CN110639062A - Temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material and preparation method thereof - Google Patents

Temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material and preparation method thereof Download PDF

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CN110639062A
CN110639062A CN201811543830.3A CN201811543830A CN110639062A CN 110639062 A CN110639062 A CN 110639062A CN 201811543830 A CN201811543830 A CN 201811543830A CN 110639062 A CN110639062 A CN 110639062A
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严永刚
邓光进
戢觅之
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Zhongding Kairui Technology Chengdu Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention discloses a temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material, which is prepared by compounding polyamino acid and nano hydroxyapatite in situ, and has a structure shown as a formula I. The invention also provides a preparation method and application of the composite bone graft material. The temperature and modulus double-control type nano hydroxyapatite and polyamino acid composite bone graft material with a bionic structure prepared by the invention comprises the following components in percentage by weight: the mechanical property is close to that of human bones; the adjustable deformation temperature and the elastic modulus are provided; easy to carry out secondary molding and convenient toThe shape of the material can be adjusted in real time according to the requirements of patients in clinical use, and the material can also be quickly injection molded; has good biological activity, biocompatibility and biological safety; the method can select proper thermal deformation temperature and mechanical property according to different clinical requirements, and is clinically suitable for the support of bone repair and reconstruction and the support repair of instant molding of some complicated irregular wounds.

Description

Temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material and preparation method thereof
Technical Field
The invention relates to a medical composite material capable of being used for load-bearing bone repair and reconstruction, in particular to a temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material and a preparation method thereof.
Background
The main components of human bone tissue include water, organic substances, inorganic salts, etc., and the content of water in the bone is small compared to other tissues and organs. Of the remaining solid materials, about 40% is organic matter (collagen) and 60% is inorganic salt (apatite), and the bone tissue can be regarded as a composite material composed of organic matter and inorganic salt. The inorganic salts in the bone are mainly crystalline hydroxyapatite, amorphous calcium phosphate and the like, and the inorganic salt components determine the hardness of the bone. Most of organic substances are collagen, and the rest are other protein peptides and lipids such as glycosamine, glycan and the like, and the organic substances determine the elasticity and toughness of bones. Typically, the bone is in concentric layers around the blood vessels, and the bone layer surrounding a single blood vessel is the lamina. In most regions, all collagen fibers are parallel, but the orientation of each layer of fibers is different. In successive layers, the fibers may change from longitudinal to circumferential or left to right spiral. The thickness of each layer is not necessarily equal, and it may be predominantly longitudinal fibers or predominantly circumferential fibers. The special structure enables the skeleton to have better mechanical properties such as tensile property, compressive property and the like. The hydroxyapatite crystals are arranged along the long axis direction of the collagen fiber, and the hydroxyapatite crystals in the collagen have proved to effectively reinforce the collagen. The above structure and composition of the bone ensures that it can impart mechanical stability to the human body to protect delicate organs, and can act as an attachment for muscles to move the body. In life, people often cause bone defects due to diseases or accidental injuries, so that the body is seriously injured, and the life quality is influenced.
The traditional bone repair materials such as ceramics, metals and the like often cause the problems of stress shielding, repair material loosening, bone tissue abrasion, necrosis, separation and the like due to the fact that the mechanical strength, hardness, rigidity and elastic modulus of the traditional bone repair materials are far away from those of bone tissues.
The biomedical composite material not only has the properties and advantages of each component material, but also can obtain new characteristics which are not possessed by single-component materials. Among many bone repair composite materials, the nano-hydroxyapatite/polymer composite material simulates the composition or structure of natural bone inorganic-organic phase, and is widely researched due to the combination of the bioactivity of the hydroxyapatite and the toughness of the polymer. The amino acid polymer-hydroxyapatite repair material in the prior art has excellent mechanical properties, but is difficult to remold after the material is formed.
In the course of therapeutic bone repair, however, bone defects are often irregular in shape, such as skull defects. The bone repair material is convenient for secondary molding, and the shape can be adjusted in real time according to the shape of the bone defect in the treatment process, so that the requirements of patients are met. Therefore, the research on the bone repair material which can meet the mechanical requirements of bones and is convenient for secondary processing is of great significance.
According to the invention, two major types of amino acids (straight-chain amino acid is used as backbone; active trifunctional amino acid is used for regulating chain structure) are selected according to the thermodynamic properties of the polyamino acid, the corresponding polyamino acid is obtained through melt polycondensation, aromatic binary or multielement active compounds are utilized to link the molecular chains (disulfide bond coupling in bionic protein), and nano hydroxyapatite and the polyamino acid are compounded in situ at the later stage to form the temperature and modulus dual-control type nano hydroxyapatite polyamino acid composite bone graft material with a bionic structure. On one hand, in the composite material, the amino acid polymer matrix is connected by peptide bonds and is very similar to the molecular structure of human collagen; and the bone mineral contains polar amido bond and carboxyl, has good hydrophilicity, can guide the growth of tissue cells, promote the formation of osteophyte by cells to mineralize, and accelerate the healing of bone wounds. On the other hand, the addition of the nano hydroxyapatite can increase the hardness of the material, improve the biological activity and facilitate quick osteogenesis.
Disclosure of Invention
The invention aims to provide a temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material and a preparation method thereof.
The invention provides a temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material, which is prepared by compounding polyamino acid and nano hydroxyapatite in situ, and has the structure shown as the formula I:
Figure BDA0001908857190000021
wherein, the polyamino acid is formed by linking polyamino acid molecular chains through a compound Z;
the molecular weight of the polyamino acid is 2-8 ten thousand, and 3-5 ten thousand is preferred;
the polyamino acid molecular chain is formed by polymerizing straight-chain amino acid and trifunctional amino acid;
the compound Z is an aromatic binary or multi-element active compound;
m in the straight-chain amino acid is 1-11;
the trifunctional amino acid is an amino acid with an active side group R1With inert or carboxylic acid side groups R2The amino acid of (1);
said group having a reactive side group R1With inert or carboxylic acid side groups R2Respectively is n1、n2And n3，n20.70 to 0.99; n is1+n3＝0.01～0.30；
The content of the nano hydroxyapatite is 15-65% of the total weight of the composite bone graft material;
the hydroxyl in the nano hydroxyapatite can be partially or completely substituted by CO3 2-And/or F-And (4) substitution.
Further, the linear amino acid is one or more of glycine (m ═ 1), β -alanine (m ═ 2), γ -aminobutyric acid (m ═ 3), δ -aminopentanoic acid (m ═ 4), ═ aminocaproic acid (m ═ 5), ζ -aminoheptanoic acid (m ═ 6), η -aminocaprylic acid (m ═ 7), θ -aminononanoic acid (m ═ 8), iota-aminodecanoic acid (m ═ 9), κ -aminoundecanoic acid (m ═ 10), and λ -aminododecanoic acid (m ═ 11);
said group having a reactive side group R1The amino acid of (a) is one or more of hydroxyproline, lysine, threonine, histidine, arginine and tryptophan;
said having inert or carboxylic acid side groups R2The amino acid of (a) is one or more of glutamic acid, aspartic acid, alanine, phenylalanine, valine, leucine and isoleucine.
Further, the mole fraction of the compound Z is provided with a reactive side group R1Amino acid (n) of (a)1) 5-50% of the total;
wherein the compound Z is one or more of the following compounds:
further, the thermal deformation temperature range of the composite bone graft material is 50-120 ℃, and the melting point is 160-220 ℃; the bending strength is 80-150 MPa, the bending modulus is 5-15 GPa, the compression strength is 100-180 MPa, and the compression modulus is 6-20 GPa.
The invention also provides a method for preparing the composite bone graft material, which comprises the following steps:
(1) a first reaction stage: mixing the straight-chain amino acid and the trifunctional amino acid, gradually heating to 180-210 ℃ under the protection of nitrogen, preserving heat at 210 ℃ for 1-5 h, gradually heating to 215-250 ℃, preserving heat at the temperature interval for 0.5-3.5 h, and obtaining a structure shown in a formula II:
Figure BDA0001908857190000041
wherein the mole fractions of the straight-chain amino acid and the trifunctional amino acid are 0.70-0.99 and 0.01-0.30 respectively;
(2) and a second reaction stage: after the first reaction stage is finished, adding a compound Z, and reacting for 15-60 min at 215-250 ℃ to obtain a structure shown in a formula III:
Figure BDA0001908857190000042
wherein the mole fraction of the compound Z is 5-50% of amino acid (n1) with an active side group R1;
(3) a third reaction stage: after the second reaction stage is finished, gradually adding nano hydroxyapatite, reacting for 1-3 hours at 220-250 ℃ to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain the structure shown in the formula I;
wherein the content of the nano hydroxyapatite is 15-65% of the total weight of the composite bone graft material.
The invention also provides application of the bone grafting material in preparing orthopedic related medical instruments.
Furthermore, the medical apparatus related to the orthopedics department is a cervical vertebra fusion device, a thoracolumbar vertebra fusion device, a vertebral body, a vertebral plate and an irregular bone wound support body.
The invention also provides a polyamino acid with controllable temperature and modulus, which is formed by linking polyamino acid molecular chains through a compound Z, and the structure is shown as the formula III:
Figure BDA0001908857190000051
wherein the molecular weight of the polyamino acid is 2-8 ten thousand, preferably 3-5 ten thousand;
the polyamino acid molecular chain is formed by polymerizing straight-chain amino acid and trifunctional amino acid;
the compound Z is an aromatic binary or multi-element active compound;
m in the straight-chain amino acid is 1-11;
the trifunctional amino acid is an amino acid with an active side group R1With inert or carboxylic acid side groups R2The amino acid of (1);
said group having a reactive side group R1With inert or carboxylic acid side groups R2Respectively is n1、n2And n3，n20.70 to 0.99; n is1+n3＝0.01～0.30；
The straight-chain amino acid is one or more of glycine (m ═ 1), β -alanine (m ═ 2), γ -aminobutyric acid (m ═ 3), δ -aminopentanoic acid (m ═ 4), ═ aminocaproic acid (m ═ 5), ζ -aminoheptanoic acid (m ═ 6), η -aminocaprylic acid (m ═ 7), θ -aminononanoic acid (m ═ 8), ι -aminodecanoic acid (m ═ 9), κ -aminoundecanoic acid (m ═ 10), and λ -aminododecanoic acid (m ═ 11);
said group having a reactive side group R1The amino acid of (a) is one or more of hydroxyproline, lysine, threonine, histidine, arginine and tryptophan;
said having inert or carboxylic acid side groups R2The amino acid of (a) is one or more of glutamic acid, aspartic acid, alanine, phenylalanine, valine, leucine and isoleucine.
Further, the mole fraction of the compound Z is provided with a reactive side group R1Amino acid (n) of (a)1) 5-50% of the total;
wherein the compound Z is one or more of the following compounds:
Figure BDA0001908857190000052
Figure BDA0001908857190000061
the invention also provides application of the polyamino acid in preparation of bone graft materials.
The temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material prepared by the invention has the heat distortion temperature range of 50-120 ℃ and the melting point of 160-220 ℃; the bending strength is 80-150 MPa, the bending modulus is 5-15 GPa, the compression strength is 100-180 MPa, the compression modulus is 6-20 GPa, and the biomechanical property of the material is close to that of human bone tissues. Meanwhile, the cytotoxicity is less than or equal to grade 1, and the composition is non-toxic and non-irritant; has good biological activity, biocompatibility and biological safety.
In conclusion, the temperature and modulus double-control type nano hydroxyapatite and polyamino acid composite bone graft material with a bionic structure prepared by the invention has the following advantages: the mechanical property is close to that of human bones; the adjustable deformation temperature and the elastic modulus are provided; the secondary molding is easy to carry out, the shape of the material can be adjusted in real time according to the requirements of patients in clinical use, and the injection molding can be carried out quickly; has good biological activity, biocompatibility and biological safety; the method can select proper thermal deformation temperature and mechanical property according to different clinical requirements, and is clinically suitable for the support of bone repair and reconstruction and the support repair of instant molding of some complicated irregular wounds.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
Example 1 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
116.16g of zeta-aminoheptanoic acid, 13.1g of hydroxyproline, 5.85g of lysine and 9.91g of phenylalanine are respectively weighed and put into a 250mL three-necked bottle, 50mL of distilled water is added, nitrogen is introduced for protection, stirring is carried out, and the temperature is increased to 180 ℃ for dehydration (whether dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is(m-6, zeta-aminoheptanoic acid) with a reactive side group R1The amino acid of (A) is
Figure BDA0001908857190000072
(hydroxyproline) and
Figure BDA0001908857190000073
(lysine) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000074
(phenylalanine).
Then under the protection of nitrogen, 4g of terephthaloyl chloride is added, and polymerization reaction is carried out for 1h at 220 ℃ to complete the second stage reaction, so as to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000075
(terephthaloyl chloride).
Under the protection of nitrogen at the temperature, gradually adding 55g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 180g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 150MPa, the bending strength is 110MPa, and the bending modulus is 7.5GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature (heat distortion temperature) was 82 ℃ and the melting point was 181 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 55.1g, accounting for 31% of the composite.
Example 2 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
Respectively weighing 117.9g of epsilon-aminocaproic acid, 6.55g of hydroxyproline and 8.26g of phenylalanine, putting the materials into a 250mL three-necked bottle, adding 50mL of distilled water, introducing nitrogen for protection, stirring, heating to 180 ℃ for dehydration (whether the dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is
Figure BDA0001908857190000081
(m ═ 5, epsilon-aminocaproic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000082
(hydroxyproline) with inert or carboxylic acid side groups R2The amino acid of (A) is(phenylalanine).
Then under the protection of nitrogen, adding 2g of terephthaloyl chloride, and carrying out polymerization reaction for 1h at 220 ℃ to complete the second-stage reaction to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000084
(terephthaloyl chloride).
Under the protection of nitrogen at the temperature, gradually adding 60g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 175g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 135MPa, the bending strength is 105MPa, and the bending modulus is 6.5GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 85 ℃ and the melting point was 187 ℃. By firing at 800 ℃ for 6 hours, the residual amount of hydroxyapatite was 59.5g, accounting for 35% of the composite.
Example 3 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
Respectively weighing 117.9g of epsilon-aminocaproic acid, 5.85g of lysine and 9.91g of phenylalanine, putting the mixture into a 250mL three-necked bottle, adding 50mL of distilled water, introducing nitrogen for protection, stirring, and heating to 180 ℃ for dehydration (whether dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is(m ═ 5, epsilon-aminocaproic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000094
(lysine) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000095
(phenylalanine).
Then under the protection of nitrogen, 2g of pyromellitic dianhydride is added, and the polymerization reaction is carried out for 1h at 220 ℃ to complete the second stage reaction, so as to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000096
(s-benzene)Tetracarboxylic dianhydride).
Under the protection of nitrogen at the temperature, gradually adding 80g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 198g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 155MPa, the bending strength of the mechanical spline is 1125MPa, and the bending modulus of the mechanical spline is 8GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 87 ℃ and the melting point was 191 ℃. By firing at 800 ℃ for 6 hours, the residual amount of hydroxyapatite was 79.5g, which accounted for 40% of the composite.
Example 4 preparation of the Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
43.56g of zeta-aminoheptanoic acid, 78.66g of epsilon-aminocaproic acid, 6.55g of hydroxyproline, 2.92g of lysine and 4.96g of phenylalanine are respectively weighed and placed into a 250mL three-necked bottle, 50mL of distilled water is added, nitrogen is introduced for protection, stirring is carried out, and the temperature is increased to 180 ℃ for dehydration (whether dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is(m ═ 6, ζ -aminoheptanoic acid) and
Figure BDA0001908857190000092
(m ═ 5, epsilon-aminocaproic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000091
(hydroxyproline) and
Figure BDA0001908857190000101
(lysine) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000102
(phenylalanine).
Then under the protection of nitrogen, 4g of terephthaloyl chloride is added, and polymerization reaction is carried out for 1h at 220 ℃ to complete the second stage reaction, so as to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000103
(terephthaloyl chloride).
Under the protection of nitrogen at the temperature, gradually adding 90g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 208g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 155MPa, the bending strength is 135MPa, and the bending modulus is 10GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 85 ℃ and the melting point was 188 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 89g, representing 43% of the composite.
Example 5 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
Weighing 5.32g of aspartic acid, putting the aspartic acid into a 250mL three-necked bottle, adding 50mL of distilled water, heating to 80 ℃ under the protection of nitrogen, then adding 2.28g of basic zinc carbonate, adding 117.9g of epsilon-aminocaproic acid, 3.93g of hydroxyproline and 4.96g of phenylalanine after fifteen minutes, supplementing 25mL of distilled water, stirring, heating to 180 ℃ and dehydrating (whether the dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is
Figure BDA0001908857190000112
(m ═ 5, epsilon-aminocaproic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000113
(hydroxyproline) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000114
(phenylalanine) and
Figure BDA0001908857190000111
(Zinc aspartate).
Then under the protection of nitrogen, adding 2g of terephthaloyl chloride, and carrying out polymerization reaction for 1h at 220 ℃ to complete the second-stage reaction to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000115
(terephthaloyl chloride).
And adding 75g of dried nano-hydroxyapatite under the protection of nitrogen at the temperature, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 192g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 136MPa, the bending strength is 115MPa, and the bending modulus is 8GPa, and is close to that of dense bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 87 ℃ and the melting point was 185 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 75.1g, which accounted for 39% of the composite. The zinc ion concentration in the solution is 120ppm and the trace element zinc necessary for human body can be provided when the zinc ion is soaked in the simulated body fluid for a week.
Example 6 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
152.5g of theta-aminononanoic acid, 6.55g of hydroxyproline, 5.85g of lysine and 3.3g of phenylalanine are respectively weighed and put into a 250mL three-necked bottle, 50mL of distilled water is added, nitrogen is introduced for protection, stirring is carried out, and the temperature is raised to 180 ℃ for dehydration (whether the dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is
Figure BDA0001908857190000121
(m-8, theta-aminononanoic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000122
(hydroxyproline) and
Figure BDA0001908857190000123
(lysine) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000124
(phenylalanine).
Then under the protection of nitrogen, 4g of terephthaloyl chloride is added, and polymerization reaction is carried out for 1h at 220 ℃ to complete the second stage reaction, so as to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000125
(terephthaloyl chloride).
Under the protection of nitrogen at the temperature, gradually adding 80g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 230g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 135MPa, the bending strength is 110MPa, and the bending modulus is 7.8GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 78 ℃ and the melting point was 179 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 79.5g, accounting for 35% of the composite.
Example 7 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
43.56g of zeta-aminoheptanoic acid, 78.66g of epsilon-aminocaproic acid, 6.55g of hydroxyproline, 2.92g of lysine and 4.96g of phenylalanine are respectively weighed and placed into a 250mL three-necked bottle, 50mL of distilled water is added, nitrogen is introduced for protection, stirring is carried out, and the temperature is increased to 180 ℃ for dehydration (whether dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is(m ═ 6, ζ -aminoheptanoic acid) and
Figure BDA0001908857190000127
(m-5, epsilon-ammonia)Aminocaproic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000128
(hydroxyproline) and
Figure BDA0001908857190000131
(lysine) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000132
(phenylalanine).
Then under the protection of nitrogen, adding 2.8g of 4,4' -biphenyl diformyl chloride, and carrying out polymerization reaction for 1h at 220 ℃ to complete the second stage reaction to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000133
(4,4' -biphenyldicarbonyl chloride).
And under the protection of nitrogen at the temperature, gradually adding 75g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 193g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 145MPa, the bending strength is 133MPa, and the bending modulus is 12GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 91 ℃ and the melting point was 187 ℃. By firing at 800 ℃ for 6 hours, the residual amount of hydroxyapatite was 76g, which accounted for 39% of the composite.
Example 8 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
Weighing 5.32g of aspartic acid, putting the aspartic acid into a 250mL three-necked bottle, adding 50mL of distilled water, heating to 80 ℃ under the protection of nitrogen, then adding 2.28g of basic zinc carbonate, adding 117.9g of epsilon-aminocaproic acid, 3.93g of hydroxyproline and 4.96g of phenylalanine after fifteen minutes, supplementing 25mL of distilled water, stirring, heating to 180 ℃ and dehydrating (whether the dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is
Figure BDA0001908857190000142
(m ═ 5, epsilon-aminocaproic acid) with reactive side groups R1The amino acid of (A) is
Figure BDA0001908857190000143
(hydroxyproline) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000144
(phenylalanine) and
Figure BDA0001908857190000141
(Zinc aspartate).
Then under the protection of nitrogen, adding 2.95g of 2,3,3',4' -biphenyl tetracarboxylic dianhydride, and carrying out polymerization reaction for 1h at 220 ℃ to complete the second stage reaction, thus obtaining the polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000145
(2,3,3',4' -biphenyltetracarboxylic dianhydride).
And adding 75g of dried nano-hydroxyapatite under the protection of nitrogen at the temperature, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 195g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 133MPa, the bending strength is 120MPa, and the bending modulus is 8GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 85 ℃ and the melting point was 182 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 75.1g, accounting for 38% of the composite. The zinc ion concentration in the solution is 110ppm and the trace element zinc necessary for human body can be provided when the zinc ion is soaked in the simulated body fluid for a week.
Example 9 preparation of a Nano-hydroxyapatite polyamino acid composite bone graft Material of the present invention
116.16g of zeta-aminoheptanoic acid, 13.1g of hydroxyproline, 5.85g of lysine and 9.91g of phenylalanine are respectively weighed and put into a 250mL three-necked bottle, 50mL of distilled water is added, nitrogen is introduced for protection, stirring is carried out, and the temperature is increased to 180 ℃ for dehydration (whether dehydration treatment is finished can be judged by observing whether the amino acid starts to melt or not). After the dehydration is finished, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, then continuously heating to 220 ℃ for carrying out polymerization reaction for 3h, and finishing the first-stage reaction to obtain a polyamino acid molecular chain shown as the formula II;
the linear amino acid in the reaction is
Figure BDA0001908857190000151
(m-6, zeta-aminoheptanoic acid) with a reactive side group R1The amino acid of (A) is
Figure BDA0001908857190000152
(hydroxyproline) and
Figure BDA0001908857190000153
(lysine) with inert or carboxylic acid side groups R2The amino acid of (A) is
Figure BDA0001908857190000154
(phenylalanine).
Then under the protection of nitrogen, 4g of terephthaloyl chloride is added, and polymerization reaction is carried out for 1h at 220 ℃ to complete the second stage reaction, so as to obtain polyamino acid shown as the formula III;
wherein Z is
Figure BDA0001908857190000155
(terephthaloyl chloride).
Under the protection of nitrogen at the temperature, gradually adding 55g of dried nano-hydroxyapatite, keeping the temperature at 220 ℃, slowly stirring for 1h under the protection of nitrogen to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain 180g of the temperature and modulus dual-control type nano-hydroxyapatite polyamino acid composite bone graft material shown in the formula I.
Crushing the temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical spline, wherein the compressive strength of the mechanical spline is 150MPa, the bending strength is 110MPa, and the bending modulus is 7.5GPa, and is close to that of compact bones of a human body; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 82 ℃ and the melting point was 181 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 55.1g, accounting for 31% of the composite.
Comparative example 1 preparation of Nano hydroxyapatite polyamino acid composite bone graft Material
Weighing 131g of epsilon-aminocaproic acid, putting the epsilon-aminocaproic acid into a 250mL three-necked bottle, adding 50mL of distilled water, introducing nitrogen for protection, stirring, heating to 180 ℃ for dehydration, raising the temperature to 202 ℃ until all water is removed, continuously heating to 210 ℃, carrying out prepolymerization for 1h in a molten state, and then continuously heating to 220 ℃ for carrying out polymerization for 4 h.
At the temperature and under the protection of nitrogen, 50g of dried nano-hydroxyapatite is added, the temperature is kept at 220 ℃, the mixture is slowly stirred for 1 hour under the protection of nitrogen, a reaction product is obtained, the reaction product is molded under the protection of nitrogen, and the mixture is cooled to room temperature, so that 162g of the composite bone graft material is obtained.
Crushing the composite bone graft material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical sample strip, wherein the compressive strength is 90MPa, the bending strength is 75MPa, and the bending modulus is 5 GPa; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 82 ℃ and the melting point was 201 ℃. By firing at 800 ℃ for 6h, the residual amount of hydroxyapatite was 55.1g, which accounted for 3% of the composite.
The polymer in the composite material is PA6, the activity is poor, and the strength and the modulus of the composite material are not matched with those of compact bones of a human body after hydroxyapatite is added.
Comparative example 2 preparation of Nano hydroxyapatite polyamino acid composite bone graft Material
Placing 105.25g, 4.45g, 4.95g, 4.6g, 5g and 3g of epsilon-aminocaproic acid, alanine, phenylalanine, proline, hydroxyproline and lysine into a 250mL three-necked bottle, adding 50mL of distilled water, heating to 200 ℃ under electric stirring, introducing nitrogen for protection, continuously heating to 210 ℃ after dehydration to melt, heating to 220 ℃, carrying out polymerization reaction for 2 hours, adding 47g of calcium-phosphorus ceramic, and continuously reacting at 220 ℃ for 2 hours, wherein the reaction time can be prolonged or shortened according to the actual reaction condition, so that the amino acid polymer ceramic composite material with the inorganic matter content of 30% is obtained.
Crushing the amino acid polymer ceramic composite material into granules with the granularity of 5-10 meshes, and performing extrusion molding by using a Haake rheometer to prepare a mechanical sample strip, wherein the compressive strength is 80MPa, the bending strength is 65MPa, and the bending modulus is 3 GPa; the glass transition temperature and the melting point were measured by DSC, and the glass transition temperature was 65 ℃ and the melting point was 177 ℃.
Although the material contains a plurality of amino acids, the main chain structure is disordered, chemical bonds cannot be formed among molecular chains, the flexibility is too high, the deformability is too large, and the material is not suitable for load-bearing bone repair.
The temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material prepared by the invention has the heat distortion temperature range of 50-120 ℃ and the melting point of 160-220 ℃; the bending strength is 80-150 MPa, the bending modulus is 5-15 GPa, the compression strength is 100-180 MPa, the compression modulus is 6-20 GPa, and the biomechanical property of the material is close to that of human bone tissues. Meanwhile, the cytotoxicity is less than or equal to grade 1, and the composition is non-toxic and non-irritant; has good biological activity, biocompatibility and biological safety.
In conclusion, the temperature and modulus double-control type nano hydroxyapatite and polyamino acid composite bone graft material with a bionic structure prepared by the invention has the following advantages: the mechanical property is close to that of human bones; the adjustable deformation temperature and the elastic modulus are provided; the secondary molding is easy to carry out, the shape of the material can be adjusted in real time according to the requirements of patients in clinical use, and the injection molding can be carried out quickly; has good biological activity, biocompatibility and biological safety; the method can select proper thermal deformation temperature and mechanical property according to different clinical requirements, and is clinically suitable for the support of bone repair and reconstruction and the support repair of instant molding of some complicated irregular wounds.

Claims (10)

1. A temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material is characterized in that: the compound is prepared by compounding polyamino acid and nano hydroxyapatite in situ, and the structure is shown as formula I:
wherein, the polyamino acid is formed by linking polyamino acid molecular chains through a compound Z;
the molecular weight of the polyamino acid is 2-8 ten thousand, and 3-5 ten thousand is preferred;
the polyamino acid molecular chain is formed by polymerizing straight-chain amino acid and trifunctional amino acid;
the compound Z is an aromatic binary or multi-element active compound;
m in the straight-chain amino acid is 1-11;
the trifunctional amino acid is an amino acid with an active side group R1With inert or carboxylic acid side groups R2The amino acid of (1);
said group having a reactive side group R1With inert or carboxylic acid side groups R2Respectively is n1、n2And n3，n20.70 to 0.99; n is1+n3＝0.01～0.30；
The content of the nano hydroxyapatite is 15-65% of the total weight of the composite bone graft material;
the hydroxyl in the nano hydroxyapatite can be partially or completely substituted by CO3 2-And/or F-And (4) substitution.
2. The composite bone graft material of claim 1, wherein: the straight-chain amino acid is one or more of glycine (m ═ 1), β -alanine (m ═ 2), γ -aminobutyric acid (m ═ 3), δ -aminopentanoic acid (m ═ 4), ═ aminocaproic acid (m ═ 5), ζ -aminoheptanoic acid (m ═ 6), η -aminocaprylic acid (m ═ 7), θ -aminononanoic acid (m ═ 8), ι -aminodecanoic acid (m ═ 9), κ -aminoundecanoic acid (m ═ 10), and λ -aminododecanoic acid (m ═ 11);
said group having a reactive side group R1The amino acid of (a) is one or more of hydroxyproline, lysine, threonine, histidine, arginine and tryptophan;
said having inert or carboxylic acid side groups R2The amino acid of (a) is one or more of glutamic acid, aspartic acid, alanine, phenylalanine, valine, leucine and isoleucine.
3. The composite bone graft material of claim 1, wherein: the mole fraction of the compound Z is provided with a reactive side group R1Amino acid (n) of (a)1) 5-50% of the total;
wherein the compound Z is one or more of the following compounds:
Figure FDA0001908857180000021
4. the composite bone graft material according to any one of claims 1 to 3, wherein: the thermal deformation temperature range of the composite bone grafting material is 50-120 ℃, and the melting point is 160-220 ℃; the bending strength is 80-150 MPa, the bending modulus is 5-15 GPa, the compression strength is 100-180 MPa, and the compression modulus is 6-20 GPa.
5. A method for preparing the composite bone graft material according to any one of claims 1 to 4, wherein: it comprises the following steps:
(1) a first reaction stage: mixing the straight-chain amino acid and the trifunctional amino acid, gradually heating to 180-210 ℃ under the protection of nitrogen, preserving heat at 210 ℃ for 1-5 h, gradually heating to 215-250 ℃, preserving heat at the temperature interval for 0.5-3.5 h, and obtaining a structure shown in a formula II:
Figure FDA0001908857180000022
wherein the mole fractions of the straight-chain amino acid and the trifunctional amino acid are 0.70-0.99 and 0.01-0.30 respectively;
(2) and a second reaction stage: after the first reaction stage is finished, adding a compound Z, and reacting for 15-60 min at 215-250 ℃ to obtain a structure shown in a formula III:
Figure FDA0001908857180000031
wherein the mole fraction of the compound Z is 5-50% of amino acid (n1) with an active side group R1;
(3) a third reaction stage: after the second reaction stage is finished, gradually adding nano hydroxyapatite, reacting for 1-3 hours at 220-250 ℃ to obtain a reaction product, forming the reaction product under the protection of nitrogen, and cooling to room temperature to obtain the structure shown in the formula I in claim 1;
wherein the content of the nano hydroxyapatite is 15-65% of the total weight of the composite bone graft material.
6. Use of the bone graft material according to any one of claims 1 to 4 in the preparation of an orthopaedic-related medical device.
7. Use according to claim 6, characterized in that: the orthopedic related medical apparatus is a cervical vertebra fusion device, a thoracolumbar vertebra fusion device, a vertebral body, a vertebral plate and an irregular bone wound support body.
8. A temperature and modulus controllable polyamino acid, wherein: the compound is formed by linking polyamino acid molecular chains through a compound Z, and the structure is shown as a formula III:
Figure FDA0001908857180000032
wherein the molecular weight of the polyamino acid is 2-8 ten thousand, preferably 3-5 ten thousand;
the polyamino acid molecular chain is formed by polymerizing straight-chain amino acid and trifunctional amino acid;
the compound Z is an aromatic binary or multi-element active compound;
m in the straight-chain amino acid is 1-11;
the trifunctional amino acid is an amino acid with an active side group R1With inert or carboxylic acid side groups R2The amino acid of (1);
said group having a reactive side group R1With inert or carboxylic acid side groups R2Respectively is n1、n2And n3，n20.70 to 0.99; n is1+n3＝0.01～0.30；
The straight-chain amino acid is one or more of glycine (m ═ 1), β -alanine (m ═ 2), γ -aminobutyric acid (m ═ 3), δ -aminopentanoic acid (m ═ 4), ═ aminocaproic acid (m ═ 5), ζ -aminoheptanoic acid (m ═ 6), η -aminocaprylic acid (m ═ 7), θ -aminononanoic acid (m ═ 8), ι -aminodecanoic acid (m ═ 9), κ -aminoundecanoic acid (m ═ 10), and λ -aminododecanoic acid (m ═ 11);
said group having a reactive side group R1The amino acid of (a) is one or more of hydroxyproline, lysine, threonine, histidine, arginine and tryptophan;
said having inert or carboxylic acid side groups R2The amino acid is glutamic acid, aspartic acid, alanine, phenylalanine, valineOne or more of an acid, leucine, and isoleucine.
9. The polyamino acid of claim 8, wherein: the mole fraction of the compound Z is provided with a reactive side group R1Amino acid (n) of (a)1) 5-50% of the total;
wherein the compound Z is one or more of the following compounds:
Figure FDA0001908857180000041
10. use of the polyamino acid of claim 8 or 9 for the preparation of bone graft material.
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