides the use of the bioactive composite material of the invention for the preparation of a bone defect repair material.
Aiming at the defects of low mechanical strength, low biological activity and the like of the existing PDC/BG composite material, the invention provides a novel citric acid-based bioactive composite material and a preparation method thereof. The composite material prepared by the invention has greatly improved mechanical property, good bioactivity, bone conductivity, biocompatibility and controllable biodegradability, and has good application prospect in the field of bone injury repair.
The invention has the following advantages:
1. the composite material of the invention is introduced with a silane coupling agent. Organic groups in the silane coupling agent can chemically react with-COOH and-OH in the PDC prepolymer, and hydrolyzable inorganic groups in molecules of the silane coupling agent can chemically react with hydroxyl on the surface of BG. Therefore, the silane coupling agent can improve the interaction between PDC and BG, so that the mechanical property of the composite material is greatly improved.
2. In the existing research, only a small amount of BG is introduced into a PDC system (the BG content is less than or equal to 30 wt.%), so that the obtained PDC/BG composite material still has stronger elastomer properties (such as compression modulus: about 7MPa, storage modulus: about 81KPa and relaxation modulus: about 39KPa), and is not suitable for repairing bone tissue defects. The composite material prepared by the invention introduces BG with high content, which is not only beneficial to improving the mechanical properties of the composite material such as compressive strength, compressive modulus and the like, but also shows higher bioactivity. At the same time, BG releases Ca2+The plasma can neutralize acidic products after the PDC is degraded, and the biocompatibility of the composite material is improved.
3. The composite material has excellent bioactivity, osteoconductivity, biocompatibility and controllable biodegradability. In Simulated Body Fluid (SBF) culture, the surface of the composite material can generate Hydroxyapatite (HA), and the composite material shows good in vitro activity. In a cytotoxicity experiment, the cell compatibility is good, and the cell proliferation promoting effect on MC3T3 cells is achieved. In addition, the degradation rate of the composite material can be adjusted by adjusting the BG content, so that the biodegradability can be controlled.
Drawings
Fig. 1 is a picture of the appearance of the composite material prepared in example 1.
FIG. 2 is a PDC-Si prepolymer prepared in example 2FTIR spectrogram of (1). Wherein, a is an FTIR spectrum of KH560, b is an FTIR spectrum of a PDC prepolymer, and c is an FTIR spectrum of a PDC-Si prepolymer. c is not present at 910cm-1A characteristic peak of epoxy resin is formed, and the peak is 1000-1150 cm-1The Si-O peak increased strongly, indicating that KH560 was successfully grafted onto the PDC prepolymer.
FIG. 3 is a graph of data for compressive strength (a) and compressive modulus (b) for bioactive composites made in examples 2-4.
Fig. 4 is a scanning electron microscope image of the surface topography of the silane coupling agent modified citric acid-based bioactive composite material prepared in example 2 after being soaked in SBF7 days in an in vitro activity experiment.
FIG. 5 is a scanning electron microscope image of the surface topography of the citric acid-based bioactive composite material of example 5 after soaking in SBF7 days in an in vitro activity experiment.
FIG. 6 is a graph showing the effect of 1, 8-octanediol citrate (POC), the silane coupling agent-modified citric acid-based bioactive composite materials prepared in examples 2 and 5 on cell proliferation. The cells were MC3T3 cells and were detected by the CCK8 method. The results show that compared with POC, the silane coupling agent modified citric acid based bioactive composite materials prepared in the examples 2 and 5 have better cell compatibility and certain promotion effect on cell proliferation.
Detailed Description
The PDC/BG composite material developed in recent years has low BG content (BG content is less than or equal to 30 wt.%) and has weak interaction between BG and PDC, and the obtained composite material still shows stronger elastomer properties (compression modulus: about 6.78 MPa; storage modulus: about 81 KPa; relaxation modulus: about 39KPa), and is not suitable for repairing bone tissue defects. The invention aims to prepare a citric acid-based composite material with high mechanical strength and bioactivity, so that the citric acid-based composite material is suitable for the field of bone injury repair. The silane coupling agent is an organosilicon compound containing two groups with different chemical properties. The organic group and the inorganic group can respectively react with the polymer matrix and the inorganic filler, thereby improving the interface acting force of the polymer matrix and the inorganic filler and improving the mechanical property and other properties of the system. Therefore, in the invention, the compressive strength and the compressive modulus of the obtained PDC/BG composite material are obviously enhanced by utilizing the property that the silane coupling agent simultaneously reacts with the PDC and the BG, namely, the mechanical property is obviously enhanced. In addition, the composite material prepared by the invention has higher bioactivity, osteoconductivity and biocompatibility due to the introduction of high-content BG, has a certain promotion effect on the proliferation of MC3T3 cells, and can be used for fracture treatment, preparation of biomedical materials for bone defect support, filling and the like.
The invention is further illustrated with reference to the following figures and examples. However, those skilled in the art will appreciate that the scope of the present invention is not limited to the following examples. In light of the present disclosure, those skilled in the art will recognize that many variations and modifications may be made to the following examples without departing from the intended features and scope of the invention. The raw materials used in the following examples are commercially available unless otherwise specified.
Example 1
(1) Preparation of PDC prepolymers
Adding citric acid and 1, 8-octanediol into a 250ml round bottom flask according to the molar ratio of 1:0.8 and the total mass of 16.1g, stirring and dissolving in an oil bath at 160 ℃ in a nitrogen atmosphere, cooling to 140 ℃ after complete dissolution, and continuing to react for 30min to obtain the PDC prepolymer.
(2) Preparation of PDC-Si prepolymer
Adding the PDC prepolymer obtained in the step (1) into an ethanol solution containing 6.15g of KH560 (the molar ratio of citric acid to KH560 is 1:0.5) to react to obtain the PDC-Si prepolymer.
(3) Preparation of silane coupling agent modified citric acid-based bioactive composite material
Mixing the PDC-Si prepolymer obtained in the step (2) and bioactive glass particles (70% SiO)230% of CaO (mol.%)) in a weight ratio of 40:60, stirring uniformly, and performing thermal curing molding at 50 ℃ to obtain the silane coupling agent modified citric acid-based bioactive composite material (see figure 1).
The composite material has the compression strength of 60 +/-4 MPa and the compression modulus of 820 +/-60 MPa, exceeds the mechanical property requirement of cancellous bone (the compression strength is 2-12 MPa and the compression modulus is 100-500 MPa), and can be used for preparing biomedical materials for bone defect support, filling, replacement or repair and the like.
Example 2
(1) Preparation of PDC prepolymers
Adding citric acid and 1, 8-octanediol into a 250ml round bottom flask according to the molar ratio of 1:1 and the total mass of 17.6g, placing the flask into a 160 ℃ oil bath in a nitrogen atmosphere, stirring and dissolving, cooling to 140 ℃ after complete dissolution, and continuing to react for 30min to obtain the PDC prepolymer.
(2) Preparation of PDC-Si prepolymer
Adding the PDC prepolymer obtained in the step (1) into an ethanol solution containing 6.15g KH560 (the molar ratio of citric acid to KH560 is 1:0.5), and reacting to obtain the PDC-Si prepolymer (see figure 2).
(3) Preparation of silane coupling agent modified citric acid-based bioactive composite material
Mixing the PDC-Si prepolymer obtained in the step (2) and bioactive glass particles (54.2% SiO)2-35％CaO-10.8％P2O5(mol.%)) is mixed according to the weight ratio of 50:50, and after being uniformly stirred, the mixture is subjected to thermosetting molding at 80 ℃ to obtain the silane coupling agent modified citric acid-based bioactive composite material.
The compression strength of the material is 57 +/-6 MPa, the compression modulus is 620 +/-26 MPa (the molar ratio of citric acid to KH560 is 1:0.5 in the figure 3), and the material shows good in-vitro activity and cell compatibility (the figures 4 and 6), and can be used for preparing biomedical materials for bone defect support, filling substitution or repair and the like.
Example 3
(1) The same procedure as in step (1) of example 2 was repeated.
(2) The PDC prepolymer obtained in step (1) was added to the same volume of ethanol as in example 2 (which did not contain KH560 so that the molar ratio of citric acid to KH560 was 1:0), to obtain a PDC prepolymer.
(3) Preparation of citric acid-based bioactive composite material
Will step withPDC prepolymer obtained in step (2) and bioactive glass particles (54.2% SiO)2-35％CaO-10.8％P2O5(mol.%)) is mixed according to the weight ratio of 50:50, and after being stirred uniformly, the mixture is subjected to thermosetting molding at 80 ℃ to obtain the citric acid-based bioactive composite material.
The composite material has a compressive strength of 24 +/-3 MPa and a compressive modulus of 160 +/-27 MPa (as shown in a 1:0 molar ratio of citric acid to KH560 in a group shown in figure 3) measured by an universal material testing machine, and has mechanical properties which are obviously lower than those of the composite material prepared in example 1 and meet the requirements of the mechanical properties of cancellous bone. This shows that adding high content of BG can improve the mechanical properties of the system, while adding KH560 can further improve the mechanical properties of the system.
Example 4
(1) The same procedure as in step (1) of example 2 was repeated.
(2) Preparation of PDC-Si prepolymer
And (2) respectively reacting the PDC prepolymer obtained in the step (1) with an ethanol solution of KH560 according to the molar ratio of citric acid to KH560 of 1:0.3, wherein the molar ratio of 1:1 is 1: 560, so as to obtain the PDC-Si prepolymer.
(3) Preparation of silane coupling agent modified citric acid-based bioactive composite material
Respectively mixing the PDC-Si prepolymer obtained in the step (2) with bioactive glass particles (54.2% SiO)2-35％CaO-10.8％P2O5(mol.%)) is mixed according to the weight ratio of 50:50, and after being uniformly stirred, the mixture is subjected to thermosetting molding at 80 ℃ to obtain the silane coupling agent modified citric acid-based bioactive composite material.
The compressive strength and the compressive modulus of the composite material measured by the universal material testing machine are shown in the attached figure 3. It can be seen that as the content of KH560 increases, the strength shows a tendency to increase first and decrease (see fig. 3). This is probably because after a certain amount of KH560 modified PDC prepolymer, it was possible to improve the interaction between PDC and BG, thus increasing the strength of the system; when KH560 exceeds a certain ratio, it consumes excessive-COOH on the PDC prepolymer, affecting the crosslinking density after the system is thermally cured, and reducing the strength of the system. But the mechanical strength of the series of materials meets the requirement of the mechanical property of the spongy bone substitute material.
Example 5
(1) The same procedure as in step (1) of example 2 was repeated.
(2) The same procedure as in step (2) of example 2 was repeated.
(3) Preparation of silane coupling agent modified citric acid-based bioactive composite material
Respectively mixing the PDC-Si prepolymer obtained in the step (2) with bioactive glass particles (54.2% SiO)2-35％CaO-10.8％P2O5(mol.%)) is mixed according to the weight ratio of 30:70, and after being uniformly stirred, the mixture is subjected to thermosetting molding at 80 ℃ to obtain the silane coupling agent modified citric acid-based bioactive composite material.
The composite material HAs the compression strength and the compression modulus of 63 +/-5 MPa and 1440 +/-110 MPa respectively measured by a universal material testing machine, and in an in-vitro soaking SBF experiment, compact HA can grow on the surface, the composite material shows good bioactivity (shown in figure 5), the pH of a system can be maintained to be basically unchanged, and the composite material also shows good cell compatibility (shown in figure 6), and can be used for preparing biomedical materials for bone defect support, filling substitution or repair and the like.
Example 6
(1) Preparation of PDC prepolymers
Adding citric acid and PEG300 into a 250ml round bottom flask according to the molar ratio of 1:1 and the total mass of 25.6g, stirring and dissolving in an oil bath at 160 ℃ in a nitrogen atmosphere, cooling to 140 ℃ after complete dissolution, and continuing to react for 30min to obtain the PDC prepolymer.
(2) Preparation of PDC-Si prepolymer
Adding the PDC prepolymer obtained in the step (1) into an ethanol solution containing 5.75g of KH550 (the molar ratio of citric acid to KH550 is 1:0.5), and reacting to obtain the PDC-Si prepolymer.
(3) Preparation of silane coupling agent modified citric acid-based bioactive composite material
Mixing the PDC-Si prepolymer obtained in the step (2) and bioactive glass particles (58% SiO)2-38％CaO-4％P2O5(mol.%)) is mixed according to the weight ratio of 70:30, and after the mixture is uniformly stirredAnd performing thermocuring molding at 120 ℃ to obtain the silane coupling agent modified citric acid-based bioactive composite material. The composite material can grow HA in SBF and shows good biological activity.
Example 7
(1) Preparation of PDC prepolymers
Adding citric acid and PEG300 into a 250ml round bottom flask according to the molar ratio of 1:1.2 and the total mass of 28.7g, stirring and dissolving in an oil bath at 160 ℃ in a nitrogen atmosphere, cooling to 140 ℃ after complete dissolution, and continuing to react for 30min to obtain the PDC prepolymer.
(2) The same procedure as in step (2) of example 6 was repeated.
(3) Preparation of silane coupling agent modified citric acid-based bioactive composite material
Mixing the PDC-Si prepolymer obtained in the step (2) and bioactive glass particles (70% SiO)2And-30% of CaO (mol.%)) according to a weight ratio of 60:40, uniformly stirring, and performing thermal curing molding at 120 ℃ to obtain the silane coupling agent modified citric acid-based bioactive composite material. The composite material HAs the compression strength of 25 +/-7 MPa, generates HA in SBF and shows in-vitro activity.

Claims (17)

1. A preparation method of a bioactive composite material is characterized by comprising the following steps:
(1) preparation of Polycitric acid diol ester prepolymer
Carrying out condensation polymerization reaction on citric acid and diol or polyol to obtain a poly (citric acid diol ester) prepolymer;
(2) preparation of silane coupling agent modified poly (glycol citrate) prepolymer
Adding the poly (glycol citrate) prepolymer into a silane coupling agent solution for reaction to obtain a silane coupling agent modified poly (glycol citrate) prepolymer;
(3) preparation of bioactive composite materials
Mixing the silane coupling agent modified poly (glycol citrate) prepolymer obtained in the step (2) with bioactive glass, uniformly stirring, and performing thermocuring molding to obtain a bioactive composite material;
wherein the weight ratio of the silane coupling agent modified poly (glycol citrate) prepolymer to the bioactive glass is 25: 75-70: 30;
wherein the silane coupling agent is KH560 or KH 550;
wherein, the bioactive glass comprises the following components: x (SiO)2)·y(CaO)·m(P2O5)·n(Na2O), wherein x, y, m, n range: x is 45-80 mol.%, y is 15-40 mol.%, m is 0-11 mol.%, and n is 0-25 mol.%.
2. The process according to claim 1, wherein in the step (1), the diol or polyol is selected from the group consisting of 1, 8-octanediol, xylitol, polyethylene glycol and a mixture of two or three thereof in any ratio.
3. The method according to claim 2, wherein the polyethylene glycol has a molecular weight of 150 to 600.
4. The method according to claim 1, wherein in the step (1), the molar ratio of citric acid to the diol or polyol is 1 (0.8-1.2).
5. The method according to claim 1, wherein the condensation polymerization is carried out at 140 to 160 ℃ in the step (1).
6. The method according to claim 5, wherein the reaction time is 10min to 2 hours.
7. The method according to claim 6, wherein the reaction time is 30 to 60 min.
8. The production method according to claim 1, wherein in the step (2), the molar ratio of the polycitraconic diol ester prepolymer to the silane coupling agent in terms of citric acid is more than 1:0 and 1:1 or less.
9. The method according to claim 8, wherein in the step (2), the molar ratio of the poly (diol citrate) prepolymer to the silane coupling agent is 1 (0.1-1) in terms of citric acid.
10. The method according to claim 9, wherein in the step (2), the molar ratio of the poly (diol citrate) prepolymer to the silane coupling agent is 1 (0.2-0.8) in terms of citric acid.
11. The method according to claim 10, wherein in the step (2), the molar ratio of the poly (diol citrate) prepolymer to the silane coupling agent is 1 (0.3-0.5) in terms of citric acid.
12. The method according to claim 1, wherein the solvent of the silane coupling agent solution is ethanol, acetone, dioxane, or dimethylformamide.
13. The production method according to claim 12, wherein the solvent of the silane coupling agent solution is ethanol.
14. The preparation method according to claim 1, wherein the weight ratio of the silane coupling agent modified poly (glycol citrate) prepolymer to the bioactive glass is 30: 70-50: 50.
15. The method according to claim 1, wherein the thermosetting molding is performed at 50 to 120 ℃.
16. A bioactive composite material prepared according to the method of any one of claims 1-15.
17. Use of the bioactive composite material according to claim 16 for the preparation of a bone defect repair material.
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