CN110917396B

CN110917396B - Novel bone repair product and preparation method thereof

Info

Publication number: CN110917396B
Application number: CN201911253587.6A
Authority: CN
Inventors: 胡方; 仇越秀; 王健; 郭创洲
Original assignee: Beijing Xingfu Yisheng Regeneration Medical Technology Co ltd
Current assignee: Beijing Xingfu Yisheng Regeneration Medical Technology Co ltd
Priority date: 2019-12-09
Filing date: 2019-12-09
Publication date: 2021-03-23
Anticipated expiration: 2039-12-09
Also published as: CN110917396A

Abstract

The invention relates to the technical field of biomedical materials, in particular to a bone repair product containing regenerative medical materials and a preparation method thereof. The material comprises: powders containing regenerative medical materials, and liquids; the powder comprises: regenerative medical materials, calcium phosphates, pyrophosphates, phosphonate functionalized gelatin; the liquid agent is an acidic buffer solution. The bone repair material of the invention contains regenerative medical materials with large specific surface area and has huge reaction activity; the bone repair material contains gelatin component, can be degraded into micropores after being implanted into human tissues, and is favorable for promoting the repair of bone defect parts; the bone repair material contains phosphonate medicinal components, can be specifically combined with hydroxyapatite in bone, and can inhibit osteoclast activity and bone absorption. The regenerative medical material with high biological activity, the degradable and microporous gelatin and the phosphonate medicinal component are synergistic, so that the effect of the bone repair material on treating bone defect and bone loss is obviously improved.

Description

Novel bone repair product and preparation method thereof

Technical Field

The invention relates to the technical field of biomedical materials, in particular to a bone repair product containing regenerative medical materials and a preparation method thereof.

Background

The loss and damage of bone tissue are common diseases in clinic, and the number of patients with bone defect or limb insufficiency caused by trauma, aging, exercise, inflammation, tumor and congenital deformity is not large, so the demand of bone repair materials is great. With the progress of social civilization, economic development and increasingly improved living standard, human pay more attention to the medical rehabilitation level of the human. Meanwhile, the social population is greatly increased, a large number of vehicles are brought forward, the rhythm of work and life is accelerated, and accidental injuries of people are greatly increased due to frequent occurrence of diseases, natural disasters, traffic accidents, sports injuries, industrial injuries and the like, local wars and the like. According to statistics, nearly 300 million bone defect patients and 1/3-1/5 total number of tooth defect patients are counted every year in China, and in addition, the number of bone defect patients related to the aging is increasing due to the fact that China is moving to the aging society at present, and the demand for biological materials is larger. The global biomedical material production value in 2008 is about over 1100 billion dollars, and the global biomedical material market has been continuously growing at an annual growth rate of around 30% for the last 10 years. Therefore, the research and development of the bone repair biomaterial have very important medical and socioeconomic values.

Tricalcium phosphate and hydroxyapatite ceramic artificial bones have been widely developed since the middle of the last 70 th century, wherein compact ceramics have been used for the transplantation and replacement of some load-bearing bones due to their high mechanical strength, but ceramic materials have poor shape adaptability to bone defects due to their high brittleness, difficulty in processing, need to be pre-formed and sintered, and are difficult to be well fitted to bone defect sites, and the formation speed of new bones in the transplanted area has been very slow. In 1983, a self-setting, optionally moldable, new bone repair material, calcium phosphate biological bone cement (CPC), was successfully developed by Brown and Chow, which marks the beginning of a new era of bone repair materials. The material can be arbitrarily shaped and processed according to the operation part, thereby solving the problem that the prior material is difficult to process the appearance; the self-curing can obtain strength, the heat release in the hydration process is slow, the temperature rise is less, and the setting time is properly long, so that the surgical condition is met; the biocompatibility is good, and the degradable is realized; it is therefore a highly potential biomaterial for repairing bone defects.

The superior performance of CPC is shown in the following aspects: (1) good biocompatibility, the hydration product is similar to inorganic substance of human bone, and forms bone combination with host bone after being implanted; (2) the operation is convenient, the molding can be carried out at will, and the defect that Hydroxyapatite (HA) ceramics is difficult to mold is overcome; (3) the heat release in the hydration process is small, and the defect that a large amount of heat is released to burn surrounding tissues in the PMMA polymerization process is overcome; (4) absorbability, gradually degraded and absorbed with the time of implantation, and finally replaced by host tissues; (5) biological activity, can form HA on the surface of the material, and form tight, direct and protrusion-like joint with the surrounding cancellous bone; (6) can promote the function and expression of cells; (7) osteoconductivity, which can provide a template and scaffold for the formation of new bone; (8) has higher compressive strength than that of cancellous bone.

However, calcium phosphate cement has the structural disadvantage of being unavoidable, that is, the finally set block is too compact, mostly microporous, and has poor connectivity, which results in slow growth and climbing of bone cells, no penetration of the bone cells through the material, difficult degradation of the material, and serious influence on the whole bone repair process. Therefore, the idea of preparing calcium phosphate cement with more excellent performance according to the structure of natural bone tissue is complied with.

In view of the defects of the existing bone repair product, the inventor provides a novel bone repair product containing regenerative medical materials and a preparation method thereof based on years of design and manufacturing experience of orthopedic medical instrument products.

Disclosure of Invention

The invention mainly aims to overcome the defects of the existing bone repair product and provide a novel bone repair product containing regenerative medical materials and a preparation method thereof.

The purpose and the technical problem to be solved of the invention are realized by adopting the following technical scheme. The specific technical scheme is as follows:

a novel bone repair material containing regenerative medical materials, comprising: powders containing regenerative medical materials, and liquids; the powder comprises the following raw materials by mass ratio, based on 100% of the total mass of the powder: 30-70% of regenerative medical material, 30-60% of calcium phosphate, 0-5% of pyrophosphate and 0-5% of phosphonate functionalized gelatin; the liquid agent is an acidic buffer solution; preferably, the powder comprises the following raw materials by mass ratio, based on 100% of the total mass of the powder: 35-60% of regenerative medical material, 40-60% of calcium phosphate, 0-3% of pyrophosphate and 0-3% of phosphonate functionalized gelatin.

In some embodiments, the regenerative medical material comprises at least one of a regenerative silicon material, a bioactive glass-based material, calcium silicate; preferably, the regenerated silicon material is Regesi regenerated silicon; preferably, the bioactive glass material is at least one of 45S5 bioactive glass powder, 58S bioactive glass powder, 70S bioactive glass powder and 77S bioactive glass powder; preferably, when in use, the mass ratio of the powder to the liquid is (1-3): 1.

In some embodiments, the regenerative medical material has a particle size in the range of 0.1 to 50 μm, preferably 0.1 to 30 μm.

In some embodiments, the regenerative medical material has a specific surface area of 100-²/g。

In some embodiments, the calcium phosphate comprises one or both of tricalcium phosphate and tetracalcium phosphate; the particle size of the calcium phosphate is 1-300 μm, preferably 50-200 μm; the calcium phosphate is preferably tricalcium phosphate and tetracalcium phosphate with the mass ratio of 1 (3-5).

In some embodiments, the pyrophosphate is selected from one or both of calcium pyrophosphate and sodium pyrophosphate; the particle size of the pyrophosphate is 1-50 μm.

In some embodiments, the phosphonate in the phosphonate-functionalized gelatin is a mixture of one or more of a bisphosphonate, pamidronate, alendronate, risedronate, ibandronate, zoledronate; wherein the mass percentage content of phosphonate functional groups in the phosphonate functionalized gelatin is 0.5-5%; preferably, the phosphonate-functionalized gelatin has a particle size of 50-500 μm, more preferably 100-200 μm.

In some embodiments, the liquid formulation is an acidic buffer comprising hyaluronic acid; wherein the acid is one or a mixture of citric acid, phosphoric acid or pyrophosphoric acid, and the molar concentration of the acid is 0.1-1.0 mol/L; the mass percentage of the hyaluronic acid is 0.01-5%, preferably 0.1-0.5%, based on 100% of the total mass of the liquid.

A preparation method of the novel bone repair material containing the regenerative medical material comprises the following steps: powder preparation steps: weighing the required raw materials and uniformly mixing to obtain the powder; a liquid preparation step: weighing required raw materials, and preparing to obtain the liquid; preferably, the method also comprises a mixing and curing step when in use: and mixing the powder and the liquid, blending for 0.5-2 min, and curing at 30-42 ℃ and 37 ℃ under the condition of relative humidity of 100% to obtain the novel bone repair material.

A novel bone repair product comprising a regenerative medical material, which comprises: the novel bone repair material or the novel bone repair material obtained by the preparation method.

Compared with the prior art, the bone repair material containing the regenerative medical material and the preparation method thereof provided by the invention have the following beneficial effects:

(1) the specific surface area of the regenerative medical material contained in the bone repair material provided by the invention is 100-1000m²The specific surface area of the material with the same granularity is 50 to 500 times that of the material with the same granularity (the specific surface area of the material with the same granularity is about 1.8 m)²In terms of/g), the reactivity is great. In addition, the regenerative medical material contains a large amount of high-coordination silicon elements, can quickly react with body fluid, and further improves the bone repair capacity of the material.

(2) The bone repair material provided by the invention contains gelatin components, can be degraded into micropores of 100-300 mu m after being implanted into human tissues, provides a natural three-dimensional space structure for adhesion, proliferation, differentiation and osteogenesis of osteoblasts, is favorable for fibrous and vascular tissue growth, and promotes repair of bone defect parts.

(3) The bone repair material provided by the invention contains phosphonate medicine components, can be specifically combined with hydroxyapatite in bone, and can inhibit osteoclast activity, thereby inhibiting bone absorption. Can be used for treating osteoporosis, osteitis deformans, hypercalcemia and ostealgia due to malignant tumor bone metastasis.

(4) The bone repair material provided by the invention contains a regenerative medical material with high biological activity, contains degradable gelatin capable of forming micropores of 100-300 mu m, and also contains phosphonate medicinal components with a treatment effect on osteoporosis, and the three components are synergistic, so that the effect of the bone repair material on treating bone defect and bone loss is obviously improved.

Detailed Description

In a first aspect, the present invention provides a bone repair material comprising a regenerative medical material.

The novel bone repair material comprises: the mass ratio of the powder to the liquid is (1-3): 1, and if the mass ratio is out of the range, the repairing material is difficult to solidify to form a repairing body.

Wherein the powder comprises the following raw materials by mass ratio, based on 100% of the total mass of the powder:

the liquid agent is an acidic buffer solution;

illustratively, the mass ratio of the regenerative medicine material may be any value or any range of 30, 40, 45, 50, 60, 65, 70%, the mass ratio of the calcium phosphate may be any value or any range of 30, 35, 40, 45, 50, 55, 60%, the mass ratio of the pyrophosphate may be any value or any range of 0, 0.5, 1, 2, 2.5, 3, 4, 5%, the mass ratio of the phosphonate functionalized gelatin may be any value or any range of 0, 0.5, 1, 2, 2.5, 3, 4, 5%, and the mass ratio of the powder and the liquid may be any value or any range of 1:1, 1.5:1, 2:1, 2.5:1, 3: 1.

Preferably, the powder comprises the following raw materials by mass ratio, based on 100% of the total mass of the powder:

the weight of each raw material of the bone repair product may be in known weight units such as μ g, mg, g, kg, etc., or multiples thereof such as 1/10, 1/100, 10, 100, etc.

The control of the amount of each raw material is advantageous for forming a cured product and for ensuring the efficacy of the material.

The specific surface area of the regenerative medical material is 100-1000m²The concentration of the water is 100, 200, 250, 300, 400, 500, 700, 750, 800, 900 and 1000m (for example)²Any value or any range in/g) of 50 to 500 times the specific surface area of the same-particle-size material (the specific surface area of the same-particle-size material is about 1.8m²/g), great reactivity; in addition, the regenerative medical material contains a large amount of high-coordination silicon elements, can quickly react with body fluid, and further improves the bone repair capacity of the material.

The phosphonate medicinal component contained in the phosphonate functionalized gelatin can be specifically combined with hydroxyapatite in bone, and can inhibit osteoclast activity, thereby inhibiting bone absorption. Can be used for treating osteoporosis, osteitis deformans, hypercalcemia and ostealgia due to malignant tumor bone metastasis.

The phosphonate functionalized gelatin is used as a gelatin component and can be degraded into micropores of 100-300 mu m after being implanted into human tissues, thereby providing a natural three-dimensional space structure for the adhesion, proliferation, differentiation and osteogenesis of osteoblasts, being beneficial to the growth of fiber and vascular tissues and promoting the repair of bone defect parts.

The bone repair material contains a regenerative medical material with high biological activity, contains degradable gelatin capable of forming micropores of 100-300 mu m, and also contains phosphonate medicinal components with a treatment effect on osteoporosis, and the three components have synergistic interaction, so that the effect of the bone repair material on treating bone defect and bone loss is obviously improved.

The above materials are mutually matched and cooperated, so that the performance of the product is further enhanced: the regenerative medical material has osteoinductivity, osteoconductivity and osseointegration capability, and can promote the rapid regeneration of bone tissues; the phosphonate medicinal component can be specifically combined with hydroxyapatite in bone, and can inhibit osteoclast activity, thereby inhibiting bone absorption, and can be used for treating osteoporosis, osteitis deformans, hypercalcemia and ostealgia caused by malignant tumor bone metastasis. The combination of the two can further promote the formation of new bones and prevent other diseases.

The regenerative medical material comprises at least one of a regenerative silicon material, a bioactive glass material and calcium silicate; further preferably, the regenerated silicon material is Regesi regenerated silicon; the bioactive glass material is at least one of 45S5 bioactive glass powder, 58S bioactive glass powder, 70S bioactive glass powder and 77S bioactive glass powder.

The regenerated silicon material is preferably the product Regesi regenerated silicon (including type I and type II) sold by Beijing Happy probiotic high-tech Co., Ltd, is solid powder of Regesi regenerated silicon consisting of SiO2, CaO and P2O5, has a large specific surface area (more than 360m 2/g), and has stable pH after contacting with body fluid.

The regenerated silicon material can also be POSS-based regenerated medical material prepared by the method described in Chinese patent application 201810030488.0; through detection, the regenerated silicon material comprises 40-70 wt% of silicon dioxide and 30-60 wt% of oxide selected from phosphorus, calcium and sodium, wherein the silicon dioxide forms a three-dimensional network structure, calcium ions and phosphorus ions are orderly distributed among three-dimensional network silicon atoms, and the content of the phosphorus oxide is 2-5 wt%.

The particle size of the regenerative medicine material is in the range of 0.1-50 μm (for example, any value or any range of 0.1, 0.5, 0.8, 1, 5, 10, 20, 25, 30, 40, 50 μm), preferably 0.1-30 μm; if the particle size is too large or too small, the system is difficult to cure and the mechanical properties are reduced.

The calcium phosphate comprises tricalcium phosphate or/and tetracalcium phosphate, and preferably consists of tricalcium phosphate and tetracalcium phosphate, wherein the mass ratio of tricalcium phosphate to tetracalcium phosphate is 1 (3-5) (for example, 1:3, 1:3.5, 1:4, 1:4.5, and 1: 5); if only one of them is used, the curing function and mechanical strength of the system are affected. The particle size of the calcium phosphate is 1-300 μm (for example, it can be any value or any range of 1, 50, 80, 100, 150, 200, 250, 300 μm), preferably 50-200 μm; if the particle size is too large or too small, the system is difficult to cure and the mechanical properties are reduced.

The pyrophosphate is one or a mixture of two of calcium pyrophosphate and sodium pyrophosphate; the particle size distribution range of the pyrophosphate is 1-50 μm (for example, the particle size distribution range can be any value or any range of 1, 5, 10, 20, 25, 30, 40, 45 and 50 μm); if the particle size is too large or too small, the system is difficult to cure and the mechanical properties are reduced.

The phosphonate in the phosphonate functionalized gelatin is a phosphonate medicinal component for treating orthopedic diseases, and comprises the following components: one or more of bisphosphonate, pamidronate, alendronate, risedronate, ibandronate and zoledronate are mixed in any proportion, and the mass percentage of phosphonate functional groups in phosphonate functionalized gelatin is 0.5-5%; if the content is too large, the stability of the system is affected or the problem of excessive drug is caused, and if the content is too small, the effect of the product is affected. The phosphonate-functionalized gelatin is preferably prepared as described in the following references: dual-functional of gelatin nanoparticles with an anti-cancer platform (II) -bisphosphate complex and minor-binding alendronate; farboc, m.diba, t.zinkevich, s.schmidt, m.j.harrington, a.p.m.kentgens, s.c.g, Leeuwenburgh; macromol. biosci.2016,16,717.

Preferably, the method for preparing the phosphate functionalized gelatin comprises the following steps:

step one, preparing a phosphonate gelatin mixed solution: dissolving phosphonate (such as bisphosphonate, pamidronate, alendronate, risedronate, ibandronate, and zoledronate) in physiological saline at room temperature, and adding gelatin to obtain mixture of phosphonate and gelatin.

Step two, swelling and dispersing: heating and dissolving the above mixed solution of phosphonate gelatin in 50-55 deg.C (50, 51, 52, 53, 54, 55 deg.C) hot water bath, stirring and swelling for 0.5-5 hr (0.5, 1, 2, 2.5, 3, 4, 5 hr), and adding glacial acetic acid to adjust pH to 1-5 to obtain pH-adjusted mixed solution; adding surfactant, and ultrasonic dispersing for 1-40min (1, 5, 10, 15, 20, 25, 30, 40min), preferably 20min to obtain suspension.

The surfactant is preferably a nonionic surfactant, more preferably tween, and further preferably tween-20; the mass ratio of the surfactant to the mixed solution after the pH value is adjusted is (0.01-0.2): 1.

step three, generating particles: adding isopropanol and glutaraldehyde into the suspension under magnetic stirring, and stirring for 5-20h (5, 8, 10, 12, 15, 20h) to obtain phosphonate functionalized gelatin (particle).

The molar ratio of glutaraldehyde to the amine (NH2) group in the gelatin corresponding to the suspension is 1-5, and the mass ratio of isopropanol to the suspension is 1: (5-100).

The particle size of the phosphonate functionalized gelatin is 50-500 μm (for example, can be any value or any value range of 50, 100, 150, 200, 250, 300, 400 and 500 μm), and is preferably 100-300 μm; if the particle size is too large or too small, the system is difficult to cure and the mechanical properties are reduced.

The liquid agent is an acidic buffer solution containing hyaluronic acid; the acid is one or more of citric acid, phosphoric acid or pyrophosphoric acid, and the molar concentration of the acid is 0.1-1.0 mol/L (for example, the molar concentration can be any value or any numerical range of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1 mol/L); the mass percentage of the hyaluronic acid is 0.01-5% (for example, any value or any numerical range of 0.01, 0.05, 0.08, 1, 1.5, 2, 2.5, 3, 4, 5%), preferably 0.1-0.5% based on 100% of the total mass of the liquid; if the molar concentration of the acid and the percentage of hyaluronic acid are too large or too small, the system is difficult to cure and the mechanical properties are reduced.

In a second aspect, the present invention provides a method of preparing a bone repair material of the first aspect, comprising the steps of:

the invention also provides a preparation method of the bone repair product, which comprises the following steps:

step one, weighing raw materials: the raw materials required for preparing the powder and the liquid are weighed according to the mixture ratio.

Step two, powder preparation: mixing the powder with the required raw materials by ball milling and stirring for 0.5-5h (0.5, 1, 2, 3, 4, 5h) to obtain powder.

Step three, preparation of liquid: the liquid agent is prepared by preparing raw materials required by the liquid agent.

Step four, mixing and curing: mixing the above powders and liquid according to the above ratio, blending thoroughly for 0.5-2 min (e.g. 0.5, 1, 1.5, 2min), and curing at 30-42 deg.C (e.g. 30, 32, 35, 38, 40, 42 deg.C), preferably 37 deg.C, and relative humidity of 100% to obtain the novel bone repair material.

In a third aspect, the invention also provides a bone repair product containing the regenerative medicine material, the main functional component of the bone repair product is the regenerative medicine material, the bone repair product contains the novel bone repair material of the first aspect or/and the second aspect, a new material is provided for treating bone defects, and the bone repair product is expected to bring good news to the rehabilitation of patients with bone diseases.

The technical solutions of the present invention will be described below with reference to specific embodiments, and the described embodiments are only a part of embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Examples 1 to 15

The preparation process of examples 1-15 comprises the following steps:

(1) weighing the raw materials according to the formula of the combination 1-5, wherein the raw materials are detailed in table 1, adding the regenerative medical material, the calcium phosphate, the pyrophosphate and the phosphonate functionalized gelatin according to the formula, and mixing to obtain the composite powder A.

(2) An acidic buffer solution B (liquid B) containing hyaluronic acid was then prepared according to the formulation of combinations 1-5, as detailed in Table 1.

(3) And (3) fully blending the composite powder A and the liquid B according to the solid-liquid mass ratio of (1-3) to 1 for 0.5-2 min, and curing at 37 ℃ and relative humidity of 100% to obtain the novel bone repair material.

The detection method comprises the following steps:

(1) blending a certain weight of composite powder and a certain weight of liquid by using a knife adjuster to form uniform and consistent slurry, namely: and (2) fully blending the composite powder A and the liquid B according to the solid-liquid mass ratio of (1-3) to 1 for 0.5-2 min, filling the uncured material into a stainless steel cylindrical mold with the diameter of 6mm and the height of 12mm, applying a certain pressure to compact the uncured material, and standing at 37 ℃ for 1h to prepare a cylindrical sample.

(2) Weighing, placing the sample into a simulated body fluid at 37 ℃, detecting the compressive strength of the sample after soaking for 24h according to the method of standard YY 0459-. The powder and liquid formulations of the bone repair product, the solid-liquid mass ratio and the performance data are listed in the following table.

The regenerative medical material adopted by the combination 1-5 comprises at least one of a regenerative silicon material, a bioactive glass material and calcium silicate.

Table 1: formulation of combination 1-5 bone repair products

Wherein, the regenerative medical materials adopted by the combinations 1-5 are respectively: combination 1: POSS-based regenerative medical material obtained from example 1 of patent application 201810030488.0; and (3) combination 2: a commercial product, Regesi type I, of the Beijing Happy probiotic high-tech limited; and (3) combination: 45S5 bioactive glass powder; and (4) combination: 70S bioactive glass powder; and (3) combination 5: calcium silicate.

The preparation method of A, B, C three phosphoric acid functionalized gelatin of combinations 1-5 comprises the following steps:

(1) respectively dissolving the corresponding phosphonate in normal temperature, then adding gelatin to prepare three phosphonate gelatin mixed solutions respectively.

(2) Swelling and dispersing: heating and dissolving the phosphonate gelatin mixed solution in a hot water bath at 50-55 ℃, continuously stirring and swelling for 0.5h (A), 2h (B) and 4h (C), and then adding glacial acetic acid to adjust the pH values to 2(A), 3(B) and 5(C) respectively to obtain a mixed solution after the pH value is adjusted; and adding Tween-20, wherein the mass ratio of each Tween-20 to the mixed solution after pH adjustment is 0.01: 1(A), 0.02:1(B), 0.2:1 (C); and then respectively carrying out ultrasonic dispersion for 20min to obtain suspension.

(3) And (3) generating particles: adding isopropanol and glutaraldehyde into each suspension under the condition of magnetic stirring, wherein the molar ratio of the glutaraldehyde added into each suspension to the amine (NH2) group in the gelatin corresponding to the suspension is respectively 1(A), 2(B) and 4(C), and the mass ratio of the isopropanol added into each suspension to the suspension is 1: 10; stirring for 5h (A), 10h (B), 18h (C) respectively to obtain the three phosphonate functionalized gelatin (particles), wherein the particle sizes of the three phosphonate functionalized gelatin (particles) are all 100-300 mu m.

Table 2 powder-liquid blend and solid-liquid mass ratio. The powder and liquid agent numbers correspond to the combination numbers, namely: powder number 1 corresponds to the powder of combination 1, and so on. The liquid agent number corresponds to the combination number, namely: liquid number 1 corresponds to liquid of combination 1, and so on; for example: in the product of example 1 on line 2 of table 2, powder No. 1, liquid No. 3, and solid-liquid mass ratio 1 are as follows: the powder of the combination 1 and the liquid of the combination 3 are adopted, and the solid-liquid mass ratio is 1: 1.

Examples	Powder numbering	Liquid agent number	Mass ratio of solid to liquid
				1	1	3	1
2	2	4	2
				3	3	5	3
4	4	2	2.5
				5	5	1	1.5
6	1	1	3
				7	2	2	2
8	3	3	1
				9	4	4	1.5
10	5	5	2.5
				11	1	5	3
12	2	4	2.5
				13	3	2	3
14	4	1	1.5
				15	5	3	2.5

Table 3 example bone repair product performance. It can be seen that the more easily the material degrades, the more porosity.

According to the requirements of the national food and drug administration on the technical review and guidance principle of calcium-phosphorus-silicon bone filling material registration, the initial setting time refers to: the time required from mixing of the powder liquid adding agent to the beginning of the loss of plasticity of the bone cement; the final setting time refers to: the time from mixing of the powder additive and the liquid additive to complete loss of plasticity of the bone cement and start to generate strength.

Example 16

Powder preparation: 65 parts by weight (granularity is 0.1-30 mu m), 5 parts by weight of tricalcium phosphate (granularity is 100-;

liquid agent: 2g of hyaluronic acid, 0.3mol of citric acid, 0.5mol of pyrophosphoric acid and 1L of deionized water;

the mass ratio of the powder to the liquid is 1: 1.

see examples 1-15 for methods of preparation.

The performance is as follows: initial setting time is 6.5min, final setting time is 24min, compressive strength is 13.2MPa, and porosity is 3.3%.

Comparative example 1

Powder preparation: octacalcium phosphate (Ca)₈H₂(PO₄)₆·5H₂O)65 parts by weight, 5 parts by weight of tricalcium phosphate (particle size 100-;

the mass ratio of the powder to the liquid is 1: 1.

the performance is as follows: initial setting time is 2min, final setting time is 9.5min, compressive strength is 15.7MPa, and porosity is 2.9%.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A novel bone repair material containing a regenerative medical material, characterized in that:

the novel bone repair material comprises: powders containing regenerative medical materials, and liquids;

the powder comprises the following raw materials by mass ratio, based on 100% of the total mass of the powder:

30-70% of regenerative medical material

30-60% of calcium phosphate

0 to 5 percent of pyrophosphate

0.05-5% of phosphonate functionalized gelatin;

the regenerative medical material comprises at least one of a regenerative silicon material, a bioactive glass material and calcium silicate;

the particle size range of the regenerative medical material is 0.1-50 μm, and the specific surface area of the regenerative medical material is 100-1000m²/g；

The calcium phosphate is composed of tricalcium phosphate and tetracalcium phosphate; the particle size of the calcium phosphate is 1-300 mu m;

the particle size of the pyrophosphate is 1-50 μm;

the particle size of the phosphonate functionalized gelatin is 50-500 μm;

the liquid agent is an acidic buffer solution containing hyaluronic acid; wherein the molar concentration of the acid is 0.1-1.0 mol/L; the mass percentage of the hyaluronic acid is 0.01-5% based on the total mass of the liquid agent as 100%;

the preparation method of the phosphate functionalized gelatin comprises the following steps:

step one, preparing a phosphonate gelatin mixed solution: dissolving phosphonate in normal saline at normal temperature, and then adding gelatin to prepare phosphonate gelatin mixed solution;

step two, swelling and dispersing: heating and dissolving the phosphonate gelatin mixed solution in a hot water bath at 50-55 ℃, continuously stirring and swelling for 0.5-5h, and then adding glacial acetic acid to adjust the pH value to 1-5 to obtain a mixed solution after the pH value is adjusted; adding surfactant, and performing ultrasonic dispersion for 1-40min to obtain suspension;

step three, generating particles: adding isopropanol and glutaraldehyde into the suspension under the condition of magnetic stirring, and stirring for 5-20h to obtain the phosphonate functionalized gelatin.

2. The novel bone repair material according to claim 1, characterized in that: the powder comprises the following raw materials by mass ratio, based on 100% of the total mass of the powder:

35 to 60 percent of regenerative medical material

Calcium phosphate 40-60%

0 to 3 percent of pyrophosphate

0.05-3% of phosphonate functionalized gelatin.

3. The novel bone repair material according to claim 1, characterized in that: when the powder agent is used, the mass ratio of the powder agent to the liquid agent is (1-3): 1.

4. The novel bone repair material according to claim 1, characterized in that: the particle size range of the regenerative medical material is 0.1-30 μm.

5. The novel bone repair material according to claim 1, characterized in that: the particle size of the calcium phosphate is 50-200 μm.

6. The novel bone repair material according to claim 1, characterized in that: the calcium phosphate is tricalcium phosphate and tetracalcium phosphate with the mass ratio of 1 (3-5).

7. The novel bone repair material according to claim 1, characterized in that: the pyrophosphate is one or two of calcium pyrophosphate and sodium pyrophosphate.

8. The novel bone repair material according to claim 1, characterized in that: the phosphonate in the phosphonate functionalized gelatin is one or a mixture of diphosphonate, pamidronate, alendronate, risedronate, ibandronate and zoledronate; wherein the mass percentage of the phosphonate functional group in the phosphonate functionalized gelatin is 0.5-5%.

9. The novel bone repair material according to claim 1, characterized in that: the particle size of the phosphonate functionalized gelatin is 100-200 μm.

10. The novel bone repair material according to claim 1, characterized in that: the acid included in the liquid agent is one or more of citric acid, phosphoric acid or pyrophosphoric acid.

11. The novel bone repair material according to claim 1, characterized in that: the mass percentage of the hyaluronic acid is 0.1-0.5%.

12. The novel bone repair material according to claim 1, characterized in that: the bioactive glass material is at least one of 45S5 bioactive glass powder, 58S bioactive glass powder, 70S bioactive glass powder and 77S bioactive glass powder.

13. A method for preparing a novel bone repair material containing regenerative medical material according to any one of claims 1 to 12, comprising the steps of:

powder preparation steps: weighing the required raw materials and uniformly mixing to obtain the powder;

a liquid preparation step: weighing the required raw materials, and preparing to obtain the liquid agent.

14. The method of claim 13,

when in use, the method also comprises a mixed curing step: and mixing the powder and the liquid, blending for 0.5-2 min, and curing at 30-42 ℃ under the condition of relative humidity of 100% to obtain the novel bone repair material.

15. The method of claim 14,

the temperature of the cure was 37 ℃.

16. A novel bone repair product comprising a regenerative medical material, which comprises: the novel bone repair material according to any one of claims 1 to 11, or the novel bone repair material obtained by the production method according to claim 13.