CN112043864B - Bone regeneration promoting composite material and preparation method thereof - Google Patents

Bone regeneration promoting composite material and preparation method thereof Download PDF

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CN112043864B
CN112043864B CN202010914619.9A CN202010914619A CN112043864B CN 112043864 B CN112043864 B CN 112043864B CN 202010914619 A CN202010914619 A CN 202010914619A CN 112043864 B CN112043864 B CN 112043864B
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hydrophilic
double
hydrophobic segment
segment polymer
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CN112043864A (en
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彭松林
何同忠
谭宝玉
陈高扬
王尚
贺小琴
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Shenzhen Peoples Hospital
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Abstract

The invention provides a preparation method of a bone regeneration promoting composite material. The preparation method of the bone regeneration promoting composite material comprises the following steps: 1) preparing a hydrophilic and hydrophobic segment polymer by taking alkane diol and polybasic acid as raw materials through a polycondensation reaction; 2) doubly bonding the hydrophilic and hydrophobic segment polymer obtained in the step 1) to obtain a doubly bonded hydrophilic and hydrophobic segment polymer; 3) carrying out polymerization reaction by taking the double-bonded hydrophilic and hydrophobic segment polymer obtained in the step 2), inorganic materials and processing aids as raw materials to obtain the bone regeneration promoting composite material. The bone regeneration promoting composite material and the preparation method thereof have the advantages of simple manufacturing process, low cost, random plasticity, high forming speed and good adhesion effect on different substrate materials, and the bone regeneration promoting composite material has good biodegradability and mechanical property and good biocompatibility.

Description

Bone regeneration promoting composite material and preparation method thereof
Technical Field
The invention belongs to the technical field of polymer medical composite materials, and relates to a bone regeneration promoting composite material and a preparation method thereof.
Background
The polyester elastomer is widely applied to bone tissue engineering with good biodegradability and adjustable mechanical property, but the growth condition of cells on the surface of the polyester elastomer is poor, the affinity of the cells is insufficient, the immune response of a host is easily triggered, the organism generates inflammation, and meanwhile, the forming needs a long time. The inorganic materials used for bone tissue engineering have good biocompatibility and osteogenic activity, but have poor degradability and are difficult to be absorbed in vivo, thereby further influencing the generation of new bones.
CN111494720A discloses a function-integrated absorbable guided tissue regeneration membrane and a preparation method thereof. The regeneration membrane component comprises degradable artificially synthesized high molecular materials, natural degradable high molecular polymers and inorganic nano particles. The method comprises the following steps: dissolving degradable artificially synthesized high molecular material and natural degradable high molecular polymer in organic solvent, stirring, adding inorganic nanometer particles, stirring, ultrasonic treating and electrostatic spinning. The regeneration membrane has good mechanical property, biocompatibility, antibacterial property and bone promoting activity, and has obvious periodontal repair effect. The method has the advantages of wide material source, low preparation cost and potential clinical application prospect. However, the adhesion effect of the regenerated film of the invention to the base material is to be improved.
CN101695584B discloses an injectable composite material for promoting bone regeneration and repair, which is prepared by compounding sodium alginate, chitosan, multi-element trace element synergistically doped calcium phosphate porous microspheres and bioactive glass nano-particles serving as components through deionized water and cell culture solution, wherein the injectable composite material for promoting bone regeneration and repair comprises the following components in percentage by mass: 0.10-0.50% of sodium alginate; 0.01-0.20% of chitosan; 5-30% of multi-element trace element synergistically doped calcium phosphate porous microspheres; 0.05-0.50% of bioactive glass; 25-55% of cell culture solution; 30-45% of deionized water. The preparation process is simple, the prepared composite material has excellent injectability and rapid degradation characteristics, the hydrogel network can enrich calcium ions, phosphorus ions and trace elements released by inorganic particle degradation, can promote osteoblast migration, growth, proliferation and differentiation, and has the effects of rapidly inducing bone regeneration and promoting bone repair on intra-osseous micro-injury, fracture or bone defect. However, the adhesion effect of the regenerated film of the present invention to the base material and the mechanical properties of the material are desired to be improved.
Therefore, it is necessary to provide a bone regeneration promoting composite material which has any plasticity, high forming speed, good adhesion effect to different substrate materials, good biodegradability, mechanical properties and biocompatibility.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a bone regeneration promoting composite material and a preparation method thereof, the preparation process is simple, the cost is low, the composite material can be randomly plastic and has high forming speed, and the adhesion effect on different substrate materials is good.
In order to achieve the purpose, the invention adopts the following technical scheme:
one of the purposes of the invention is to provide a preparation method of a bone regeneration promoting composite material, which comprises the following steps:
1) preparing a hydrophilic and hydrophobic segment polymer by taking alkane diol and polybasic acid as raw materials through a polycondensation reaction;
2) double-bonding the hydrophilic and hydrophobic segment polymer obtained in the step 1) to obtain a double-bonded hydrophilic and hydrophobic segment polymer;
3) carrying out polymerization reaction by taking the double-bonded hydrophilic and hydrophobic segment polymer obtained in the step 2), inorganic materials and processing aids as raw materials to obtain the bone regeneration promoting composite material.
The composite material prepared by the preparation method of the bone regeneration promoting composite material is a rapidly formed organic-inorganic integrated composite material and is prepared by uniformly mixing an organic high molecular polymer and an inorganic material, so that the composite material not only has good biodegradability and adjustable mechanical property, but also has good biocompatibility. Through the design of the hydrophilic and hydrophobic segment polymer, a certain adhesion effect is given to the material. In the composite material, a hydrocarbon chain in alkane diol provides a hydrophobic segment, plays a role in water drainage in a water environment, and can generate hydrophobic adhesion with a contacted substrate material; the polybasic acid in the compound provides hydrophilic adhesion sites, and unreacted hydrophilic groups in molecular chains of the compound and a substrate material form stronger acting force, wherein the acting force comprises hydrogen bonds, ionic bonds and the like. Therefore, under the wet condition, the composite material realizes the adhesion effect on different substrate materials through dynamic hydrophilic and hydrophobic acting force. Because the hydrophilic and hydrophobic segment polymer has double bonds, the composite material can be injection molded and has short molding time.
In the step 1), the polycondensation reaction comprises the following specific processes: putting alkane diol and polybasic acid into a three-neck flask, then putting the three-neck flask into a preheated oil bath kettle, and adding N2Stirring to be completely melted under protection, cooling, continuously stirring for reaction to obtain an initial polymer, dissolving the initial polymer in an organic solvent, repeatedly washing with ultrapure water, centrifuging at high speed, collecting precipitate, and drying in a vacuum drying oven to prepare the purified hydrophilic and hydrophobic fragment polymer.
The molar ratio of the alkane diol to the polybasic acid is (1:10) - (10:1), for example, a molar ratio of 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1, etc.
Preferably, the alkane diol is any one of 1, 4-butanediol, 1, 6-hexanediol, 1, 8-octanediol, 1, 10-decanediol, 1, 12-dodecanediol, 1, 14-tetradecanediol, and 1, 16-hexadecanediol, or a mixture of at least two thereof.
Preferably, the polybasic acid is a dibasic acid or a tribasic acid.
Preferably, the dibasic acid is sebacic acid.
Preferably, the tribasic acid is any one or a mixture of at least two of citric acid, tricarballylic acid and 1,2, 4-butanetricarboxylic acid, and the mixture is a mixture of citric acid and tricarballylic acid, a mixture of tricarballylic acid and 1,2, 4-butanetricarboxylic acid, a mixture of citric acid and 1,2, 4-butanetricarboxylic acid, and a mixture of citric acid, tricarballylic acid and 1,2, 4-butanetricarboxylic acid.
In step 1), the temperature for heating the oil bath is 160-165 ℃, for example, the temperature for heating the oil bath is 160 ℃, 161 ℃, 162 ℃, 163 ℃, 164 ℃ or 165 ℃.
Preferably, the temperature after temperature reduction is 140 ℃, and the reaction time after temperature reduction is 0.5-10h, for example, the reaction time after temperature reduction is 0.5h, 0.6h, 0.7h, 0.8h, 0.9h or 1h, etc.
Preferably, the organic solvent is absolute ethanol, 1, 4-dioxane, DMF or tetrahydrofuran.
Preferably, the drying temperature is 30-50 deg.C, such as the drying temperature of 30 deg.C, 31 deg.C, 32 deg.C, 33 deg.C, 34 deg.C, 35 deg.C, 36 deg.C, 37 deg.C, 38 deg.C, 39 deg.C, 40 deg.C, 41 deg.C, 42 deg.C, 43 deg.C, 44 deg.C, 45 deg.C, 46 deg.C, 47 deg.C, 48 deg.C, 49 deg.C or 50 deg.C etc.
In the step 2), the double-bonding process of the hydrophilic-hydrophobic segment polymer comprises the following specific steps: adding a double bonding reagent into the hydrophilic and hydrophobic segment polymer prepared in the step 1), N2Under protection, stirring and mixing evenly at high temperature, and reacting for 0.5-10h at the temperature of 60-140 ℃ to obtain the double-bonded hydrophilic-hydrophobic segment polymer.
Preferably, the mass of the double-bonding agent is 5-50% of the mass of the hydrophilic-hydrophobic segment polymer, for example, the mass of the double-bonding agent is 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% of the mass of the hydrophilic-hydrophobic segment polymer, and the like.
Preferably, the double-bonding agent is any one of itaconic acid, fumaric acid, maleic acid or isocyano ethyl methacrylate or a mixture of at least two of itaconic acid, fumaric acid, maleic acid and isocyano ethyl methacrylate.
In the step 2), the double-bonding process of the hydrophilic-hydrophobic segment polymer comprises the following specific steps: dissolving the hydrophilic and hydrophobic segment polymer prepared in the step 1) in dichloromethane, and adding triethylamine and N2Under protection, a double-bonding reagent is dripped, the mixture is stirred in ice bath for reaction for 0.5 to 12 hours, petroleum ether is added, and the lower layer substance is collected to obtain the double-bonded hydrophilic and hydrophobic fragment polymer.
Preferably, the mass percentage of the double-bonding agent in the hydrophilic-hydrophobic segment polymer is 5-50%;
preferably, the double bonding agent is acryloyl chloride and/or methacrylic anhydride.
In the step 3), the mass percentage of the double-bonded hydrophilic-hydrophobic segment polymer is 89-98.9%, for example, the mass percentage of the double-bonded hydrophilic-hydrophobic segment polymer is 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 98.9%, etc., the mass percentage of the nano-hydroxyapatite is 0.1-10%, for example, the mass percentage of the nano-hydroxyapatite is 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, etc., and the mass percentage of the processing aid is 1%.
Preferably, the inorganic material is any one of nano hydroxyapatite, nano black phosphorus, nano clay and bioceramic or a mixture of at least two of the nano hydroxyapatite, the nano black phosphorus, the nano clay and the bioceramic.
Preferably, the processing aid comprises a photoinitiator and/or a free radical provider.
Preferably, the photoinitiator is 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone and/or 2-hydroxy-2-methyl-1-phenyl-1-propanone.
Preferably, the free radical provider is benzoyl peroxide and/or N, N-dimethyl-p-toluidine.
In the step 3), the polymerization reaction is accelerated by ultrasonic or heating.
When the processing aid contains the photoinitiator, polymerization is carried out by irradiating 1-5J ultraviolet light for 80-100 s.
The second purpose of the invention is to provide the bone regeneration promoting composite material prepared by the preparation method.
Compared with the prior art, the invention has the following beneficial effects:
the bone regeneration promoting composite material realizes the adhesion effect on different substrate materials such as glass, metal, wood, skin and the like through dynamic hydrophilic and hydrophobic acting force, can be injected and molded and has short molding time; the bone regeneration promoting composite material is prepared by uniformly mixing an organic high molecular polymer and inorganic nano particles, has good biodegradability and adjustable mechanical property, and also has good biocompatibility, specifically, the stress is 7.21-38.62MPa, the strain is 36.88-42.61%, the compressive modulus is 10.21-45.26MPa, and the biodegradability at 14 days is 20.51-50.21%.
Drawings
FIG. 1 is a graph showing the results of stress performance tests of the composite materials of examples 2, 5, 7 and comparative example 2 according to the present invention;
FIG. 2 is a graph showing the results of the compression modulus test of the composite materials of examples 2, 5, 7 and comparative example 2 according to the present invention;
FIG. 3 is a graph showing the results of biodegradability tests of the composite materials of examples 2, 5, 7 and comparative example 2 according to the present invention;
FIG. 4 is a graph showing the results of the MTS assay for cell activity in the control group and the composites of examples 2, 5 and 7;
FIG. 5 is a schematic diagram showing the result of the Calcein-AM/PI/dying cell staining test without adding composite material in the control group of the present invention;
FIG. 6 is a schematic diagram showing the result of Calcein-AM/PI/dying cells staining detection experiment of the composite material of example 2 of the present invention;
FIG. 7 is a schematic diagram showing the results of Calcein-AM/PI/dying cells staining detection experiment of the composite material of example 5 of the present invention;
FIG. 8 is a schematic diagram showing the result of the Calcein-AM/PI/dying cell staining detection experiment of the composite material of example 7 of the present invention.
Detailed Description
The technical scheme of the invention is further explained by the specific implementation mode in combination with the attached figures 1-8.
Unless otherwise specified, various starting materials of the present invention are commercially available or prepared according to conventional methods in the art.
Example 1
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 8-octanediol and citric acid are put into a 250mL three-necked flask according to a molar ratio of 1:1, and are put into an oil bath pan, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pan is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Adding itaconic acid into the hydrophilic and hydrophobic segment polymer obtained by preparation, N2And (4) under the protection, fully stirring and uniformly mixing at high temperature. Then reacting for 3h at 140 ℃ to obtain the double-bonded hydrophilic and hydrophobic segment polymer. Wherein the mass fraction of the itaconic acid in the hydrophilic and hydrophobic segment polymer is 5%.
3) Preparation of composite materials
The bone regeneration promoting composite material is prepared by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano-hydroxyapatite and 1% of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone as raw materials, uniformly mixing the raw materials by ultrasonic waves for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for forming.
Example 2
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 8-octanediol and citric acid are put into a 250mL three-necked flask according to a molar ratio of 1:1, and are put into an oil bath pan, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pan is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Dissolving the hydrophilic and hydrophobic fragment polymer in dichloromethane, adding triethylamine and N2Under protection, dropwise adding acryloyl chloride, stirring in an ice bath for reaction for 3 hours, adding petroleum ether, and collecting lower-layer substances to obtain the double-bonded hydrophilic-hydrophobic fragment polymer. Wherein, the mass fraction of the acryloyl chloride in the hydrophilic and hydrophobic segment polymer is 10%.
3) Preparation of composite materials
89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano-hydroxyapatite and 1% of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone are taken as raw materials, the raw materials are mixed evenly by ultrasound for 90s, and the mixture is irradiated under an ultraviolet lamp for 2J molding, so that the bone regeneration promoting composite material is obtained.
Example 3
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 8-octanediol and citric acid are put into a 250mL three-necked flask according to the molar ratio of 1:1, put into an oil bath pot, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pot is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Adding itaconic acid into the prepared hydrophilic and hydrophobic segment polymer, N2Under the protection, the mixture is fully stirred and evenly mixed at high temperature. Then reacting for 3h at 140 ℃ to obtain the double-bonded hydrophilic and hydrophobic segment polymer. Wherein the mass fraction of the itaconic acid in the hydrophilic and hydrophobic segment polymer is 5%.
3) Preparation of composite materials
The bone regeneration promoting composite material is prepared by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano black phosphorus, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by using ultrasound for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for forming.
Example 4
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 8-octanediol and citric acid are put into a 250mL three-necked flask according to a molar ratio of 1:1, and are put into an oil bath pan, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pan is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Dissolving the hydrophilic and hydrophobic fragment polymer in dichloromethane, adding triethylamine and N2Under protection, dropwise adding acryloyl chloride, stirring in an ice bath for reaction for 3 hours, adding petroleum ether, and collecting lower-layer substances to obtain the double-bonded hydrophilic-hydrophobic fragment polymer. Wherein, the mass fraction of the acryloyl chloride in the hydrophilic and hydrophobic segment polymer is 20%.
3) Preparation of composite materials
The bone regeneration promoting composite material is prepared by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano black phosphorus, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by using ultrasound for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for forming.
Example 5
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 8-octanediol and citric acid are put into a 250mL three-necked flask according to a molar ratio of 1:1, and are put into an oil bath pan, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pan is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction, 100mL of absolute ethanol was added to completely dissolve the prepolymer, and then the high molecular prepolymer was precipitated with ultrapure water at a ratio of 1:1, and the resulting precipitate was centrifuged at a centrifugation speed of 10000rpm/min for 10min to retain the precipitate. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Adding itaconic acid into the prepared hydrophilic and hydrophobic segment polymer, N2Under the protection, the mixture is fully stirred and evenly mixed at high temperature. Then reacting for 3h at 140 ℃ to obtain the double-bonded hydrophilic and hydrophobic segment polymer. Wherein the mass fraction of itaconic acid in the hydrophilic and hydrophobic segment polymer is 25%.
3) Preparation of composite materials
The bone regeneration promoting composite material is prepared by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano black phosphorus, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by using ultrasound for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for forming.
Example 6
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 12-dodecanediol and citric acid are placed into a 250mL three-necked flask according to the molar ratio of 1:1, the flask is placed into an oil bath pot, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pot is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction, 100mL of absolute ethanol was added to completely dissolve the prepolymer, and then the high molecular prepolymer was precipitated with ultrapure water at a ratio of 1:1, and the resulting precipitate was centrifuged at a centrifugation speed of 10000rpm/min for 10min to retain the precipitate. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Adding itaconic acid into the prepared hydrophilic and hydrophobic segment polymer, N2Under the protection, the mixture is fully stirred and evenly mixed at high temperature. Then reacting for 3h at 140 ℃ to obtain the double-bonded hydrophilic and hydrophobic segment polymer. Wherein the mass fraction of itaconic acid in the hydrophilic and hydrophobic segment polymer is 30%.
3) Preparation of composite materials
The bone regeneration promoting composite material is obtained by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano black phosphorus, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by using ultrasound for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for molding.
Example 7
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 12-dodecanediol and citric acid are placed into a 250mL three-necked flask according to a molar ratio of 1:1, the flask is placed into an oil bath pot, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely dissolved, the temperature of the oil bath pot is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Dissolving the hydrophilic and hydrophobic fragment polymer in dichloromethane, adding triethylamine and N2Under protection, dropping acryloyl chloride, stirring in ice bath for reaction for 3h, adding petroleum ether, and collecting lower-layer substances to obtain the double-bonded hydrophilic and hydrophobic fragment polymer. Wherein, the mass fraction of the acryloyl chloride in the hydrophilic and hydrophobic segment polymer is 35%.
3) Preparation of composite materials
The bone regeneration promoting composite material is prepared by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano black phosphorus, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by using ultrasound for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for forming.
Example 8
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 12-dodecanediol and citric acid are placed into a 250mL three-necked flask according to a molar ratio of 1:1, the flask is placed into an oil bath pot, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely dissolved, the temperature of the oil bath pot is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Dissolving the hydrophilic and hydrophobic segment polymer in dichloromethane, adding triethylamine and N2Under protection, dropping acryloyl chloride, stirring in ice bath for reaction for 3h, adding petroleum ether, and collecting lower-layer substances to obtain the double-bonded hydrophilic and hydrophobic fragment polymer. Wherein the mass fraction of the acryloyl chloride in the hydrophilic and hydrophobic segment polymer is 40 percent.
3) Preparation of composite materials
The bone regeneration promoting composite material is obtained by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano clay, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by using ultrasound for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for molding.
Example 9
1) Synthesis of hydrophilic-hydrophobic segment polymers
1, 12-dodecanediol and citric acid are placed into a 250mL three-necked flask according to the molar ratio of 1:1, the flask is placed into an oil bath pot, the temperature is adjusted to 165 ℃, nitrogen is introduced, after the three substances are completely melted, the temperature of the oil bath pot is adjusted to 140 ℃, and the reaction is continued for 3 hours. After the reaction is finished, 100mL of absolute ethyl alcohol is added to completely dissolve the prepolymer, then the high molecular prepolymer is precipitated by ultrapure water according to the proportion of 1:1, the polymer prepolymer is centrifuged for 10min at the centrifugal speed of 10000rpm/min, and the precipitate is reserved. The pellet centrifugation was repeated three times. And (3) putting the mixture into a vacuum drying oven at 40 ℃ to remove residual moisture to obtain the purified hydrophilic and hydrophobic fragment polymer.
2) Double bonding of polymers of hydrophilic and hydrophobic segments
Adding itaconic acid into the prepared hydrophilic and hydrophobic segment polymer, N2And (4) under the protection, fully stirring and uniformly mixing at high temperature. Then reacting for 3 hours at 140 ℃ to obtainDouble-bonded hydrophilic-hydrophobic segment polymers. Wherein the mass fraction of itaconic acid in the hydrophilic and hydrophobic segment polymer is 50%.
3) Preparation of composite materials
The bone regeneration promoting composite material is prepared by taking 89% of double-bonded hydrophilic and hydrophobic segment polymer, 10% of nano clay, 0.67% of benzoyl peroxide and 0.33% of N, N-dimethyl-p-toluidine as raw materials, uniformly mixing the raw materials by ultrasonic waves for 90s, and irradiating the mixture under an ultraviolet lamp for 2J for forming.
Example 10
This example differs from example 1 in that in step 1), the molar ratio of 1, 8-octanediol to citric acid was 1:20, and the rest was the same as in example.
Example 11
This example differs from example 1 in that in step 1) the molar ratio of 1, 8-octanediol to citric acid was 20:1, and the rest was the same as in the example.
Comparative example 1
This comparative example is different from example 1 in that double bonding of the hydrophilic-hydrophobic segment polymer in step 2) is not performed, and the others are the same as those of example 1.
Comparative example 2
This comparative example is different from example 1 in that no inorganic material is added in step 3), and the rest is the same as example.
The composite materials obtained in examples 1 to 11 and comparative examples 1 to 2 were subjected to performance tests, and the test results are shown in Table 1.
The method for testing the adhesion effect of different substrate materials comprises the following steps: the prepared composite material is adhered to glass, metal, wood and skin substrates, and the adhesion condition is observed.
The test standard and the test method of the mechanical property are as follows: each sample was prepared in a mold into a cylinder having a bottom diameter of 8mm and a height of 10mm, and mechanical properties thereof were measured at a compression rate of 5mm/min using a mechanical tester having a measuring range of 10kN, wherein the results of stress property measurement of the composite materials of example 2, example 5, example 7 and comparative example 2 are shown in fig. 1, and the results of compressive modulus are shown in fig. 2.
The biodegradability test standards and test methods are as follows: each sample was prepared, molded, and then put into 10mL of PBS (pH 7.4) at 37 ℃ to perform degradation test, wherein the results of the biodegradability test of the composite materials of examples 2, 5, 7 and comparative examples 25 and 7 are shown in fig. 3.
The test criteria and test methods for biocompatibility are as follows: each sample was UV-sterilized after molding, co-cultured with C2C12 cells, and stained for MTS and Calcein-AM/PI/viable/dead cells to detect their cellular activity. Wherein, the control group refers to cells cultured normally without adding any composite material. The results of the MTS-test cell activity test of the composite materials of the control group, example 2, example 5 and example 7 are shown in fig. 4, and the results of the Calcein-AM/PI/dead cell staining test of the control group, example 2, example 5 and example 7 are shown in fig. 5, 6, 7 and 8, respectively.
As can be seen from FIG. 4, on the third day of C2C12 cell culture, the cell activity of example 2 reached 85.0%, the cell activity of example 5 reached 90.5%, and the cell activity of example 7 reached 99.0%, as compared to the blank control (100%).
As can be seen from fig. 5, 6, 7 and 8, the cell viability of the composite materials prepared in examples 2, 5 and 7 of the present invention is almost the same as that of the blank control group, which indicates that the composite materials prepared in examples 2, 5 and 7 have no cytotoxicity.
TABLE 1
Figure BDA0002664563430000151
As can be seen from table 1, the composite materials prepared in examples 1 to 9 have good mechanical properties, biodegradability and biocompatibility, and can be adhered to various substrates such as glass, metal, wood, skin, etc.
The molar ratio of 1, 8-octanediol to citric acid of example 10 was too small at 1:20, making the hydrophobic and hydrophilic segment in step 1) unable to be synthesized.
Too large a molar ratio of 1, 8-octanediol and citric acid of example 11 of 20:1 would also make the synthesis of the hydrophilic and hydrophobic segments in step 1) impossible.
Comparative example 1 does not undergo double bonding of the hydrophilic and hydrophobic segment polymer of step 2), and the material cannot be molded after ultraviolet irradiation.
In step 3) of comparative example 2, no inorganic material is added, which may lower the mechanical properties of the material and deteriorate the biocompatibility.
The present invention is illustrated by the above examples, but the present invention is not limited to the above detailed process equipment and process flow, which means that the present invention must not be implemented by the above detailed process equipment and process flow. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are all within the protection scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention can be made, and the same should be considered as the disclosure of the present invention as long as the idea of the present invention is not violated.

Claims (22)

1. The preparation method of the bone regeneration promoting composite material is characterized by comprising the following steps:
1) preparing a hydrophilic and hydrophobic segment polymer by taking alkane diol and polybasic acid as raw materials through a polycondensation reaction;
2) double-bonding the hydrophilic and hydrophobic segment polymer obtained in the step 1) to obtain a double-bonded hydrophilic and hydrophobic segment polymer;
3) carrying out polymerization reaction by taking the double-bonded hydrophilic and hydrophobic segment polymer obtained in the step 2), inorganic materials and processing aids as raw materials to obtain the bone regeneration promoting composite material;
in the step 2), the double-bonding process of the hydrophilic-hydrophobic segment polymer comprises the following specific steps: adding a double-bonding reagent into the hydrophilic and hydrophobic segment polymer prepared in the step 1), and adding N2Under protection, stirring and mixing uniformly at high temperature, and reacting for 0.5-10h at 60-140 ℃ to obtain double-bonded hydrophilic and hydrophobic segment polymer;
the double-bonding reagent is any one or a mixture of at least two of itaconic acid, fumaric acid, maleic acid, acryloyl chloride or isocyano ethyl methacrylate;
in the step 3), the mass percent of the double-bonded hydrophilic and hydrophobic segment polymer is 89-98.9%, the mass percent of the inorganic material is 0.1-10%, and the mass percent of the processing aid is 1%.
2. The preparation method according to claim 1, wherein in the step 1), the polycondensation reaction is carried out in the following specific process: putting alkane diol and polybasic acid into a three-neck flask, then putting the three-neck flask into a preheated oil bath pot, and adding N2Stirring to be completely melted under protection, cooling, continuously stirring for reaction to obtain an initial polymer, dissolving the initial polymer in an organic solvent, repeatedly washing with ultrapure water, centrifuging at high speed, collecting precipitate, and drying in a vacuum drying oven to prepare the purified hydrophilic and hydrophobic fragment polymer.
3. The method according to claim 2, wherein the molar ratio of the alkane diol to the polybasic acid is (1:10) to (10: 1).
4. The method according to claim 2, wherein the alkane diol is any one of 1, 4-butanediol, 1, 6-hexanediol, 1, 8-octanediol, 1, 10-decanediol, 1, 12-dodecanediol, 1, 14-tetradecanediol, and 1, 16-hexadecanediol, or a mixture of at least two thereof.
5. The method according to claim 2, wherein the polybasic acid is a dibasic acid or a tribasic acid.
6. The method of claim 5, wherein the dibasic acid is sebacic acid.
7. The method according to claim 5, wherein the triacid is any one of citric acid, tricarballylic acid, and 1,2, 4-butanetricarboxylic acid or a mixture of at least two thereof.
8. The method as claimed in claim 2, wherein the temperature of the oil bath is 160-165 ℃ in the step 1).
9. The preparation method according to claim 2, wherein the temperature after the temperature reduction is 140 ℃, and the reaction time after the temperature reduction is 0.5 to 10 hours.
10. The method according to claim 2, wherein the organic solvent is absolute ethanol, 1, 4-dioxane, DMF or tetrahydrofuran.
11. The method according to claim 2, wherein the drying temperature is 30 to 50 ℃.
12. The method according to claim 1, wherein the mass of the double-bonding agent is 5 to 50% of the mass of the hydrophilic-hydrophobic segment polymer.
13. The method of claim 1The preparation method is characterized in that in the step 2), the double bonding of the hydrophilic and hydrophobic segment polymer comprises the following specific processes: dissolving the hydrophilic and hydrophobic segment polymer prepared in the step 1) in dichloromethane, and adding triethylamine and N2Under protection, a double-bonding reagent is dripped, stirring and reacting are carried out in ice bath for 0.5-12h, petroleum ether is added, and lower-layer substances are collected to obtain the double-bonded hydrophilic and hydrophobic fragment polymer.
14. The method according to claim 13, wherein the mass of the double-bonding agent is 5-50% of the mass of the hydrophilic-hydrophobic segment polymer.
15. The method according to claim 13, wherein the double-bonding agent is acryloyl chloride and/or methacrylic anhydride.
16. The method according to claim 1, wherein the inorganic material is any one of or a mixture of at least two of nano hydroxyapatite, nano black phosphorus, nano clay and bioceramic.
17. The method of claim 1, wherein the processing aid comprises a photoinitiator and/or a free radical provider.
18. The method of claim 17, wherein the photoinitiator is 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone and/or 2-hydroxy-2-methyl-1-phenyl-1-propanone.
19. The method of claim 17, wherein the radical generator is benzoyl peroxide and/or N, N-dimethyl-p-toluidine.
20. The method according to claim 1, wherein in step 3), the polymerization is accelerated by ultrasonic or thermal means.
21. The method of claim 17, wherein the processing aid, when containing a photoinitiator, is polymerized by 1 to 5J of uv light for 80 to 100 seconds.
22. A bone regeneration promoting composite obtained by the production method according to any one of claims 1 to 21.
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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN101954119A (en) * 2010-09-10 2011-01-26 北京化工大学 Method for preparing light-cured bone repair material from double bond-containing siloxane coated and modified hydroxyapatite
CN105504251A (en) * 2015-12-17 2016-04-20 西安交通大学 Degradable silica-based hybrid polymer biomedical elastomer and preparation method thereof
CN108530851A (en) * 2017-03-02 2018-09-14 中国科学院化学研究所 A kind of bioactive composite material and its preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101954119A (en) * 2010-09-10 2011-01-26 北京化工大学 Method for preparing light-cured bone repair material from double bond-containing siloxane coated and modified hydroxyapatite
CN105504251A (en) * 2015-12-17 2016-04-20 西安交通大学 Degradable silica-based hybrid polymer biomedical elastomer and preparation method thereof
CN108530851A (en) * 2017-03-02 2018-09-14 中国科学院化学研究所 A kind of bioactive composite material and its preparation method and application

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