WO2023065474A1 - Calcium phosphate-based organic-inorganic composite bioactive material and preparation method therefor - Google Patents

Calcium phosphate-based organic-inorganic composite bioactive material and preparation method therefor Download PDF

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WO2023065474A1
WO2023065474A1 PCT/CN2021/135111 CN2021135111W WO2023065474A1 WO 2023065474 A1 WO2023065474 A1 WO 2023065474A1 CN 2021135111 W CN2021135111 W CN 2021135111W WO 2023065474 A1 WO2023065474 A1 WO 2023065474A1
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water
phosphate
calcium
bioactive material
organic
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PCT/CN2021/135111
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French (fr)
Chinese (zh)
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杨伟国
唐睿康
潘海华
吴隽
姚沙沙
黄可洁
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香港大学深圳医院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention relates to the technical field of biomedicine, in particular to an organic-inorganic composite bioactive material based on calcium phosphate and a preparation method thereof.
  • Bone cement is a kind of bone filling material that can be solidified and shaped in situ after being injected into the human body. It is mainly used clinically in vertebroplasty and as a large bone defect. Cement has formed a variety of systems during the development process, the two most important systems are polymethylmethacrylate bone cement (polymethylmethacrylate, PMMA) and calcium phosphate cement (calcium phosphate cement, CPC).
  • PMMA polymethylmethacrylate
  • CPC calcium phosphate cement
  • the precursor of PMMA bone cement has a certain degree of toxicity, and it will release a lot of heat when it is cured in the human body, causing edema or necrosis of the surrounding tissue.
  • the product will gradually transform into hydroxyapatite in the body. Therefore, CPC is expected to replace PMMA bone cement as a safer and more effective bone filling material.
  • the existing CPC has a small Young's modulus, high brittleness, and is easy to collapse in a liquid environment.
  • the technical problem to be solved by the present invention is to provide a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof, aiming at solving the mechanical strength and The problem of insufficient mechanical stability.
  • a calcium phosphate-based organic-inorganic composite bioactive material including: water and powder
  • the water includes water-soluble calcium salt, water-soluble phosphate , polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water
  • the powder includes calcium hydrogen phosphate and tetracalcium phosphate.
  • the ratio between the volume of the water preparation and the mass of the powder preparation is 0.65-35 mg of powder preparation per 1 ⁇ l of the water preparation.
  • the mass percentage of polyvinylpyrrolidone in the water formulation is 1.2% to 20%.
  • the calcium phosphate-based organic-inorganic composite bioactive material wherein the water-soluble calcium salt is calcium chloride.
  • the calcium phosphate-based organic-inorganic composite bioactive material wherein the water-soluble phosphate is one or more of orthophosphate, monohydrogen phosphate and dihydrogen phosphate.
  • the calcium phosphate-based organic-inorganic composite bioactive material wherein the molar ratio of Ca in the water-soluble calcium salt to P in the water-soluble phosphate is 0.5-1.5:1.
  • the calcium phosphate-based organic-inorganic composite bioactive material wherein the mass ratio of the water-soluble calcium salt to the polyaspartic acid is 1:1-10.
  • the mass ratio of the water-soluble phosphate to the polyacrylic acid is 1:1-10.
  • a preparation method of the calcium phosphate-based organic-inorganic composite bioactive material comprising:
  • the powder and the water are mixed, stirred, and left to solidify to obtain an organic-inorganic composite bioactive material.
  • the present invention forms organic-inorganic crosslinked bioactive materials through the combination of calcium phosphate nanoclusters, organic polymer calcium stabilizers and inorganic small molecule calcium crosslinkers, and retains the good biocompatibility of CPC , self-curing and less heat release in the curing process, can be molded before complete curing, the molding time is controlled by parameters such as water agent, powder ratio, and citric acid content, after complete curing, it can absorb moisture in the environment like a sponge in a liquid environment It expands to form a porous structure, and has good toughness and long-term mechanical stability.
  • the porous structure formed after water absorption is conducive to cell growth and fusion with patient tissue, and the expansion of the material will form a continuous micro-stress on the surrounding bone, which is conducive to promoting bone loss. regeneration.
  • the material can be injected in the shaping stage, its mechanical strength can be adjusted in a wide range, and it has good biocompatibility, so it can be used in many fields such as oral cavity, plastic surgery, tissue regeneration, etc.
  • Fig. 1 is the water absorption performance figure of the organic-inorganic composite bioactive material prepared by the embodiment of the present invention
  • Fig. 2 is the cytotoxic figure of the organic-inorganic composite bioactive material prepared by the embodiment of the present invention
  • Fig. 3 is the F-N diagram of the compression fatigue test of the organic-inorganic composite bioactive material prepared by the embodiment of the present invention.
  • Fig. 4 is a partially enlarged view of the F-N diagram of the compression fatigue test of the organic-inorganic composite bioactive material prepared in the embodiment of the present invention.
  • the present invention provides a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof.
  • a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof.
  • Bone cement is a kind of bone filling material that can be solidified and shaped in situ after being injected into the human body.
  • PMMA polymethyl methacrylate bone cement
  • CPC calcium phosphate cement
  • PMMA bone cement has stable mechanical properties and good application effect.
  • the polymerized product is non-toxic and corrosion-resistant, but it lacks biological activity and cannot be degraded in vivo. In some cases, a second operation is required to remove it.
  • PMMA bone cement The precursor has certain toxicity, because it must be injected into the human body to be repaired before it is fully cured, serious complications caused by leakage of the precursor have also been reported. In addition, PMMA bone cement will release a lot of heat when solidified in the human body, causing edema or necrosis of surrounding tissues.
  • Both the precursor and the cured product of CPC are non-toxic, and there is little heat release during curing.
  • the cured product will gradually transform into hydroxyapatite in the body.
  • Hydroxyapatite is the main inorganic component of human bone. Therefore, CPC is expected to replace PMMA bone. Cement becomes a safer and more effective bone filling material.
  • the Young's modulus of CPC is small, brittle, and easy to collapse in a liquid environment.
  • Some CPCs use high-temperature calcination and crystallization to improve their mechanical stability, but this method loses the bone cement before curing.
  • the advantages of regular shape shaping, and the crystals obtained after calcination are very different from the hydroxyapatite crystal form and crystallinity of human bone, and it is difficult to degrade in the human body.
  • an embodiment of the present invention provides a calcium phosphate-based organic-inorganic composite bioactive material, including: water and powder, the water includes water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, Polyaspartic acid, polyvinylpyrrolidone and citric acid, the powders include calcium hydrogen phosphate and tetracalcium phosphate.
  • the inventor found through research that water-soluble calcium salt and water-soluble phosphate are used as raw materials, and polyacrylic acid and polyaspartic acid are used as stabilizers to obtain calcium phosphate nano-clusters with small particle sizes.
  • the present invention uses water-soluble calcium salt, water-soluble Calcium phosphate nanoclusters are formed from permanent phosphate, polyacrylic acid and polyaspartic acid, and nanoscale calcium phosphate crystals, organic polymer calcium stabilizers and inorganic small molecule calcium cross-linking agents are simultaneously introduced into bioactive materials to obtain biological activity.
  • the material retains the good biocompatibility of CPC, self-curing and less heat release during the curing process, can be molded for a period of time before complete curing, and can absorb moisture in the environment after complete curing in a liquid environment and has good toughness and long-term mechanics Stability, the porous structure formed after water absorption is conducive to cell growth and fusion with patient tissue, and the expansion of the material will form a continuous slight stress on the surrounding bone, which is conducive to promoting bone regeneration.
  • the water agent provides the calcium phosphate nanoparticles required for curing, the organic polymer calcium stabilizer and the inorganic small molecule calcium cross-linking agent, the powder provides the calcium ions and phosphate ions required for curing, and the volumetric mass of the water agent and the powder Ratio will affect the performance of the resulting bioactive material.
  • the ratio between the volume of the liquid and the mass of the powder is 0.65-35 mg of powder per 1 ⁇ l of water, for example, 400 ⁇ l of water is added to 400 mg of powder. Under this volume-to-mass ratio, The liquid and powder can be mixed thoroughly to form a complete jelly.
  • polyvinylpyrrolidone and citric acid are used as an organic polymer calcium stabilizer and an inorganic small molecule calcium cross-linking agent respectively, and their content in the aqueous solution will affect the toughness and long-term mechanical stability of the obtained bioactive material in a liquid environment sex.
  • the mass percentage of polyvinylpyrrolidone in the water preparation is 1.2% to 20%
  • the mass percentage of citric acid in the water preparation is 0.5% to 20%
  • the active material obtained at this ratio Not only has good toughness, but also has a certain mechanical strength.
  • polyaspartic acid is used to form chelates with calcium ions in water-soluble calcium salts to stabilize calcium ions. Considering that too little polyaspartic acid added will cause calcium ion precipitation, the added polyaspartic acid Too much amino acid will lead to excess organic matter.
  • the mass ratio of the water-soluble calcium salt to polyaspartic acid is 1:(1-10).
  • polyacrylic acid is used to form a gel solution with water-soluble phosphate, so that the finally formed calcium phosphate nanoclusters have gel properties.
  • the mass ratio of described water-soluble phosphate and polyacrylic acid is 1:( 1 ⁇ 10). Since the water-soluble calcium salt and the water-soluble phosphate are first stabilized by polyaspartic acid and polyacrylic acid respectively, the prepared calcium phosphate nanoclusters are more stable and smaller in particle size than other amorphous calcium phosphates.
  • the relative molecular mass of the polyacrylic acid used in this example is 10-500kDa, and the obtained calcium phosphate nano
  • the cluster is a transparent, amorphous gel-like substance with good fluidity, injectability, biocompatibility and osteoinductivity, and can be transformed into crystalline hydroxyapatite after being placed at room temperature for seven days.
  • the water-soluble calcium salt is calcium chloride, and calcium chloride will not introduce oxidizing acid or toxic substances, so impurities will not appear. Considering that too high concentration of calcium ions will cause precipitation in subsequent reactions, the concentration of water-soluble calcium salts in the water solution should not be greater than 0.1 mol/L.
  • the water-soluble phosphate is one or more of orthophosphate, monohydrogen phosphate and dihydrogen phosphate. Considering that monohydrogen phosphate is weakly alkaline, it can act as an acid-base buffer without interfering with the formation of nanoclusters. In a specific embodiment, the water-soluble phosphate is monohydrogen phosphate, so The concentration of water-soluble phosphate in the above water preparation is not more than 0.1mol/L.
  • the present invention also provides a method for preparing the calcium phosphate-based organic-inorganic composite bioactive material, comprising:
  • calcium hydrogen phosphate and tetracalcium phosphate were first mixed to obtain a powder, and then water-soluble calcium salt, water-soluble phosphate, polyacrylic acid , polyaspartic acid, polyvinylpyrrolidone and citric acid are mixed to obtain an aqueous solution, and finally the powder and the aqueous solution are mixed, stirred into a viscous state, and left to solidify at 4-37°C to obtain an organic- Inorganic composite bioactive materials.
  • the present invention forms calcium phosphate nanoclusters through water-soluble calcium salt, water-soluble phosphate, polyacrylic acid and polyaspartic acid, and simultaneously introduces nanoscale calcium phosphate crystals, organic polymer calcium cross-linking agent and inorganic small Molecular calcium crosslinking agent, the obtained bioactive material retains the good biocompatibility of CPC, self-curing and less heat release during curing, can be molded for a period of time before complete curing, and can absorb in a liquid environment after complete curing It has good toughness and long-term mechanical stability.
  • the porous structure formed after water absorption is conducive to cell growth and fusion with patient tissues, and the expansion of the material will form a continuous micro-stress on the surrounding bone, which is conducive to promoting bone regeneration.
  • the organic-inorganic composite bioactive materials prepared in Example 1 and Example 2 of the present invention were weighed and soaked in phosphate buffered saline (phosphate buffer saline, PBS) respectively, soaked for 4 hours to dry the surface moisture of the bioactive materials, and After weighing again, the water absorption capacity of the bioactive material was calculated, and the water absorption performance diagram shown in Figure 1 was obtained. It can be seen from Figure 1 that the organic-inorganic composite bioactive materials prepared in Examples 1 and 2 of the present invention can absorb moisture in the environment, and will swell after absorbing water.
  • phosphate buffered saline phosphate buffer saline
  • the organic-inorganic composite bioactive material prepared in Example 1 of the present invention was soaked in deionized water for more than 4 hours and then subjected to a compression fatigue test.
  • the test parameters were loading waveform: sine wave. Number of tests: 1000 times. Frequency: 1Hz.
  • Test environment in air room temperature, 20.1°C ⁇ 2/28%RH ⁇ 5.
  • the F-N diagram of the compression fatigue test as shown in Fig. 3 and Fig. 4 is obtained. It can be seen from Fig. 3 and Fig. 4 that the organic-inorganic composite bioactive material prepared in Example 1 of the present invention has elasticity.
  • the present invention discloses a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof, including: water and powder, the water includes water-soluble calcium salt, water-soluble phosphate, poly Acrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water, the powders include calcium hydrogen phosphate and tetracalcium phosphate.
  • the present invention forms calcium phosphate nanoclusters through water-soluble calcium salt, water-soluble phosphate, polyacrylic acid and polyaspartic acid, and simultaneously introduces nanoscale calcium phosphate crystals, organic polymer calcium stabilizers and inorganic small molecules into bioactive materials.
  • the obtained bioactive material retains the good biocompatibility of CPC, self-curing and less heat release in the curing process, can be molded for a period of time before complete curing, and can absorb the environment in a liquid environment after complete curing Moisture has good toughness and long-term mechanical stability.
  • the porous structure formed after water absorption is conducive to cell growth and fusion with patient tissues, and the expansion of the material will form continuous micro-stress on the surrounding bone, which is conducive to promoting bone regeneration.

Abstract

Disclosed are a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method therefor. The organic-inorganic composite bioactive material comprises: a water preparation and a powder preparation, the water preparation comprises a water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water, and the powder preparation comprises calcium hydrogen phosphate and tetracalcium phosphate. In the present invention, a bioactive material of an organic-inorganic cross-linked structure is formed by a means of combining a calcium phosphate nanocluster, an organic polymer calcium stabilizer and an inorganic small molecule calcium cross-linking agent, thus retaining the good biocompatibility of CPC, the bioactive material self-cures, less heat is released during curing, and the bioactive material may be injected before curing is complete and may be shaped, the mechanical strength thereof may be adjusted within a wide range, and biocompatibility is good; in addition, the present invention may be applied in many fields. After being fully cured, the bioactive material may absorb moisture in the environment and expand to form a porous structure, facilitating cell growth and fusion with patient tissue. Moreover, the material expansion forms a slight continuous stress on surrounding bone, which facilitates the promotion of bone regeneration.

Description

基于磷酸钙的有机-无机复合生物活性材料及其制备方法Organic-inorganic composite bioactive material based on calcium phosphate and preparation method thereof 技术领域technical field
本发明涉及生物医药技术领域，具体涉及基于磷酸钙的有机-无机复合生物活性材料及其制备方法。The invention relates to the technical field of biomedicine, in particular to an organic-inorganic composite bioactive material based on calcium phosphate and a preparation method thereof.
背景技术Background technique
骨水泥是一类可以在注射到人体后，原位固化塑形的骨填充材料，在临床上主要应用于椎体成形术及充当大段骨缺损，有广泛的临床需求和巨大市场价值，骨水泥在发展过程中形成了多种体系，其中最重要的两大体系是聚甲基丙烯酸甲酯骨水泥(polymethylmethacrylate,PMMA)和磷酸钙骨水泥(calcium phosphate cement，CPC)。Bone cement is a kind of bone filling material that can be solidified and shaped in situ after being injected into the human body. It is mainly used clinically in vertebroplasty and as a large bone defect. Cement has formed a variety of systems during the development process, the two most important systems are polymethylmethacrylate bone cement (polymethylmethacrylate, PMMA) and calcium phosphate cement (calcium phosphate cement, CPC).
PMMA骨水泥的前体具有一定的毒性，在人体内固化时会放出大量的热，造成周围组织的水肿或坏死，CPC的前体和固化后产物都没有毒性，固化时放热很少，固化产物在体内会逐渐转变为羟基磷灰石，因此，CPC有望取代PMMA骨水泥成为更安全、有效的骨填充材料。然而，现有CPC的杨氏模量较小，脆性大，在液体环境中易溃散。The precursor of PMMA bone cement has a certain degree of toxicity, and it will release a lot of heat when it is cured in the human body, causing edema or necrosis of the surrounding tissue. The product will gradually transform into hydroxyapatite in the body. Therefore, CPC is expected to replace PMMA bone cement as a safer and more effective bone filling material. However, the existing CPC has a small Young's modulus, high brittleness, and is easy to collapse in a liquid environment.
因此，现有技术还有待于改进和发展。Therefore, the prior art still needs to be improved and developed.
发明内容Contents of the invention
本发明要解决的技术问题在于，针对现有技术的上述缺陷，提供一种基于磷酸钙的有机-无机复合生物活性材料及其制备方法，旨在解决现有CPC在液体环境下的力学强度和力学稳定性不足的问题。The technical problem to be solved by the present invention is to provide a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof, aiming at solving the mechanical strength and The problem of insufficient mechanical stability.
本发明解决该技术问题所采用的技术方案是：一种基于磷酸钙的有机-无机复合生物活性材料，其中，包括：水剂和粉剂，所述水剂包括水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水，所述粉剂包括磷酸氢钙和磷酸四钙。The technical solution adopted by the present invention to solve the technical problem is: a calcium phosphate-based organic-inorganic composite bioactive material, including: water and powder, the water includes water-soluble calcium salt, water-soluble phosphate , polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water, the powder includes calcium hydrogen phosphate and tetracalcium phosphate.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水剂的体积与所述粉剂的质量之间的比例为每1μl水剂加入0.65～35mg粉剂。In the calcium phosphate-based organic-inorganic composite bioactive material, the ratio between the volume of the water preparation and the mass of the powder preparation is 0.65-35 mg of powder preparation per 1 μl of the water preparation.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水剂中聚乙烯吡咯烷酮的质量百分比为1.2％～20％。In the calcium phosphate-based organic-inorganic composite bioactive material, the mass percentage of polyvinylpyrrolidone in the water formulation is 1.2% to 20%.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水剂中柠檬酸的质量百分比为0.5％～20％。In the calcium phosphate-based organic-inorganic composite bioactive material, the mass percentage of citric acid in the water formulation is 0.5% to 20%.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水溶性钙盐为氯化钙。The calcium phosphate-based organic-inorganic composite bioactive material, wherein the water-soluble calcium salt is calcium chloride.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水溶性磷酸盐为正磷酸盐、磷酸一氢盐和磷酸二氢盐中的一种或多种。The calcium phosphate-based organic-inorganic composite bioactive material, wherein the water-soluble phosphate is one or more of orthophosphate, monohydrogen phosphate and dihydrogen phosphate.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水溶性钙盐中的Ca与所述水溶性磷酸盐中的P的摩尔比为0.5～1.5:1。The calcium phosphate-based organic-inorganic composite bioactive material, wherein the molar ratio of Ca in the water-soluble calcium salt to P in the water-soluble phosphate is 0.5-1.5:1.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水溶性钙盐与所述聚天冬氨酸的质量比为1:1～10。The calcium phosphate-based organic-inorganic composite bioactive material, wherein the mass ratio of the water-soluble calcium salt to the polyaspartic acid is 1:1-10.
所述的基于磷酸钙的有机-无机复合生物活性材料，其中，所述水溶性磷酸盐与所述聚丙烯酸的质量比为1:1～10。In the organic-inorganic composite bioactive material based on calcium phosphate, the mass ratio of the water-soluble phosphate to the polyacrylic acid is 1:1-10.
一种所述的基于磷酸钙的有机-无机复合生物活性材料的制备方法，其中，包括：A preparation method of the calcium phosphate-based organic-inorganic composite bioactive material, comprising:
将磷酸氢钙和磷酸四钙混合，得到粉剂；Calcium hydrogen phosphate and tetracalcium phosphate are mixed to obtain a powder;
将水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水混合，得到水剂；mixing water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water to obtain an aqueous solution;
将所述粉剂和所述水剂混合，搅拌，静置固化，得到有机-无机复合生物活性材料。The powder and the water are mixed, stirred, and left to solidify to obtain an organic-inorganic composite bioactive material.
有益效果：本发明通过磷酸钙纳米簇、有机高分子钙稳定剂和无机小分子钙交联剂结合的方式，形成有机-无机交联结构的生物活性材料，保留了CPC的良好生物相容性，自固化且固化过程放热少，完全固化前可塑形，塑形时间通过水剂、粉剂比例，及柠檬酸含量等参数调控，完全固化后在液体环境下可像海绵一样吸收环境中的水分膨胀而形成多孔结构，并且具有良好的韧性和长期力学稳定性，吸水后形成的多孔结构有利于细胞长入与患者组织融合，且材料膨胀会对周围骨形成持续微小的应力，有利于促进骨再生。不仅如此，由于该材料塑形阶段可注射，力学强度可在较大范围内调控，且生物相容性好，可应用于口腔，整形 外科，组织再生等多个领域。Beneficial effects: the present invention forms organic-inorganic crosslinked bioactive materials through the combination of calcium phosphate nanoclusters, organic polymer calcium stabilizers and inorganic small molecule calcium crosslinkers, and retains the good biocompatibility of CPC , self-curing and less heat release in the curing process, can be molded before complete curing, the molding time is controlled by parameters such as water agent, powder ratio, and citric acid content, after complete curing, it can absorb moisture in the environment like a sponge in a liquid environment It expands to form a porous structure, and has good toughness and long-term mechanical stability. The porous structure formed after water absorption is conducive to cell growth and fusion with patient tissue, and the expansion of the material will form a continuous micro-stress on the surrounding bone, which is conducive to promoting bone loss. regeneration. Not only that, because the material can be injected in the shaping stage, its mechanical strength can be adjusted in a wide range, and it has good biocompatibility, so it can be used in many fields such as oral cavity, plastic surgery, tissue regeneration, etc.
附图说明Description of drawings
图1是本发明实施例制备的有机-无机复合生物活性材料的吸水性能图；Fig. 1 is the water absorption performance figure of the organic-inorganic composite bioactive material prepared by the embodiment of the present invention;
图2是本发明实施例制备的有机-无机复合生物活性材料的细胞毒性图；Fig. 2 is the cytotoxic figure of the organic-inorganic composite bioactive material prepared by the embodiment of the present invention;
图3是本发明实施例制备的有机-无机复合生物活性材料的的压缩疲劳试验F-N图；Fig. 3 is the F-N diagram of the compression fatigue test of the organic-inorganic composite bioactive material prepared by the embodiment of the present invention;
图4是本发明实施例制备的有机-无机复合生物活性材料的的压缩疲劳试验F-N图的局部放大图。Fig. 4 is a partially enlarged view of the F-N diagram of the compression fatigue test of the organic-inorganic composite bioactive material prepared in the embodiment of the present invention.
具体实施方式Detailed ways
本发明提供一种基于磷酸钙的有机-无机复合生物活性材料及其制备方法，为使本发明的目的、技术方案及优点更加清楚、明确，以下对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。The present invention provides a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof. In order to make the purpose, technical solution and advantages of the present invention clearer and clearer, the present invention will be further described in detail below. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention.
由于疾病和创伤等原因，全球每年约有百万患者需要进行骨移植手术，利用骨填充材料修复缺失的骨质。自体骨是临床使用的骨填充材料的金标准，但来源有限，且供体部位可能发生并发症。异体骨需要灭活以消除免疫原性，但灭活过程同时也降低了异体骨的生物活性，造成移植后发生重吸收和骨不连，严重的会导致患者畸形，因此研究可替代骨组织的生物材料得到了骨组织修复领域研究人员的广泛重视。Due to diseases and trauma, about one million patients around the world need bone grafting surgery every year, using bone filling materials to repair missing bone. Autologous bone is the gold standard of clinically used bone filling material, but its source is limited and complications may occur at the donor site. Allogeneic bone needs to be inactivated to eliminate immunogenicity, but the inactivation process also reduces the biological activity of allogeneic bone, resulting in reabsorption and nonunion after transplantation, which will seriously cause deformity in patients. Biomaterials have received extensive attention from researchers in the field of bone tissue repair.
骨水泥是一类可以在注射到人体后，原位固化塑形的骨填充材料，骨水泥在发展过程中形成了多种体系，其中最重要的两大体系是聚甲基丙烯酸甲酯骨水泥(polymethylmethacrylate，PMMA)和磷酸钙骨水泥(calcium phosphate cement，CPC)。PMMA骨水泥力学性能稳定，应用效果好，聚合后的产物无毒性，耐腐蚀，但其缺乏生物活性，不能在体内降解，部分情况下需进行二次手术取出，更严重的是，PMMA骨水泥的前体具有一定的毒性，由于其须在完全固化前注射到人体待修复部位，因前体渗漏造成的严重并发症也有见报道。另外，PMMA骨水泥在人体内固化时会放出大量的热，造成周围组织的水肿或坏死。Bone cement is a kind of bone filling material that can be solidified and shaped in situ after being injected into the human body. During the development of bone cement, a variety of systems have been formed, and the two most important systems are polymethyl methacrylate bone cement (polymethylmethacrylate, PMMA) and calcium phosphate cement (calcium phosphate cement, CPC). PMMA bone cement has stable mechanical properties and good application effect. The polymerized product is non-toxic and corrosion-resistant, but it lacks biological activity and cannot be degraded in vivo. In some cases, a second operation is required to remove it. What is more serious is that PMMA bone cement The precursor has certain toxicity, because it must be injected into the human body to be repaired before it is fully cured, serious complications caused by leakage of the precursor have also been reported. In addition, PMMA bone cement will release a lot of heat when solidified in the human body, causing edema or necrosis of surrounding tissues.
CPC的前体和固化后产物都没有毒性，固化时放热很少，固化产物在体内会逐渐转变为羟基磷灰石，羟基磷灰石是人骨的主要无机成分，因此，CPC有望取代PMMA骨水泥成为更安全、有效的骨填充材料。然而，CPC的杨氏模量较小，脆性大，在液体环境中易溃散，部分CPC采用高温煅烧结晶的方法提高其力学稳定性，但该方法丧失了骨水泥固化前可根据患者缺损的不规则形状塑形的优势，且煅烧后获得的晶体与人骨的羟基磷灰石晶型及结晶度都差别很大，在人体内难以降解。Both the precursor and the cured product of CPC are non-toxic, and there is little heat release during curing. The cured product will gradually transform into hydroxyapatite in the body. Hydroxyapatite is the main inorganic component of human bone. Therefore, CPC is expected to replace PMMA bone. Cement becomes a safer and more effective bone filling material. However, the Young's modulus of CPC is small, brittle, and easy to collapse in a liquid environment. Some CPCs use high-temperature calcination and crystallization to improve their mechanical stability, but this method loses the bone cement before curing. The advantages of regular shape shaping, and the crystals obtained after calcination are very different from the hydroxyapatite crystal form and crystallinity of human bone, and it is difficult to degrade in the human body.
为了解决上述问题，本发明实施例提供了一种基于磷酸钙的有机-无机复合生物活性材料，包括：水剂和粉剂，所述水剂包括水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮以及柠檬酸，所述粉剂包括磷酸氢钙和磷酸四钙。发明人经研究发现以水溶性钙盐和水溶性磷酸盐为原料，聚丙烯酸和聚天冬氨酸为稳定剂，可以得到小粒径的磷酸钙纳米簇，本发明通过水溶性钙盐、水溶性磷酸盐、聚丙烯酸以及聚天冬氨酸形成磷酸钙纳米簇，在生物活性材料中同时引入纳米级磷酸钙晶体、有机高分子钙稳定剂和无机小分子钙交联剂，得到的生物活性材料保留了CPC的良好生物相容性，自固化且固化过程放热少，完全固化前一段时间内可塑形，完全固化后在液体环境下可吸收环境中的水分而具有良好的韧性和长期力学稳定性，吸水后形成的多孔结构有利于细胞长入与患者组织融合，且材料膨胀会对周围骨形成持续微小的应力，有利于促进骨再生。In order to solve the above problems, an embodiment of the present invention provides a calcium phosphate-based organic-inorganic composite bioactive material, including: water and powder, the water includes water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, Polyaspartic acid, polyvinylpyrrolidone and citric acid, the powders include calcium hydrogen phosphate and tetracalcium phosphate. The inventor found through research that water-soluble calcium salt and water-soluble phosphate are used as raw materials, and polyacrylic acid and polyaspartic acid are used as stabilizers to obtain calcium phosphate nano-clusters with small particle sizes. The present invention uses water-soluble calcium salt, water-soluble Calcium phosphate nanoclusters are formed from permanent phosphate, polyacrylic acid and polyaspartic acid, and nanoscale calcium phosphate crystals, organic polymer calcium stabilizers and inorganic small molecule calcium cross-linking agents are simultaneously introduced into bioactive materials to obtain biological activity. The material retains the good biocompatibility of CPC, self-curing and less heat release during the curing process, can be molded for a period of time before complete curing, and can absorb moisture in the environment after complete curing in a liquid environment and has good toughness and long-term mechanics Stability, the porous structure formed after water absorption is conducive to cell growth and fusion with patient tissue, and the expansion of the material will form a continuous slight stress on the surrounding bone, which is conducive to promoting bone regeneration.
具体地，水剂提供固化所需的磷酸钙纳米颗粒、有机高分子钙稳定剂和无机小分子钙交联剂，粉剂提供固化所需的钙离子和磷酸根离子，水剂和粉剂的体积质量比会影响得到的生物活性材料的性能。在一具体实施例中，所述水剂的体积与所述粉剂的质量之间的比例为每1μl水剂加入0.65～35mg粉剂，例如，400μl水剂加入400mg粉剂，在该体积质量比下，水剂和粉剂可以充分混合，形成一块完整的胶状物。Specifically, the water agent provides the calcium phosphate nanoparticles required for curing, the organic polymer calcium stabilizer and the inorganic small molecule calcium cross-linking agent, the powder provides the calcium ions and phosphate ions required for curing, and the volumetric mass of the water agent and the powder Ratio will affect the performance of the resulting bioactive material. In a specific embodiment, the ratio between the volume of the liquid and the mass of the powder is 0.65-35 mg of powder per 1 μl of water, for example, 400 μl of water is added to 400 mg of powder. Under this volume-to-mass ratio, The liquid and powder can be mixed thoroughly to form a complete jelly.
具体地，聚乙烯吡咯烷酮和柠檬酸分别作为有机高分子钙稳定剂和无机小分子钙交联剂，其在水剂中的含量会影响得到的生物活性材料在液体环境下的韧性和长期力学稳定性。在一具体实施方式中，所述水剂中聚乙烯吡咯烷酮的质量百分比为1.2％～20％，所述水剂中柠檬酸的质量百分比为0.5％～20％，在该比例下得到的活性材料不仅具有良好的韧性，而且具有一定的力学强度。Specifically, polyvinylpyrrolidone and citric acid are used as an organic polymer calcium stabilizer and an inorganic small molecule calcium cross-linking agent respectively, and their content in the aqueous solution will affect the toughness and long-term mechanical stability of the obtained bioactive material in a liquid environment sex. In a specific embodiment, the mass percentage of polyvinylpyrrolidone in the water preparation is 1.2% to 20%, the mass percentage of citric acid in the water preparation is 0.5% to 20%, and the active material obtained at this ratio Not only has good toughness, but also has a certain mechanical strength.
具体地，聚天冬氨酸用于与水溶性钙盐中的钙离子形成螯合物，稳定钙离子，考虑到加入的聚天冬氨酸过少会引起钙离子沉淀，加入的聚天冬氨酸过多会导致有机物过量，在一具体实施例中，所述水溶性钙盐和聚天冬氨酸的质量比为1:(1～10)。Specifically, polyaspartic acid is used to form chelates with calcium ions in water-soluble calcium salts to stabilize calcium ions. Considering that too little polyaspartic acid added will cause calcium ion precipitation, the added polyaspartic acid Too much amino acid will lead to excess organic matter. In a specific embodiment, the mass ratio of the water-soluble calcium salt to polyaspartic acid is 1:(1-10).
具体地，聚丙烯酸用于与水溶性磷酸盐形成凝胶溶液，使最终形成的磷酸钙纳米簇具有凝胶性质。考虑到加入的聚丙烯酸过少会引起后续的磷酸钙沉淀，加入的聚丙烯酸过多会导致有机物过量，在一具体实施例中，所述水溶性磷酸盐和聚丙烯酸的质量比为1:(1～10)。由于水溶性钙盐和水溶性磷酸盐分别先被聚天冬氨酸和聚丙烯酸稳定，制备的磷酸钙纳米簇相对其它无定形磷酸钙更加稳定，并且粒径较小。Specifically, polyacrylic acid is used to form a gel solution with water-soluble phosphate, so that the finally formed calcium phosphate nanoclusters have gel properties. Considering that too little polyacrylic acid added can cause subsequent calcium phosphate precipitation, too much polyacrylic acid added can cause excessive organic matter, in a specific embodiment, the mass ratio of described water-soluble phosphate and polyacrylic acid is 1:( 1~10). Since the water-soluble calcium salt and the water-soluble phosphate are first stabilized by polyaspartic acid and polyacrylic acid respectively, the prepared calcium phosphate nanoclusters are more stable and smaller in particle size than other amorphous calcium phosphates.
进一步地，考虑到低分子量的聚丙烯酸，如相对分子质量为1800Da或5100Da的聚丙烯酸，不能形成纳米簇，本实施例中使用的聚丙烯酸的相对分子质量为10～500kDa，得到的磷酸钙纳米簇为透明的、无定形态的凝胶状物质，具有良好的流动性、注射性、生物相容性和成骨诱导性，在室温放置七天后，可以转变为结晶态的羟基磷灰石。Further, considering that low-molecular-weight polyacrylic acid, such as polyacrylic acid with a relative molecular mass of 1800Da or 5100Da, cannot form nanoclusters, the relative molecular mass of the polyacrylic acid used in this example is 10-500kDa, and the obtained calcium phosphate nano The cluster is a transparent, amorphous gel-like substance with good fluidity, injectability, biocompatibility and osteoinductivity, and can be transformed into crystalline hydroxyapatite after being placed at room temperature for seven days.
在一具体实施方式中，所述水溶性钙盐为氯化钙，氯化钙不会引入氧化性酸或有毒物质，所以不会导致杂质出现。考虑到钙离子浓度过高会在后续反应中引发沉淀，所述水剂中水溶性钙盐的浓度不大于0.1mol/L。In a specific embodiment, the water-soluble calcium salt is calcium chloride, and calcium chloride will not introduce oxidizing acid or toxic substances, so impurities will not appear. Considering that too high concentration of calcium ions will cause precipitation in subsequent reactions, the concentration of water-soluble calcium salts in the water solution should not be greater than 0.1 mol/L.
在一具体实现方式中，所述水溶性磷酸盐为正磷酸盐、磷酸一氢盐和磷酸二氢盐中的一种或多种。考虑到磷酸一氢盐为弱碱性，可以起到酸碱缓冲作用，且不会对纳米簇的形成产生干扰，在一具体实施例中，所述水溶性磷酸盐为磷酸一氢盐，所述水剂中水溶性磷酸盐的浓度不大于0.1mol/L。In a specific implementation manner, the water-soluble phosphate is one or more of orthophosphate, monohydrogen phosphate and dihydrogen phosphate. Considering that monohydrogen phosphate is weakly alkaline, it can act as an acid-base buffer without interfering with the formation of nanoclusters. In a specific embodiment, the water-soluble phosphate is monohydrogen phosphate, so The concentration of water-soluble phosphate in the above water preparation is not more than 0.1mol/L.
基于上述基于磷酸钙的有机-无机复合生物活性材料，本发明还提供一种所述的基于磷酸钙的有机-无机复合生物活性材料的制备方法，包括：Based on the above calcium phosphate-based organic-inorganic composite bioactive material, the present invention also provides a method for preparing the calcium phosphate-based organic-inorganic composite bioactive material, comprising:
S1、将磷酸氢钙和磷酸四钙混合，得到粉剂；S1, mixing calcium hydrogen phosphate and tetracalcium phosphate to obtain a powder;
S2、将水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水混合，得到水剂；S2, mixing water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water to obtain an aqueous solution;
S3、将所述粉剂和所述水剂混合，搅拌，静置固化，得到有机-无机复合生物活性材料。S3, mixing the powder and the water, stirring, and standing to solidify to obtain an organic-inorganic composite bioactive material.
具体地，本实施例在制备上述基于磷酸钙的有机-无机复合生物活性材料时，首先将磷酸氢钙和磷酸四钙混合，得到粉剂，然后将水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮以及柠檬酸混合，得到水剂，最后将所述粉剂和所述水剂混合，搅拌成粘稠状，在4～37℃下静置固化，得到有机-无机复合生物活性材料。本发明通过水溶性钙盐、水溶性磷酸盐、聚丙烯酸以及聚天冬氨酸形成磷酸钙纳米簇，在生物活性材料中同时引入纳米级磷酸钙晶体、有机高分子钙交联剂和无机小分子钙交联剂，得到的生物活性材料保留了CPC的良好生物相容性，自固化且固化过程放热少，完全固化前一段时间内可塑形，完全固化后在液体环境下可吸收环境中的水分而具有良好的韧性和长期力学稳定性，吸水后形成的多孔结构有利于细胞长入与患者组织融合，且材料膨胀会对周围骨形成持续微小的应力，有利于促进骨再生。Specifically, in this embodiment, when preparing the above calcium phosphate-based organic-inorganic composite bioactive material, calcium hydrogen phosphate and tetracalcium phosphate were first mixed to obtain a powder, and then water-soluble calcium salt, water-soluble phosphate, polyacrylic acid , polyaspartic acid, polyvinylpyrrolidone and citric acid are mixed to obtain an aqueous solution, and finally the powder and the aqueous solution are mixed, stirred into a viscous state, and left to solidify at 4-37°C to obtain an organic- Inorganic composite bioactive materials. The present invention forms calcium phosphate nanoclusters through water-soluble calcium salt, water-soluble phosphate, polyacrylic acid and polyaspartic acid, and simultaneously introduces nanoscale calcium phosphate crystals, organic polymer calcium cross-linking agent and inorganic small Molecular calcium crosslinking agent, the obtained bioactive material retains the good biocompatibility of CPC, self-curing and less heat release during curing, can be molded for a period of time before complete curing, and can absorb in a liquid environment after complete curing It has good toughness and long-term mechanical stability. The porous structure formed after water absorption is conducive to cell growth and fusion with patient tissues, and the expansion of the material will form a continuous micro-stress on the surrounding bone, which is conducive to promoting bone regeneration.
下面通过具体实施例对本发明进行进一步的解释说明。The present invention will be further explained by specific examples below.
实施例1Example 1
(1)将100mg磷酸氢钙和300mg磷酸四钙混合，得到400mg粉剂；(1) 100mg calcium hydrogen phosphate and 300mg tetracalcium phosphate are mixed to obtain 400mg powder;
(2)将水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水混合，得到400μl水剂；其中，聚乙烯吡咯烷酮的质量百分比为2％，柠檬酸的质量百分比为2％；(2) Mix water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water to obtain 400 μl of water; wherein, the mass percentage of polyvinylpyrrolidone is 2 %, the mass percent of citric acid is 2%;
(3)将所述粉剂和所述水剂混合，搅拌，静置固化，得到有机-无机复合生物活性材料。(3) The powder and the water are mixed, stirred, and left to solidify to obtain an organic-inorganic composite bioactive material.
实施例2Example 2
(1)将100mg磷酸氢钙和300mg磷酸四钙混合，得到400mg粉剂；(1) 100mg calcium hydrogen phosphate and 300mg tetracalcium phosphate are mixed to obtain 400mg powder;
(2)将水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水混合，得到380μl水剂；其中，聚乙烯吡咯烷酮的质量百分比为2.2％，柠檬酸的质量百分比为2.2％；(2) Mix water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water to obtain 380 μl of water; wherein, the mass percentage of polyvinylpyrrolidone is 2.2 %, the mass percentage of citric acid is 2.2%;
(3)将所述粉剂和所述水剂混合，搅拌，静置固化，得到有机-无机复合生物活性材料。(3) The powder and the water are mixed, stirred, and left to solidify to obtain an organic-inorganic composite bioactive material.
将本发明实施例1和实施例2制备的有机-无机复合生物活性材料称重后分别浸泡在磷酸缓冲盐溶液(phosphate buffer saline，PBS)中，浸泡4h后吸干生物活性材料表面水分，并再次称重后计算生物活性材料的吸水量，得到如图1所示 的吸水性能图。从图1可以看出本发明实施例1和实施例2制备的有机-无机复合生物活性材料可吸收环境中的水分，吸水后会发生膨胀。The organic-inorganic composite bioactive materials prepared in Example 1 and Example 2 of the present invention were weighed and soaked in phosphate buffered saline (phosphate buffer saline, PBS) respectively, soaked for 4 hours to dry the surface moisture of the bioactive materials, and After weighing again, the water absorption capacity of the bioactive material was calculated, and the water absorption performance diagram shown in Figure 1 was obtained. It can be seen from Figure 1 that the organic-inorganic composite bioactive materials prepared in Examples 1 and 2 of the present invention can absorb moisture in the environment, and will swell after absorbing water.
将本发明实施例1和实施例2制备的有机-无机复合生物活性材料分别浸泡于浸提液中，浸泡24h后使用浸提液培养人骨髓间充质干细胞(hMSCs)，并采用cck-8法分别在第1天和第3天测定细胞毒性，得到如图2所示的细胞毒性图。从图2可以看出，本发明实施例1和实施例2制备的有机-无机复合生物活性材料无细胞毒性。Soak the organic-inorganic composite bioactive materials prepared in Example 1 and Example 2 of the present invention in the extract solution respectively, and use the extract solution to cultivate human bone marrow mesenchymal stem cells (hMSCs) after soaking for 24 hours, and use cck-8 The cytotoxicity was measured on the 1st day and the 3rd day respectively, and the cytotoxicity graph shown in Figure 2 was obtained. It can be seen from Figure 2 that the organic-inorganic composite bioactive materials prepared in Example 1 and Example 2 of the present invention have no cytotoxicity.
将本发明实施例1制备的有机-无机复合生物活性材料在去离子水中浸泡4h以上后进行压缩疲劳试验，测试参数为加载波形：正弦波。测试次数：1000次。频率：1Hz。测试环境：空气室温中，20.1℃±2/28％RH±5。得到如图3和图4所示的压缩疲劳试验F-N图。从图3和图4可以看出，本发明实施例1制备的有机-无机复合生物活性材料具有弹性。The organic-inorganic composite bioactive material prepared in Example 1 of the present invention was soaked in deionized water for more than 4 hours and then subjected to a compression fatigue test. The test parameters were loading waveform: sine wave. Number of tests: 1000 times. Frequency: 1Hz. Test environment: in air room temperature, 20.1℃±2/28%RH±5. The F-N diagram of the compression fatigue test as shown in Fig. 3 and Fig. 4 is obtained. It can be seen from Fig. 3 and Fig. 4 that the organic-inorganic composite bioactive material prepared in Example 1 of the present invention has elasticity.
综上所述，本发明公开了一种基于磷酸钙的有机-无机复合生物活性材料及其制备方法，包括：水剂和粉剂，所述水剂包括水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水，所述粉剂包括磷酸氢钙和磷酸四钙。本发明通过水溶性钙盐、水溶性磷酸盐、聚丙烯酸以及聚天冬氨酸形成磷酸钙纳米簇，在生物活性材料中同时引入纳米级磷酸钙晶体、有机高分子钙稳定剂和无机小分子钙交联剂，得到的生物活性材料保留了CPC的良好生物相容性，自固化且固化过程放热少，完全固化前一段时间内可塑形，完全固化后在液体环境下可吸收环境中的水分而具有良好的韧性和长期力学稳定性，吸水后形成的多孔结构有利于细胞长入与患者组织融合，且材料膨胀会对周围骨形成持续微小的应力，有利于促进骨再生。In summary, the present invention discloses a calcium phosphate-based organic-inorganic composite bioactive material and a preparation method thereof, including: water and powder, the water includes water-soluble calcium salt, water-soluble phosphate, poly Acrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water, the powders include calcium hydrogen phosphate and tetracalcium phosphate. The present invention forms calcium phosphate nanoclusters through water-soluble calcium salt, water-soluble phosphate, polyacrylic acid and polyaspartic acid, and simultaneously introduces nanoscale calcium phosphate crystals, organic polymer calcium stabilizers and inorganic small molecules into bioactive materials. Calcium cross-linking agent, the obtained bioactive material retains the good biocompatibility of CPC, self-curing and less heat release in the curing process, can be molded for a period of time before complete curing, and can absorb the environment in a liquid environment after complete curing Moisture has good toughness and long-term mechanical stability. The porous structure formed after water absorption is conducive to cell growth and fusion with patient tissues, and the expansion of the material will form continuous micro-stress on the surrounding bone, which is conducive to promoting bone regeneration.
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。It should be understood that the application of the present invention is not limited to the above examples, and those skilled in the art can make improvements or transformations according to the above descriptions, and all these improvements and transformations should belong to the protection scope of the appended claims of the present invention.

Claims (10)

  1. 一种基于磷酸钙的有机-无机复合生物活性材料，其特征在于，包括：水剂和粉剂，所述水剂包括水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水，所述粉剂包括磷酸氢钙和磷酸四钙。An organic-inorganic composite bioactive material based on calcium phosphate, characterized in that it includes: an aqueous agent and a powder, the aqueous agent includes water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, poly Vinylpyrrolidone, citric acid and deionized water, the powders include calcium hydrogen phosphate and tetracalcium phosphate.
  2. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水剂的体积与所述粉剂的质量之间的比例为每1μl水剂加入0.65～35mg粉剂。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, characterized in that the ratio between the volume of the water preparation and the mass of the powder preparation is 0.65-35 mg of powder preparation per 1 μl of the preparation.
  3. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水剂中聚乙烯吡咯烷酮的质量百分比为1.2％～20％。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, characterized in that the mass percentage of polyvinylpyrrolidone in the water formulation is 1.2% to 20%.
  4. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水剂中柠檬酸的质量百分比为0.5％～20％。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, characterized in that the mass percentage of citric acid in the water formulation is 0.5% to 20%.
  5. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水溶性钙盐为氯化钙。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, wherein the water-soluble calcium salt is calcium chloride.
  6. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水溶性磷酸盐为正磷酸盐、磷酸一氢盐和磷酸二氢盐中的一种或多种。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, wherein the water-soluble phosphate is one or more of orthophosphate, monohydrogen phosphate and dihydrogen phosphate .
  7. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水溶性钙盐中的Ca与所述水溶性磷酸盐中的P的摩尔比为0.5～1.5:1。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, wherein the mol ratio of Ca in the water-soluble calcium salt to P in the water-soluble phosphate is 0.5～1.5: 1.
  8. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水溶性钙盐与所述聚天冬氨酸的质量比为1:1～10。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, wherein the mass ratio of the water-soluble calcium salt to the polyaspartic acid is 1:1-10.
  9. 根据权利要求1所述的基于磷酸钙的有机-无机复合生物活性材料，其特征在于，所述水溶性磷酸盐与所述聚丙烯酸的质量比为1:1～10。The organic-inorganic composite bioactive material based on calcium phosphate according to claim 1, wherein the mass ratio of the water-soluble phosphate to the polyacrylic acid is 1:1-10.
  10. 一种如权利要求1～9任一项所述的基于磷酸钙的有机-无机复合生物活性材料的制备方法，其特征在于，包括：A method for preparing an organic-inorganic composite bioactive material based on calcium phosphate according to any one of claims 1 to 9, characterized in that it comprises:
    将磷酸氢钙和磷酸四钙混合，得到粉剂；Calcium hydrogen phosphate and tetracalcium phosphate are mixed to obtain a powder;
    将水溶性钙盐、水溶性磷酸盐、聚丙烯酸、聚天冬氨酸、聚乙烯吡咯烷酮、柠檬酸以及去离子水混合，得到水剂；mixing water-soluble calcium salt, water-soluble phosphate, polyacrylic acid, polyaspartic acid, polyvinylpyrrolidone, citric acid and deionized water to obtain an aqueous solution;
    将所述粉剂和所述水剂混合，搅拌，静置固化，得到有机-无机复合生物活性材料。The powder and the water are mixed, stirred, and left to solidify to obtain an organic-inorganic composite bioactive material.
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