CN110801537A

CN110801537A - Plastic artificial bone composite material and preparation method thereof

Info

Publication number: CN110801537A
Application number: CN201910820129.XA
Authority: CN
Inventors: 孙杨; 向冬; 凡小山; 赵金忠; 蒋佳; 燕晓宇; 王立人
Original assignee: Shenzhen City Heart Science Co Ltd; Shanghai Sixth Peoples Hospital
Current assignee: Lixin (Shenzhen) Medical Devices Co.,Ltd.
Priority date: 2019-08-31
Filing date: 2019-08-31
Publication date: 2020-02-18
Anticipated expiration: 2039-08-31
Also published as: CN113041400B; CN110801537B; CN113289065A; CN113289065B; CN113041400A

Abstract

The invention provides a plastic artificial bone composite material and a preparation method thereof, which are characterized in that the material is a composition formed by mixing a degradable polymer material and inorganic particles distributed in the polymer material, the average molecular weight of the polymer material is 1000Da to 20000Da, the inorganic particles are composed of calcium-phosphorus compounds, and the artificial bone composite material is in a plastic plasticine shape. According to the present disclosure, a moldable artificial bone composite capable of both free molding and free injection and a method for preparing the same can be provided.

Description

Plastic artificial bone composite material and preparation method thereof

Technical Field

The disclosure belongs to the field of biomedical composite materials, and particularly relates to a plastic artificial bone composite material and a preparation method thereof.

Background

Bone defects are a common disease, and various factors such as trauma, inflammation, bone diseases, operation and the like can cause bone tissue defects. At present, the bone defect is repaired by artificial bone materials and the like, and the artificial bone materials usually contain hydroxyapatite and other main inorganic components which form human bones.

Patent document 1 proposes an injectable artificial bone suspension prepared by mixing hydroxyapatite, recombinant human bone morphogenetic protein-2, chitosan solution and heparin saline to form a suspension, and a method for preparing the same, which has a disadvantage in that hydroxyapatite particles are easily precipitated in a liquid during storage, resulting in uneven dispersion of hydroxyapatite. In addition, prior patent document 2 proposes an artificial bone made of a collagen/hydroxyapatite composite material, which is degradable and absorbable in vivo.

However, the artificial bone material of patent document 1 is easily broken when injected in a clinical aqueous environment operation because it needs to be fluidized by water, and thus cannot be used normally, while the material of patent document 2 is in the form of a massive hard solid, and cannot be freely plasticized flexibly and conveniently, so that it is inconvenient to use in an operation, and it is not easy to fill a bone defect, and a large number of voids remain, which affects bone growth. Therefore, there is a need for an artificial bone repair material that can be shaped and injected to meet the requirements of different shaped fills and can be used in clinical minimally invasive procedures in an aqueous environment.

[ Prior art documents ]

[ patent document ]

Patent document 1: chinese granted patent zl02134874.x

Patent document 2: chinese granted patent ZL201610987810.X

Disclosure of Invention

The present disclosure has been made in view of the above-mentioned state of the art, and an object thereof is to provide a moldable artificial bone composite material capable of being freely molded and injected, and a method for preparing the same.

To this end, the present disclosure provides a shapeable artificial bone composite, which is a composition mixed by a degradable polymer material having an average molecular weight of 1000Da to 20000Da, and inorganic particles distributed in the polymer material, the inorganic particles being composed of a calcium-phosphorus compound, and the artificial bone composite being in a shapeable plasticine shape.

In the present disclosure, the degradable polymer material has an average molecular weight of 1000Da to 20000Da, can be mixed with inorganic particles, binds the inorganic particles into one body, and forms an artificial bone composite material in which the inorganic particles are distributed in the polymer material, the artificial bone composite material being in a moldable plasticine shape, so that it can be freely molded and can be used by injection. In addition, the degradable polymer material is not easy to dissolve in an aqueous environment, and can keep the stable shape of the artificial bone composite material in the aqueous environment.

In addition, in the artificial bone composite material according to one aspect of the present disclosure, optionally, the polymer material is a homopolymer or a copolymer of at least one monomer selected from caprolactone and p-dioxanone, or a copolymer of caprolactone or p-dioxanone and lactide or glycolide. Under the condition, the degradable polymer material can be formed, and the application of the artificial bone composite material in the field of orthopedics, in particular the field of absorbable orthopedics materials is facilitated.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, the polymer material is a copolymer of caprolactone and lactide, and a molar ratio of caprolactone to lactide in the polymer material is 1: 1 to 2.5: 1. Thereby, a degradable polymer material having desired viscosity and fluidity can be formed.

Further, in the artificial bone composite according to an aspect of the present disclosure, optionally, the inorganic particles include at least one selected from among hydroxyapatite, calcium polyphosphate, and tricalcium phosphate. In this case, since the composition of the inorganic particles is similar to that of human bone tissue, the bioactivity and biocompatibility of the artificial bone composite material can be improved.

In addition, in the artificial bone composite according to an aspect of the present disclosure, optionally, the inorganic particles are present in a mass fraction of 10% to 60%. Therefore, the restoration effect of the artificial bone composite material on the skeleton can be improved under the condition of considering the plasticity of the artificial bone composite material.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, the inorganic particles are present in a mass fraction of 25% to 50%. Therefore, the repair effect of the artificial bone composite material on the bone can be further improved under the condition of considering the plasticity of the artificial bone composite material.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, the artificial bone composite is in a moldable plasticine shape in a first predetermined temperature range, and the artificial bone composite has fluidity in a second predetermined temperature range, the second predetermined temperature being greater than the first predetermined temperature. Under the condition, the artificial bone composite material has both plasticity and injectability, thereby being beneficial to the application of the artificial bone composite material in the orthopedic field.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, the first predetermined temperature is in a range of 25 ℃ to 40 ℃ and the second predetermined temperature is in a range of 40 ℃ to 60 ℃. In this case, the artificial bone composite can be conveniently applied in an actual clinical application environment.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, the storage modulus of the artificial bone composite is equal to the loss modulus when a predetermined shear strain is applied to the artificial bone composite. Therefore, the artificial bone composite material has both elasticity and plasticity.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, when the shear strain applied to the artificial bone composite is less than the predetermined shear strain, the storage modulus of the artificial bone composite is greater than the loss modulus, and when the shear strain applied to the artificial bone composite is greater than the predetermined shear strain, the loss modulus of the artificial bone composite is greater than the storage modulus. Under the condition, the artificial bone composite material can present elasticity under small strain, so that a certain force can be borne, and the artificial bone composite material can be self-formed in the bone defect and is not easy to collapse; the artificial bone composite material can present viscous flow property when being subjected to large strain, so that the artificial bone composite material can have certain fluidity and larger deformation value and is irreversible, and the artificial bone composite material can be freely shaped and injected.

Further, in an artificial bone composite according to an aspect of the present disclosure, optionally, the predetermined shear strain is in a range of 20% to 80%. Therefore, the artificial bone composite material has both elasticity and plasticity in a proper shear strain range.

Another aspect of the present disclosure provides a method for preparing a shapeable artificial bone composite, comprising: preparing a degradable polymer material, and dissolving the polymer material in an organic solvent to obtain a polymer solution; adding inorganic particles composed of calcium-phosphorus compounds into the polymer solution and mixing to obtain a mixture solution; drying the mixture solution and performing drying in vacuum to obtain an artificial bone composite material composed of the polymer material and the inorganic particles, wherein the polymer material has an average molecular weight of 1000Da to 20000Da, and the inorganic particles are distributed in the polymer material, and the artificial bone composite material is in a plastic plasticine shape.

In the present disclosure, the polymer material has an average molecular weight of 1000Da to 20000Da, and can have fluidity and viscosity at normal temperature. The polymer material is mixed with the inorganic particles to form the artificial bone composite material with the inorganic particles distributed in the polymer material, and the artificial bone composite material is in a plastic plasticine shape, so that the artificial bone composite material can be freely shaped and can be used by injection.

In addition, in a method for preparing an artificial bone composite according to another aspect of the present disclosure, optionally, in preparing the degradable polymer material, a catalyst and an initiator are added to at least one monomer selected from caprolactone, p-dioxanone, or both monomers selected from caprolactone or p-dioxanone and lactide or glycolide, and are thermally reacted to obtain the polymer material. In this case, a degradable polymer material having fluidity and viscosity at normal temperature can be prepared.

In addition, in the method for preparing the artificial bone composite according to another aspect of the present disclosure, optionally, the catalyst is at least one selected from stannous octoate, zinc oxide, lead stearate, zinc borate, calcium formate, and magnesium oxide, the initiator is an alcohol substance, and the thermal reaction is performed at a temperature of 80 ℃ to 180 ℃ for 2 to 48 hours. In this case, the catalyst can catalyze the polymerization during the polymerization of the monomers, the initiator can initiate the polymerization of the monomers, and the thermal reaction can enable the polymerization to proceed better.

In addition, in the method of preparing an artificial bone composite according to another aspect of the present disclosure, the inorganic particles may be present in an amount of 10 to 60% by mass. Therefore, the bone repair capability of the artificial bone composite material can be improved.

According to the present disclosure, a moldable artificial bone composite capable of both free molding and free injection and a method for preparing the same can be provided.

Drawings

Fig. 1 is a schematic diagram illustrating the structure of a shapeable artificial bone composite according to an example of the present disclosure.

Fig. 2 is a schematic diagram illustrating steps for preparing a moldable artificial bone composite according to an example of the present disclosure.

Detailed Description

Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. In the following description, the same components are denoted by the same reference numerals, and redundant description thereof is omitted. The drawings are schematic and the ratio of the dimensions of the components and the shapes of the components may be different from the actual ones.

In the present disclosure, unless otherwise specifically indicated, "aqueous environment" generally refers to a liquid environment containing water.

Fig. 1 is a schematic diagram illustrating the structure of a shapeable artificial bone composite 1 according to an example of the present disclosure.

As shown in fig. 1, in the present embodiment, the shapeable artificial bone composite 1 may include a degradable polymer material 11 and inorganic particles 12. Wherein the degradable polymer material 11 may have an average molecular weight of 1000Da to 20000Da, and the inorganic particles 12 may be distributed in the polymer material 11. In some examples, the inorganic particles 12 may be composed of a calcium-phosphorus compound. In addition, the artificial bone composite material 1 may be in the form of a moldable plasticine.

In the artificial bone composite material 1 according to the present embodiment, the degradable polymer material 11 has an average molecular weight of 1000Da to 20000Da, and can be mixed with the inorganic particles 12 to bond the inorganic particles 12 together and form the artificial bone composite material 1 in which the inorganic particles 12 are distributed in the polymer material 11. The artificial bone composite material 1 is in a moldable plasticine shape, so that it can be freely molded and can be used by injection. In addition, the degradable polymer material 11 is not easy to dissolve in an aqueous environment, and can maintain the shape stable state of the artificial bone composite material 1 in the aqueous environment.

In some examples, the artificial bone composite 1 may be in the form of a moldable plasticine over a first predetermined temperature range. In other words, the artificial bone composite material may be freely shaped within the range of the first predetermined temperature. Additionally, in some examples, the first predetermined temperature may range from 25 ℃ to 40 ℃. In this case, the artificial bone composite material 1 can be conveniently applied in a practical clinical application environment. For example, the first predetermined temperature may be 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃ or 40 ℃.

In addition, in some examples, the artificial bone composite 1 may have fluidity in a second predetermined temperature range. Wherein the second predetermined temperature is greater than the first predetermined temperature. In this case, the artificial bone composite material 1 can be endowed with both moldability and injectability, thereby facilitating the application of the artificial bone composite material 1 in the orthopedic field. In other words, when the artificial bone composite 1 is heated to the second predetermined temperature, the artificial bone composite 1 has fluidity so as to facilitate the implantation operation of the artificial bone composite 1, and thus can be used for injection, for example, injection through a syringe. In this case, the heating can improve the fluidity of the artificial bone composite material 1, thereby being able to contribute to the injection of the artificial bone composite material 1.

In some examples, the second predetermined temperature may range between 40 ℃ and 60 ℃. In this case, the artificial bone composite material 1 can be conveniently applied in a practical clinical application environment. For example, the second predetermined temperature may be 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃.

In some examples, the polymeric material 11 may be flowable and tacky at a temperature of 20 ℃ to 60 ℃.

In some examples, the polymeric material 11 may be a degradable polymeric material 11. Additionally, in some examples, the average molecular weight of the polymeric material 11 may be 1000Da to 20000 Da. For example, the average molecular weight of the polymeric material 11 may be 1000Da, 2000Da, 3000Da, 4000Da, 6000Da, 8000Da, 9000Da, 10000Da, 12000Da, 15000Da, 18000Da, 20000Da, etc.

In the present embodiment, the average molecular weight of the polymer material 11 refers to the number average molecular weight of the polymer material 11. In other words, the number average molecular weight of the polymeric material 11 may be 1000Da to 20000 Da. Additionally, in some examples, the average molecular weight of the polymeric material 11 may be measured by a time-of-flight mass spectrometer, a nuclear magnetic resonance spectrometer, or gel permeation chromatography. Further, in some examples, the number average molecular weight of the polymeric material 11 may be determined by a time-of-flight mass spectrometer, a nuclear magnetic resonance spectrometer, or gel permeation chromatography.

In some examples, in the gel permeation chromatography, the polymer material 11 may be dissolved using, for example, Tetrahydrofuran (THF) as a solvent to form a sample solution to be measured, and the sample solution to be measured may be subjected to gel permeation chromatography measurement with tetrahydrofuran as a mobile phase and polystyrene as a reference standard of molecular weight, whereby the average molecular weight (number average molecular weight) of the polymer material 11 can be obtained.

In the present embodiment, as described above, the average molecular weight of the polymer material 11 may be 1000Da to 20000 Da. If the average molecular weight of the polymer material 11 is less than 1000Da, the inorganic particles 12 are difficult to bind to the polymer material 11, so that the inorganic particles 12 in the artificial bone composite material 1 are easily exfoliated and cannot be stably molded in water, and exfoliation of the inorganic particles 12 easily causes insufficient osteogenic properties. If the average molecular weight of the polymer material 11 is more than 20000Da, the fluidity of the polymer material 11 is poor, and thus the artificial bone composite material 1 mixed with the inorganic particles 12 becomes too hard to be freely shaped.

In some examples, polymeric material 11 may be a homopolymer or copolymer of at least one monomer selected from caprolactone, p-dioxanone, or a copolymer of caprolactone or p-dioxanone with lactide or glycolide. In this case, the degradable polymer material 11 can be formed, which is beneficial to the application of the artificial bone composite material 1 in the orthopedic field, especially the absorbable orthopedic material field. For example, the polymer material 11 may be a homopolymer of caprolactone or p-dioxanone, or may be a copolymer of caprolactone and p-dioxanone, a copolymer of caprolactone and lactide or glycolide, or a copolymer of p-dioxanone and lactide or glycolide.

In some examples, the polymeric material 11 may be a copolymer of caprolactone and lactide, and the molar ratio of caprolactone to lactide in the polymeric material 11 is 1: 1 to 2.5: 1. Thereby, the degradable polymer material 11 having desired viscosity and fluidity can be formed. For example, the molar ratio of caprolactone to lactide in polymeric material 11 may be 1: 1, 1.2: 1, 1.5: 1, 1.8: 1, 2: 1, 2.3: 1, or 2.5: 1.

In some examples, the mass fraction of the polymer material 11 may be 40% to 90%. In this case, the moldability of the artificial bone composite material 1 can be improved. For example, the mass fraction of the polymeric material 11 may be 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc.

In addition, in the present embodiment, since the polymer material 11 itself does not contain moisture, and does not evaporate and is not easily denatured at normal temperature and pressure, the form of the artificial bone composite material 1 can be stably maintained for a long time, and the stable form of the artificial bone composite material 1 in water can be maintained without dissolving in water in an aqueous environment.

In some examples, the inorganic particles 12 may include at least one selected from among hydroxyapatite, calcium polyphosphate, tricalcium phosphate. In this case, since the composition of the inorganic particles 12 is similar to that of human bone tissue, the bioactivity and biocompatibility of the artificial bone composite material 1 can be improved.

In the present embodiment, the inorganic particles 12 are not limited to the hydroxyapatite, calcium polyphosphate, tricalcium phosphate, and the like described above. In the present embodiment, the inorganic particles 12 may contain other substances having a composition similar to that of the human bone tissue, and thus the effect of the artificial bone composite material 1 on repairing the human bone tissue can be similarly improved.

In some examples, the mass fraction of the inorganic particles 12 may be 10% to 60%. Therefore, the restoration effect of the artificial bone composite material on the skeleton can be improved under the condition of considering the plasticity of the artificial bone composite material. For example, the mass fraction of the inorganic particles 12 may be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or 60%.

In some examples, if the mass fraction of the inorganic particles 12 is less than 10%, it is difficult to effectively assist the growth and repair of bone due to insufficient inorganic particles 12 resulting in insufficient release of elements such as calcium, phosphorus, etc. from the inorganic particles 12 after the artificial bone composite material 1 is implanted into a body (a body of a human or animal body). In other words, if the mass fraction of the inorganic particles 12 is less than 10%, the osteogenesis property of the artificial bone composite material 1 is insufficient, and the ability to promote bone repair is poor.

In some examples, if the mass fraction of the inorganic particles 12 is higher than 60%, the amount of the inorganic particles 12 in the polymer material 11 that can be distributed in the polymer structure formed by the polymer material 11 is easily saturated, and it is difficult to continue mixing with more inorganic particles 12, thereby causing the formed artificial bone composite material 1 to be easily exfoliated, i.e., the artificial bone composite material 1 may drop excess inorganic particles 12.

In some examples, the mass fraction of the inorganic particles 12 may be preferably 25% to 50% in order to compromise the plasticity of the artificial bone composite material and the repairing effect on the bone. Therefore, the repair effect of the artificial bone composite material on the bone can be further improved under the condition of considering the plasticity of the artificial bone composite material.

Additionally, in some examples, the inorganic particles 12 may be preferably rigid particles. In some examples, the inorganic particles 12 may have a young's modulus greater than 2 x 10¹¹Pa of rigid particles. In this case, the mechanical strength of the artificial bone composite material 1 can be improved.

In the present embodiment, the shape of the inorganic particles 12 is not particularly limited. For example, in some examples, the inorganic particles 12 may be spherical. However, the present embodiment is not limited thereto, and in other examples, the inorganic particles 12 may have an ellipsoidal shape, an irregular solid shape, or the like.

In the present embodiment, the average particle diameter of the inorganic particles 12 is not particularly limited. In some examples, the average particle size of the inorganic particles 12 may be 5nm to 200 μm, for example, the average particle size of the inorganic particles 12 may be 5nm, 10nm, 30nm, 50nm, 100nm, 200nm, 500nm, 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, 30 μm, 50 μm, 80 μm, 100 μm, 130 μm, 150 μm, 180 μm, or 200 μm. The average particle size of the inorganic particles 12 may be selected to be different depending on the usage situation.

In some examples, the surface of the inorganic particles 12 may be modified, such as by coating the surface of the inorganic particles 12 with a bonding layer that readily bonds to the polymeric material 11. In this case, the bonding force between the inorganic particles 12 and the polymer material 11 can be increased, whereby the inorganic particles 12 can be better bonded into one body. In some examples, the surface of the inorganic particle 12 may be covered with polyethyleneimine.

In some examples, the growth factor may be at least one selected from the group consisting of collagen, bone morphogenetic protein-2, fibroblast growth factor-2, transforming growth factor- β, insulin-like growth factor-1, platelet-derived growth factor.

In addition, in some examples, the artificial bone composite 1 may further include an antibacterial substance. This reduces reinfection of the bone defect and accelerates healing. In some examples, the antimicrobial substance may be an antibacterial ion, a sulfonamide, a quinolone, a nitroimidazole, or the like.

In some examples, the antimicrobial ions may be at least one of silver ions, gallium ions, copper ions, and zinc ions. In addition, the sulfa drugs can be more than one of trimethoprim, sulfadiazine, sulfamethoxazole, compound sulfamethoxazole and sulfamethazine. In addition, in some examples, the quinolone drug may be one or more of norfloxacin, ofloxacin, ciprofloxacin, fleroxacin. In addition, the nitroimidazole drug can be more than one of metronidazole, iprazole, secazole, ornidazole, tinidazole and metronidazole.

In some examples, preferably, the artificial bone composite material 1 may be composed of the polymer material 11 and the inorganic particles 12. Specifically, the artificial bone composite 1 may be a composition in which a degradable polymer material 11 and inorganic particles 12 distributed in the polymer material 11 are mixed.

In some examples, as described above, the inorganic particles 12 may be distributed in the polymeric material 11. In addition, in some examples, the inorganic particles 12 may be uniformly distributed in the polymer material 11 in the artificial bone composite material 1. In other examples, inorganic particles 12 may also be randomly distributed within polymeric material 11. Further, in some examples, the inorganic particles 12 may be distributed in a stepped arrangement density or a dense-on-sparse-on-dense-.

In the present embodiment, the moldable artificial bone composite material 1 can be freely molded (for example, a physician or the like can freely mold with hands), is convenient for clinical use, and can fill, for example, bone defects in a full manner, thereby effectively helping bone growth and repair. In addition, since the artificial bone composite material 1 has the inorganic particles 12 such as hydroxyapatite, for example, the artificial bone composite material 1 can have osteogenesis property, and induce bone growth to complete the repair. In addition, artificial bone combined material 1 has the degradation gradient layer in the human body, and degradable polymer material 11 can be preferentially quick degradation, forms the inorganic particle 12 structure of taking a large amount of holes, provides enough space for bone to grow into, and this inorganic particle 12 structure degradation is slower, can effectively induce bone tissue to grow in the hole, promotes bone repair fast.

In some examples, the artificial bone composite 1 may be sterilized. This can improve the biosafety of the artificial bone composite material 1. In addition, in some examples, the artificial bone composite 1 may be radiation sterilized. For example, the artificial bone composite 1 may be electron beam sterilized, X-ray sterilized, or gamma-ray sterilized.

In the present embodiment, as described above, the artificial bone composite 1 may have fluidity in the second predetermined temperature range. In this case, the artificial bone composite material 1 is a material that can be injected. In addition, in some examples, the artificial bone composite 1 may be heated prior to injecting the artificial bone composite 1. For example, the artificial bone composite material 1 may be first heated, for example, to a second predetermined temperature (e.g., 40-60 ℃) to form a moldable material having fluidity and viscosity, and then injected into an aqueous environment at room temperature.

In some examples, the storage modulus G' and the loss modulus G "of the artificial bone composite 1 are related to the shear strain γ applied to the artificial bone composite 1. In the present embodiment, in some examples, the shear strain γ may range from 0.01% to 100%, for example, the shear strain γ may be 0.01%, 0.1%, 0.5%, 1%, 2%, 5%, 10%, 20%, 40%, 50%, 80%, 90%, 100%. However, the present embodiment is not limited thereto, and the shear strain γ may be larger than 100%, for example.

In some examples, the artificial bone material 1 may be subjected to shear strain using a rotational rheometer. For example, the range of shear strain can be set on a rotational rheometer, and the artificial bone composite material 1 can be subjected to amplitude scanning to apply a corresponding shear strain γ (e.g., 0.01% -100%) to the artificial bone composite material 1, so that the relationship between the shear strain of the artificial bone composite material 1 and the storage modulus G' and the loss modulus G ″ can be obtained.

In some examples, the shear strain γ when applied to the artificial bone composite 1 is equal to the predetermined shear strain γ₀When the storage modulus G' of the artificial bone composite material 1 is equal to the loss modulus G ″. In other words, the storage modulus G' of the artificial bone composite material 1 is equal to the loss modulus G ″ when a predetermined shear strain is applied to the artificial bone composite material 1. This makes it possible to provide the artificial bone composite material 1 with both elasticity and moldability. Additionally, in some examples, the predetermined shear strain γ₀May range from 20% to 80%. This enables the artificial bone composite material 1 to have both elasticity and moldability in an appropriate shear strain range.

In some examples, the shear strain γ when applied to the artificial bone composite 1 is less than a predetermined shear strain γ₀When the artificial bone composite material 1 has the storage modulus G' greater than the loss modulus G ″. In this case, the artificial bone composite material 1 can exhibit elasticity so as to be able to withstand a certain force, thereby enabling the artificial bone composite material 1 to be self-formed without collapse in the bone defect. In other words, the artificial bone composite material 1 can exhibit elasticity when subjected to a small strain.

In some examples, the shear strain γ when applied to the artificial bone composite 1 is greater than a predetermined shear strain γ₀When the storage modulus G' of the artificial bone composite material 1 is less than the loss modulus G ″. In this case, the artificial bone composite material 1 can exhibit a viscous flow property, and thus, the artificial bone composite material 1 can have both a certain fluidity and a large deformation value and be irreversible, and thus the artificial bone composite material 1 can be freely shaped and injected. In other words, the artificial bone composite material 1 can exhibit a viscous flow property when a large strain occurs. The processes of injecting and shaping the artificial bone composite material belong to the processes of large strain.

Hereinafter, a method for preparing the moldable artificial bone composite material 1 according to the present disclosure will be described in detail with reference to fig. 2. Fig. 2 is a schematic diagram illustrating the steps of preparing a shapeable artificial bone composite 1 according to the present disclosure.

As shown in fig. 2, the preparation method of the moldable artificial bone composite material 1 according to the present disclosure may include the steps of: preparing a degradable polymer material 11, and dissolving the polymer material 11 in an organic solvent to obtain a polymer solution (step S10); adding inorganic particles 12 composed of a calcium-phosphorus compound to the polymer solution and mixing them to obtain a mixture solution (step S20); the mixture solution is dried and dried in vacuum, thereby obtaining the artificial bone composite material 1 composed of the polymer material 11 and the inorganic particles 12, the polymer material 11 having an average molecular weight of 1000Da to 20000Da, and in the artificial bone composite material 1, the inorganic particles 12 are distributed in the polymer material 11, the artificial bone composite material 1 is in a moldable plasticine shape (step S30). In addition, the average molecular weight of the polymer material 11 may refer to the number average molecular weight of the polymer material 11.

In the method for preparing the moldable artificial bone composite material 1 according to the present embodiment, the polymer material 11 and the inorganic particles 12 are mixed to form the artificial bone composite material 1 in which the inorganic particles 12 are distributed in the polymer material 11, and the artificial bone composite material 1 is in a moldable plasticine shape, so that it can be freely molded and can be used by injection.

In the present embodiment, as described above, in step S10, the degradable polymer material 11 may be prepared, and the polymer material 11 may be dissolved in an organic solvent to obtain a polymer solution.

In step S10, degradable polymer material 11 may be prepared first. Specifically, in preparing the degradable polymer material 11, a catalyst and an initiator may be added to at least one monomer selected from caprolactone, p-dioxanone, or both monomers selected from caprolactone or p-dioxanone and lactide or glycolide, and subjected to a thermal reaction to obtain the polymer material 11. In this case, a degradable polymer material 11 having both fluidity and viscosity at normal temperature can be prepared.

In some examples, the polymer material 11 having an average molecular weight of 1000Da to 20000Da may be obtained by controlling the thermal reaction temperature, the thermal reaction time, the molar ratio between the monomers, the ratio of the monomers to the initiator, and the like. The average molecular weight of the polymer material 11 can be determined by a time-of-flight mass spectrometer, a nuclear magnetic resonance spectrometer or gel permeation chromatography.

In some examples, the catalyst used in step S10 may be at least one selected from stannous octoate, zinc oxide, lead stearate, zinc borate, calcium formate, magnesium oxide. In this case, the catalyst is capable of catalyzing polymerization during the polymerization of the monomers. In other examples, the catalyst may also be dibutyltin dilaurate, triethanolamine, or the like. In some examples, the initiator may be an alcohol species. In this case, the initiator is capable of initiating polymerization of the monomer. For example, the initiator may be at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-dodecanol, benzyl alcohol, phenethyl alcohol, phenylpropyl alcohol, and ethylene glycol.

In some examples, the thermal reaction may be a reaction performed at a temperature of 80 ℃ to 180 ℃ for 2 to 48 hours. In this case, the polymerization reaction can be made to proceed better. In some examples, the thermal reaction may be a reaction heated to 80 ℃ for 48 hours, for example. In other examples, the thermal reaction may be a reaction heated to 130 ℃ for 24 hours. In addition, in some examples, the thermal reaction may be a reaction heated to 180 ℃ for 2 hours. In some examples, the temperature at which the thermal reaction is heated may also be 90 ℃, 100 ℃, 110 ℃, 120 ℃, 140 ℃, 150 ℃, 160 ℃, or 170 ℃. Additionally, in some examples, the thermal reaction may also be conducted for 4, 6, 8, 10, 12, 14, 16, 18, 20, or 22 hours.

Next, in step S10, the prepared polymer material 11 may be dissolved in an organic solvent to obtain a polymer solution. In addition, in some examples, the organic solvent may be dichloromethane, trichloromethane, tetrahydrofuran, or the like.

In the present embodiment, as described above, in step S20, the inorganic particles 12 composed of a calcium-phosphorus compound are added to the polymer solution and mixed to obtain a mixture solution.

In some examples, the inorganic particles 12 composed of a calcium phosphorus compound may be prepared first. In some examples, the inorganic particles 12 may be selected from one or more of hydroxyapatite, calcium polyphosphate, and tricalcium phosphate. In this case, since the composition of the inorganic particles 12 is similar to that of human bone tissue, the bioactivity and biocompatibility of the artificial bone composite material 1 can be improved. For example, a blend of calcium hydroxy phosphate and tricalcium phosphate may be prepared as the inorganic particles 12.

The inorganic particles 12 are not limited to the hydroxyapatite, calcium polyphosphate, tricalcium phosphate, and the like. In the present embodiment, the inorganic particles 12 may include other materials having a composition similar to that of the human bone tissue, and thus the effect of the artificial bone composite material 1 on repairing the human bone tissue can be similarly improved.

In some examples, the surface of the prepared inorganic particles 12 may be modified. Thereby, when the inorganic particles 12 are mixed with the polymer material 11 later, the bonding force between the inorganic particles 12 and the polymer material 11 can be increased, and thus the inorganic particles 12 can be better bonded with the polymer material 11.

In the present embodiment, in step S20, the polymer solution in step S10 may be sufficiently mixed with the inorganic particles 12 to obtain a mixture solution. In addition, in some examples, the polymer solution and the inorganic particles 12 may be thoroughly mixed by manual stirring, ultrasonic stirring, magnetic stirring, and the like.

In some examples, in step S20, the inorganic particles 12 may be added in a ratio of the mass of the polymer material 11 to the mass of the inorganic particles 12 of 2: 3 to 9: 1. In other words, in the artificial bone composite material 1, the mass fraction of the inorganic particles 12 may be 10% to 60%. In this case, the mechanical strength of the artificial bone composite material 1 can be improved, and the moldable plasticine-like characteristic of the artificial bone composite material 1 can be ensured. In addition, in order to balance the plasticity of the artificial bone composite material and the bone repairing effect, the mass fraction of the inorganic particles 12 may be preferably 25% to 50%.

In addition, in some examples, the growth factor may be at least one selected from the group consisting of collagen, bone morphogenetic protein-2, fibroblast growth factor-2, transforming growth factor- β, insulin-like growth factor-1, platelet-derived growth factor.

In some examples, in step S20, an antimicrobial substance may be in the polymer solution. Additionally, in some examples, the antimicrobial substance may be an antibacterial ion, a sulfonamide, a quinolone, a nitroimidazole, or the like.

In the present embodiment, as described above, in step S30, the mixture solution in step S20 may be dried and dried in vacuum to obtain the artificial bone composite material 1. In addition, in some examples, the mixture solution may be dried in an oven and then dried in a vacuum oven.

In some examples, the artificial bone composite 1 may also be subjected to a sterilization process in step S30. This can improve the biosafety of the artificial bone composite material 1. In addition, in some examples, the artificial bone composite 1 may be radiation sterilized in step S30. For example, the artificial bone composite 1 may be electron beam sterilized, X-ray sterilized, or gamma-ray sterilized.

In order to further illustrate the present disclosure, the moldable artificial bone composite material 1 provided by the present disclosure and the preparation method thereof are described in detail below with reference to examples, and the advantageous effects achieved by the present disclosure are fully illustrated with reference to comparative examples.

[ example 1 ] to [ example 22 ]

First, the monomers of each of examples 1 to 22 were prepared. According to table 1, monomers of each example of example 1 to example 22 were prepared, and monomers having average molecular weights and types shown in table 1 were obtained. Next, the catalyst and the initiator shown in table 1 were added to the monomers of each of examples 1 to 22, respectively, to obtain a monomer-containing mixture. The mixture was heated to a predetermined reaction temperature and reacted for a predetermined time according to the reaction temperature and reaction time shown in table 1, to obtain degradable polymer materials of each of examples 1 to 22.

Next, the degradable polymer materials of each example (example 1 to example 22) were taken, sample solutions of each example (example 1 to example 22) were prepared in a ratio of 0.2g of the polymer material to 1ml of tetrahydrofuran, and then GPC tests were performed using tetrahydrofuran as a mobile phase and polystyrene as a reference standard for molecular weight to obtain the number average molecular weight of the degradable polymer materials of each example (example 1 to example 22).

Then, in each example (example 1 to example 22), the obtained degradable polymer materials were respectively dissolved in dichloromethane as an organic solvent, and inorganic particles were added in a predetermined mass ratio as shown in table 1, and ultrasonic stirring was performed to obtain mixture solutions of example 1 to example 22. Finally, the mixture solutions were respectively heat-dried and vacuum-heat-dried, thereby obtaining artificial bone composites of respective examples (example 1 to example 22).

The artificial bone composite of each example (example 1 to example 22) prepared according to table 1 was subjected to a performance test, the specific procedure of which is as follows:

(1) rheological property test: the artificial bone composite of each example was placed on a rotational rheometer (model: antopa MCR302) to perform amplitude scanning under conditions of shear strain (γ) of 0.01 to 100%, normal force of 0n, angular frequency of 1rad/s, temperature of 37 ℃ to obtain a shear strain γ (x) -modulus (y, including storage modulus G 'and loss modulus G ") curve, and then the relationship between G' and G ″ was judged at shear strains γ of 0.01 to 1% and 90 to 100% for the artificial bone composites of each example (example 1 to example 22).

(2) Water resistance test: the artificial bone composite material of each embodiment is respectively prepared into cubes with the size of 10 multiplied by 10mm, the mass of each cube is weighed and then is soaked in physiological saline at the temperature of 37 ℃, whether each cube can be stably molded in the physiological saline is observed, after 24 hours, each cube is taken out and dried and then is weighed, the mass ratio of each cube after soaking to before soaking is calculated, and the falling condition of inorganic particles of the artificial bone composite material of each embodiment (embodiment 1 to embodiment 22) in the water phase environment is judged according to the mass ratio. The water resistance test results are shown in Table 3;

(3) and (3) shaping test: respectively taking 4g of the artificial bone composite material of each embodiment as a test sample, and kneading each test sample by hands at 25-40 ℃ to judge whether the artificial bone composite material can be freely shaped and whether the artificial bone composite material is powder-falling;

(4) bone defect repair experiment: the injected artificial bone composite material of each example was taken, heated to 40 ℃ to 60 ℃, then injected into a rabbit femoral condyle bone defect (10mm depth, 6mm diameter), and the repair effect was observed after three months. The results of bone defect repair are shown in table 3.

[ COMPARATIVE EXAMPLES 1 TO COMPARATIVE EXAMPLES 12 ]

First, the monomers of each of comparative examples 1 to 12 were prepared. According to table 1, monomers of each of comparative examples 1 to 12 were prepared, and monomers having the average molecular weights and types shown in table 1 were obtained. Next, the catalyst and the initiator shown in table 1 were added to the monomers of each of comparative examples 1 to 12, respectively, to obtain a monomer-containing mixture. The mixture was heated to a predetermined reaction temperature and reacted for a predetermined time according to the reaction temperature and the reaction time shown in table 1, to obtain degradable polymer materials of each of comparative examples 1 to 12.

Next, the degradable polymer materials of the respective comparative examples (comparative examples 1 to 12) were taken, sample solutions of the respective comparative examples (comparative examples 1 to 12) were prepared in a ratio of 0.2g of the polymer material plus 1ml of tetrahydrofuran, and then GPC tests were performed using a chromatography column with tetrahydrofuran as a mobile phase and polystyrene as a reference standard for molecular weight to obtain the number average molecular weight of the degradable polymer materials of the respective comparative examples (comparative examples 1 to 12).

Then, in each of comparative examples (comparative example 1 to comparative example 12), the obtained degradable polymer materials were respectively dissolved in dichloromethane as an organic solvent, and inorganic particles were added in a predetermined mass ratio as shown in table 1 and subjected to ultrasonic stirring to obtain mixture solutions of comparative examples 1 to 12. Finally, the mixture solutions were respectively heat-dried and vacuum-heat-dried, thereby obtaining artificial bone composites of respective comparative examples (comparative example 1 to comparative example 12).

The artificial bone composite of each comparative example (comparative example 1 to comparative example 12) prepared according to table 1 was subjected to a performance test, the specific procedure of which is as follows:

(1) rheological property test: the artificial bone of each of the comparative examples (comparative examples 1 to 12) was placed on a rotational rheometer (model: antopa MCR302) to perform amplitude scanning under conditions of shear strain (γ) of 0.01 to 100%, normal force of 0n, angular frequency of 1rad/s, temperature of 37 ℃ to obtain a shear strain γ (x) -modulus (y, including storage modulus G 'and loss modulus G ") curve, and then the relationship between G' and G ″ was judged for the artificial bone composite of each of the comparative examples (comparative examples 1 to 12) at shear strains γ of 0.01 to 1% and 90 to 100% and at 0.01 to 100%.

(2) Water resistance test: respectively taking the artificial bone composite material of each comparative example to prepare a cube of 10 multiplied by 10mm, weighing the mass of each cube, then soaking the cube in physiological saline at 37 ℃, observing whether each cube can be stably molded in the physiological saline, taking out and drying the cube after 24 hours, weighing the mass of each cube, calculating the mass ratio of each cube after soaking to the cube before soaking, and judging the falling condition of the inorganic particles of the artificial bone composite material of each comparative example in an aqueous phase environment according to the mass ratio. The water resistance test results are shown in Table 3;

(3) and (3) shaping test: respectively taking 4g of the artificial bone composite material of each comparative example as a test sample, and kneading each test sample by hands at 25-40 ℃ to judge whether the artificial bone composite material can be freely shaped and whether the artificial bone composite material is powder-falling;

(4) bone defect repair experiment: the artificial bone injection composite material of each comparative example is heated to 40 ℃ to 60 ℃, and then injected into the bone defect (10mm depth and 6mm diameter) of the rabbit femoral condyle, and the repair effect is observed after three months. The results of bone defect repair are shown in table 3.

TABLE 1

TABLE 2

TABLE 3

As can be seen from table 3, the artificial bone composites obtained in each example (example 1 to example 22) exhibited the viscoelasticity at a shear strain γ of 90% to 100% when G "> G', that is, the artificial bone composites were freely shaped by kneading with hands, and the inorganic particle powder was not easily exfoliated (without dusting), as compared with the comparative examples. However, although the artificial bone composite materials of examples 2, 4 and 6 were hard, the artificial bone composite materials of examples 2, 4 and 6 could be shaped by hand, but the shaping resistance was large.

In addition, most of the artificial bone composite materials obtained in the examples (examples other than examples 1, 3 and 5) can be stably molded in an aqueous environment, and the results of the water resistance test are all above 90%, i.e., the water resistance is excellent, i.e., the artificial bone composite materials have less inorganic particle shedding in the aqueous environment. In addition, the artificial bone composite material obtained in each embodiment has ideal repairing effect in rabbit bone defect filling and repairing experiments within three months. Moreover, although the results of the water resistance test of the artificial bone composites of examples 1, 3 and 5 are less than 90%, that is, the artificial bone composites of examples 1, 3 and 5 are liable to fall off when meeting water, and the rabbit bone defect repair implant is liable to swell in the early stage, the artificial bone composites obtained in examples 1, 3 and 5 have ideal repair effects in the rabbit bone defect repair test in three months.

In conclusion, the artificial bone composite materials obtained in examples 1 to 22 were both freely moldable and freely injectable, and had good bone repair ability.

In contrast, the artificial bone composites obtained in comparative examples 1 to 12 cannot simultaneously achieve all the performance effects of the artificial bone composites obtained in the above-described respective examples.

While the present disclosure has been described in detail above with reference to the drawings and the embodiments, it should be understood that the above description does not limit the present disclosure in any way. Those skilled in the art can make modifications and variations to the present disclosure as needed without departing from the true spirit and scope of the disclosure, which fall within the scope of the disclosure.

Claims

1. A plastic artificial bone composite material, which is characterized in that,

is a composition formed by mixing degradable polymer material and inorganic particles distributed in the polymer material,

the polymer material has an average molecular weight of 1000Da to 20000Da, the inorganic particles are composed of a calcium-phosphorus compound, and

the artificial bone composite material is in a plastic plasticine shape.

2. The artificial bone composite of claim 1, wherein:

the polymer material is a homopolymer or a copolymer of at least one monomer selected from caprolactone and p-dioxanone, or a copolymer formed by caprolactone or p-dioxanone and lactide or glycolide.

3. The artificial bone composite of claim 1 or 2, wherein:

the polymer material is a copolymer of caprolactone and lactide, and the molar ratio of caprolactone to lactide in the polymer material is 1: 1 to 2.5: 1.

4. The artificial bone composite of claim 1, wherein:

the inorganic particles comprise at least one selected from among hydroxyapatite, calcium polyphosphate, tricalcium phosphate.

5. The artificial bone composite of claim 1 or 4, wherein:

the inorganic particles are present in a mass fraction of 10% to 60%.

6. The artificial bone composite of claim 5, wherein:

the inorganic particles are present in a mass fraction of 25% to 50%.

7. The artificial bone composite of claim 1, wherein:

the artificial bone composite is in the form of a moldable plasticine over a first predetermined temperature range and has a fluidity over a second predetermined temperature range, the second predetermined temperature being greater than the first predetermined temperature.

8. The artificial bone composite of claim 7, wherein:

the first predetermined temperature is in the range of 25 ℃ to 40 ℃ and the second predetermined temperature is in the range of 40 ℃ to 60 ℃.

9. The artificial bone composite of claim 7, wherein:

the storage modulus of the artificial bone composite is equal to the loss modulus when a predetermined shear strain is applied to the artificial bone composite.

10. The artificial bone composite of claim 9, wherein:

when the shear strain applied to the artificial bone composite is less than the predetermined shear strain, the storage modulus of the artificial bone composite is greater than the loss modulus,

when the shear strain applied to the artificial bone composite is greater than the predetermined shear strain, the loss modulus of the artificial bone composite is greater than the storage modulus.

11. The artificial bone composite of claim 9, wherein:

the predetermined shear strain ranges from 20% to 80%.

12. A method for preparing a plastic artificial bone composite material, which is characterized in that,

the method comprises the following steps:

preparing a degradable polymer material, and dissolving the polymer material in an organic solvent to obtain a polymer solution;

adding inorganic particles composed of calcium-phosphorus compounds into the polymer solution and mixing to obtain a mixture solution;

drying the mixture solution and drying in vacuum to obtain an artificial bone composite material consisting of the polymeric material and the inorganic particles, the polymeric material having an average molecular weight of 1000Da to 20000Da and

in the artificial bone composite material, the inorganic particles are distributed in the polymer material, and the artificial bone composite material is in a plastic plasticine shape.

13. The method of claim 12, wherein:

in preparing the degradable polymer material, adding a catalyst and an initiator into at least one monomer selected from caprolactone and p-dioxanone, or two monomers selected from caprolactone or p-dioxanone and lactide or glycolide, and carrying out a thermal reaction to obtain the polymer material.

14. The production method according to claim 12 or 13, characterized in that:

the catalyst is at least one selected from stannous octoate, zinc oxide, lead stearate, zinc borate, calcium formate and magnesium oxide, the initiator is an alcohol substance,

the thermal reaction is a reaction carried out at a temperature of 80 to 180 ℃ for 2 to 48 hours.

15. The production method according to claim 12 or 13, characterized in that:

the inorganic particles are present in a mass fraction of 10% to 60%.