阅读说明：本技术 一种温度与模量双控型纳米羟基磷灰石聚氨基酸复合骨移植材料及其制备方法 (Temperature and modulus dual-control type nano hydroxyapatite and polyamino acid composite bone graft material and preparation method thereof ) 是由 严永刚 邓光进 戢觅之 于 2018-12-17 设计创作，主要内容包括：本发明公开了一种温度与模量双控型纳米羟基磷灰石聚氨基酸复合骨移植材料,它是由聚氨基酸与纳米羟基磷灰石原位复合而成,结构如式Ⅰ所示。本发明还提供了该复合骨移植材料的制备方法和应用。本发明制备的具有仿生结构的温度与模量双控型纳米羟基磷灰石聚氨基酸复合骨移植材料：力学性能与人骨接近；具有可调控的变形温度和弹性模量；易于进行二次塑型,便于临床使用中根据患者需求即时调整材料形状,也可快速注塑成型；具有良好的生物活性、生物相容性和生物安全性；可根据不同的临床需求选择适宜的热变形温度和力学性能,临床上适用于骨修复重建的支撑以及一些复杂不规则创伤即时塑型的支撑修复。<Image he="383" wi="700" file="DDA0001908857200000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(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.)

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:

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:

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:

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:

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:

10. use of the polyamino acid of claim 8 or 9 for the preparation of bone graft material.

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:

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:

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:

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:

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:

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