WO2023109377A1 - 一种载药介孔硅酸钙改性的pmma骨水泥的制备方法及其产品和应用 - Google Patents

一种载药介孔硅酸钙改性的pmma骨水泥的制备方法及其产品和应用 Download PDF

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WO2023109377A1
WO2023109377A1 PCT/CN2022/130652 CN2022130652W WO2023109377A1 WO 2023109377 A1 WO2023109377 A1 WO 2023109377A1 CN 2022130652 W CN2022130652 W CN 2022130652W WO 2023109377 A1 WO2023109377 A1 WO 2023109377A1
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calcium silicate
drug
mesoporous calcium
bone cement
preparation
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French (fr)
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崔大祥
杨迪诚
朱君
余将明
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上海纳米技术及应用国家工程研究中心有限公司
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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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/025—Other specific inorganic materials not covered by A61L27/04 - A61L27/12
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222—Gelatin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B33/00—Silicon; Compounds thereof
    • C01B33/20—Silicates
    • C01B33/24—Alkaline-earth metal silicates
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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 a method in the technical field of biomedical materials, in particular to a preparation method of drug-loaded mesoporous calcium silicate-modified PMMA bone cement and its product and application.
  • Osteoporosis is a common systemic bone metabolic disease characterized by low bone mass and damage to bone microstructure, which can easily lead to non-traumatic fractures.
  • Osteoporotic vertebral compression fractures are the most common osteoporotic fractures, accounting for about 45% of osteoporotic fractures.
  • Percutaneous vertebroplasty PVP is the most commonly used minimally invasive technique for the treatment of OVCFs.
  • the commonly used bone cement in PVP is PMMA bone cement.
  • the bone cement has high mechanical strength, but has a large elastic modulus and is not Possesses osteogenic bioactivity.
  • the element strontium is mixed into the calcium phosphate bone cement, and strontium can be used to promote the proliferation and osteogenic activity of osteoblasts, and locally improve the vertebral osteoporosis after PVP/PKP [Lode, Acta Biomaterialia, 2018];
  • the collagen material is mixed into the PMMA bone cement to construct a bioactive MC-PMMA bone cement with high mechanical strength and osteogenic effect [Zhu, Theranostics, 2020].
  • bioactive drugs such as protein peptides that are not resistant to high temperature to the modification of PMMA bone cement, which limits its further development and application in bone repair.
  • the present invention uses gelatin coating and mesoporous material drug loading technology to prepare mesoporous calcium silicate nanoparticles coated with gelatin and covalently modified drugs, which are mixed with PMMA powder as a filler to prepare drug-loaded mesoporous Calcium silicate modified PMMA bone cement.
  • the object of the present invention is to provide a preparation method of drug-loaded mesoporous calcium silicate modified PMMA bone cement.
  • Another object of the present invention is to provide a drug-loaded mesoporous calcium silicate modified PMMA bone cement product prepared by the above method.
  • Another object of the present invention is to provide an application of the above product.
  • a kind of preparation method of the PMMA bone cement of drug-loaded mesoporous calcium silicate modification is characterized in that, comprises the following steps:
  • mesoporous calcium silicate into the ethanol reflux solution at 80°C, add APTES, continue to reflux for 24 hours, centrifuge to collect the precipitate and wash it with ethanol three times.
  • the PMMA bone cement solid-phase powder is composed of 94% gelatin-coated drug-loaded mesoporous calcium silicate, 5% barium sulfate as an initiator developer, and 1% benzoyl peroxide as an initiator, and the above percentages are mass fractions.
  • the PMMA bone cement powder is mixed with the solidifying solution at a solid-to-liquid ratio of 1.5-2 g/mL to obtain the drug-loaded mesoporous calcium silicate modified PMMA bone cement.
  • the surfactant described in step (1) includes P123, polyethylene glycol, sodium stearate, sodium dodecylbenzenesulfonate.
  • the preparation method of the MES buffer solution described in step (2) is to take by weighing 4.875g MES (0.022mol) and be dissolved in 200mL ultrapure water, dropwise add the NaOH solution of 1mol/L to pH5.5, then settle to 250mL , stored at 4°C.
  • the drugs described in the step (2) include biologically active angiogenesis-promoting, bone-growth-promoting and anti-tumor drugs containing carboxyl groups.
  • the preparation method of the bone cement solid-phase powder described in step (4) is to mix the powder with a dry ball at a speed of 120 rpm.
  • the present invention provides a drug-loaded mesoporous calcium silicate modified PMMA bone cement, which is prepared according to any of the methods described above.
  • the invention provides an application of bone cement in the preparation of drug-loaded mesoporous calcium silicate modified PMMA bone cement material.
  • mesoporous calcium silicate powder for mesoporous silicon Carboxylated calcium silicate is subjected to amination grafting treatment, and then the bioactive drug with carboxyl group is connected by EDC/NHS reaction; drug-loaded mesoporous calcium silicate is dispersed in gelatin solution, and freeze-dried to obtain gelatin-coated drug-loaded mesoporous calcium silicate powder, which is added to PMMA powder to prepare drug-loaded mesoporous calcium silicate modified PMMA bone cement.
  • the present invention comprises the following steps:
  • the reaction was carried out under stirring in a water bath at 38°C for 24 hours. After drying the solvent by rotary evaporation at 60°C, the product was calcined in a muffle furnace at 600°C for 6 hours, and then cooled naturally.
  • the product is subjected to wet ball milling with ethanol as the medium at a rotational speed of 400rpm, ball milled for 2-4 hours, dried by rotary evaporation at 45°C, and then passed through a 300-mesh sieve to obtain mesoporous calcium silicate powder.
  • the PMMA bone cement solid-phase powder is composed of 94% gelatin-coated drug-loaded mesoporous calcium silicate, 5% barium sulfate initiator developer, and 1% benzoyl peroxide initiator. The above percentages are mass fractions.
  • the present invention uses gelatin-coated drug-loaded mesoporous calcium silicate as a drug carrier and filler, which can promote the biocompatibility and osteogenesis ability of PMMA bone cement, and reduce the elastic modulus of bone cement;
  • the dissolution rate in water, the bioactive drugs are cross-linked and fixed in the mesoporous pores, and under the protection of the gelatin coating, it can avoid the deactivation caused by the heat of polymerization, which expands the clinical application range of this type of bone cement.
  • the gelatin-coated drug-loaded mesoporous calcium silicate can promote the biocompatibility and osteogenesis ability of PMMA bone cement, reduce the elastic modulus of bone cement, and make it more suitable for clinical needs.
  • a drug-loaded mesoporous calcium silicate modified PMMA bone cement prepared according to the following steps:
  • the PMMA bone cement solid phase powder is composed of 94% gelatin-coated drug-loaded mesoporous calcium silicate, 5% initiator developer barium sulfate, and 1% initiator benzoyl peroxide in terms of mass percentage; the PMMA bone cement powder and The solidification solution is mixed according to the solid-liquid ratio of 1.5-2g/mL to obtain the drug-loaded mesoporous calcium silicate modified PMMA bone cement.
  • Example 2 Other steps and proportions are the same as in Example 1, except that the SVVYGLR polypeptide is replaced by silk fibroin to prepare drug-loaded mesoporous calcium silicate modified PMMA bone cement.
  • Example 2 Other steps and proportions were the same as in Example 1, except that the SVVYGLR polypeptide was replaced with VEGF to prepare drug-loaded mesoporous calcium silicate-modified PMMA bone cement.
  • Example 2 The other steps and proportions were the same as in Example 1, except that the SVVYGLR polypeptide was replaced by bmp-2 to prepare drug-loaded mesoporous calcium silicate modified PMMA bone cement.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Silicates, Zeolites, And Molecular Sieves (AREA)

Abstract

本发明涉及一种载药介孔硅酸钙改性的PMMA骨水泥的制备方法及其产品和应用，包括介孔硅酸钙的制备、载药介孔硅酸钙的制备、明胶包覆处理和改性PMMA骨水泥制备。本发明使用明胶包覆的载药介孔硅酸钙作为药物载体和填充剂，能促进PMMA骨水泥的生物相容性和成骨能力，降低骨水泥的弹性模量；明胶吸热能加速其水中的溶解速度，生物活性药物在介孔中交联固定，并在明胶包覆的保护下，能避免聚合放热导致其失去活性，扩大了该类骨水泥在临床中的应用范围。

Description

一种载药介孔硅酸钙改性的PMMA骨水泥的制备方法及其产品和应用 技术领域
本发明涉及一种生物医用材料技术领域的方法，具体是一种载药介孔硅酸钙改性的PMMA骨水泥的制备方法及其产品和应用。
背景技术
骨质疏松症(osteoporosis，OP)是一种常见的全身性骨代谢性病，以骨量低下、骨微结构组织损坏为特征，易导致非外伤性骨折。骨质疏松性椎体压缩性骨折(osteoporotic vertebral compression fractures，OVCFs)是最常见的骨质疏松性骨折，约占骨质疏松性骨折的45％。经皮椎体成形术(percutaneous vertebroplasty，PVP)是最常用的治疗OVCFs微创技术，目前PVP术中常用填充骨水泥为PMMA骨水泥，该骨水泥力学强度高，但弹性模量大，并且不具备刺激成骨生物活性。部分学者专注于研究PVP术后局部改善骨质疏松的骨水泥材料与方法，
如将元素锶混入磷酸钙骨水泥中，利用锶促进成骨细胞增殖与成骨活性的作用，局部改善PVP/PKP术后椎体骨质疏松情况[Lode,Acta Biomaterialia,2018]；如将矿化胶原材料混入PMMA骨水泥中，构建出同时具备高力学强度和成骨效应的生物活性MC-PMMA骨水泥[Zhu,Theranostics,2020]。但由于PMMA骨水泥固化过程中伴随着聚合放热，蛋白多肽类不耐高温的生物活性药物往往难以应用于PMMA骨水泥的改性，限制了其在骨修复中的进一步发展和应用。
基于以上研究背景，本发明使用明胶包覆和介孔材料载药技术，制备明胶包覆的共价修饰药物的介孔硅酸钙纳米颗粒，作为填充物与PMMA粉末混合，制备载药介孔硅酸钙改性的PMMA骨水泥。
发明内容
本发明的目的在于提供一种载药介孔硅酸钙改性的PMMA骨水泥的制备方法。
本发明的再一目的在于：提供一种上述方法制备的载药介孔硅酸钙改性的PMMA骨水泥产品。
本发明的又一目的在于：提供一种上述产品的应用。
本发明目的通过下述方案实现：一种载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，包括以下步骤：
(1)介孔硅酸钙的制备：
将摩尔比1:1的正硅酸四乙酯、四水硝酸钙加入溶有硝酸、表面活性剂的水溶液中，38℃水 浴搅拌下反应24小时；60℃旋转蒸发干溶剂后，产物置于马弗炉中600℃煅烧6小时，之后自然冷却；产物用乙醇为介质进行湿法球磨，转速为400rpm，球磨2-4小时，45℃旋蒸干燥，之后过300目筛网，得到介孔硅酸钙粉末；
(2)载药介孔硅酸钙的制备
将介孔硅酸钙加入80℃的乙醇回流溶液中，加入APTES，继续回流24小时，离心收集沉淀并用乙醇清洗3次。产物分散于MES缓冲液(0.1mol/L，p H＝5.5)中。配制药物溶液，加入EDC、NHS活化羧基基团，之后加入上述氨基化介孔硅酸钙的MES缓冲液中，常温避光反应12小时。产物离心，水洗3次，于37℃下干燥，得到载药介孔硅酸钙；
(3)明胶包覆处理
将载药介孔硅酸钙按0.1-1：1(g/mL)的比例加入1％(g/mL)明胶水溶液中，高速搅拌10min，用液氮冰冻，进行冷冻干燥，干燥后产物粉碎，得到明胶包覆的载药介孔硅酸钙粉末；
(4)改性PMMA骨水泥制备
PMMA骨水泥固相粉末由明胶包覆载药介孔硅酸钙94％、引发剂显影剂硫酸钡5％，引发剂过氧化苯甲酰1％组成，以上百分比为质量分数。将PMMA骨水泥粉末与固化液按固液比1.5-2g/mL进行混合，得到载药介孔硅酸钙改性PMMA骨水泥。
步骤(1)所述的表面活性剂包括P123、聚乙二醇、硬质酸钠、十二烷基苯磺酸钠。
步骤(2)所述的MES缓冲溶液的配制方法为称取4.875g MES(0.022mol)溶于200mL超纯水中，逐滴加入1mol/L的NaOH溶液至pH5.5，然后定容至250mL，4℃保存。
步骤(2)所述的药物包括包含羧基基团的生物活性促血管化、促骨生长、抗肿瘤药物。
步骤(4)所述的骨水泥固相粉末的配制方式为将粉末用干法球混合，转速为120rpm。
本发明提供一种载药介孔硅酸钙改性的PMMA骨水泥，根据上述任一所述方法制备得到。
本发明提供一种骨水泥在制备载药介孔硅酸钙改性的PMMA骨水泥材料中的应用。
将摩尔比1:1的正硅酸四乙酯、四水硝酸钙加入溶有硝酸、表面活性剂的水溶液中，反应结束后干燥、煅烧、球磨得到介孔硅酸钙粉末；对介孔硅酸钙进行氨基化接枝处理，之后通过EDC/NHS反应连接带羧基的生物活性药物；将载药介孔硅酸钙分散于明胶溶液，冻干得到明胶包覆的载药介孔硅酸钙粉末，将其加入PMMA粉末中，制备得到载药介孔硅酸 钙改性的PMMA骨水泥。
本发明包括以下步骤：
1、将摩尔比1:1的正硅酸四乙酯、四水硝酸钙加入溶有硝酸、表面活性剂的水溶液中，
38℃水浴搅拌下反应24小时。60℃旋转蒸发干溶剂后，产物置于马弗炉中600℃煅烧6小时，之后自然冷却。
2、产物用乙醇为介质进行湿法球磨，转速为400rpm，球磨2-4小时，45℃旋蒸干燥，之后过300目筛网，得到介孔硅酸钙粉末。
3、将介孔硅酸钙加入80℃的乙醇回流溶液中，加入APTES，继续回流24小时，离心收集沉淀并用乙醇清洗3次。产物分散于MES缓冲液(0.1mol/L，p H＝5.5)中。
4、配制药物溶液，加入EDC、NHS活化羧基基团，之后加入上述氨基化介孔硅酸钙的MES缓冲液中，常温避光反应12小时。产物离心，水洗3次，于37℃下干燥，得到载药介孔硅酸钙。
5、将载药介孔硅酸钙按0.1-1：1(g/mL)的比例加入1％(g/mL)明胶水溶液中，高速搅拌10min，用液氮冰冻，进行冷冻干燥，干燥后产物粉碎，得到明胶包覆的载药介孔硅酸钙粉末。
6、PMMA骨水泥固相粉末由明胶包覆载药介孔硅酸钙94％、引发剂显影剂硫酸钡5％，引发剂过氧化苯甲酰1％组成，以上百分比为质量分数。
7、将PMMA骨水泥粉末与固化液按固液比1.5-2g/mL进行混合，得到载药介孔硅酸钙改性PMMA骨水泥。
本发明使用明胶包覆的载药介孔硅酸钙作为药物载体和填充剂，能促进PMMA骨水泥的生物相容性和成骨能力，降低骨水泥的弹性模量；明胶吸热能加速其水中的溶解速度，生物活性药物在介孔中交联固定，并在明胶包覆的保护下，能避免聚合放热导致其失去活性，扩大了该类骨水泥在临床中的应用范围。
本发明的优点在于：
1、明胶包覆的载药介孔硅酸钙能促进PMMA骨水泥的生物相容性和成骨能力，降低骨水泥的弹性模量，使其更满足临床需求。
2、明胶吸热能加速其水中的溶解速度，生物活性药物在介孔中交联固定，并在明胶包覆的保护下，能避免聚合放热导致其失去活性，扩大了该类骨水泥在临床中的应用范围。
具体实施方式
以下实施例以发明技术方案为前提进行实施，给出了详细的实施方式和具体的操作过 程，但本发明的保护范围并不限于下述的实施例。
实施例1
一种载药介孔硅酸钙改性的PMMA骨水泥，按以下步骤制备：
(1)介孔硅酸钙的制备：
将390mL去离子水、60mL硝酸、9g表面活性剂P123混合，搅拌至溶液澄清得水溶液；在上述水溶液中加入25.5g正硅酸四乙酯、28.8g四水硝酸钙，38℃水浴搅拌下反应24小时；反应完后，60℃旋转蒸发干溶剂后，产物置于马弗炉中600℃煅烧6小时，之后自然冷却的产物用乙醇为介质进行湿法球磨，转速为400rpm，球磨2-4小时，45℃旋蒸干燥，之后过300目筛网，得到介孔硅酸钙粉末；
(2)载药介孔硅酸钙的制备
将500mg介孔硅酸钙粉末分散于150mL乙醇中，加入加热至80℃回流，加入1.5mL硅烷偶联剂APTES，继续回流24小时，离心收集沉淀，并用乙醇清洗3次，得到氨基化介孔硅酸钙；将该氨基化介孔硅酸钙产物分散于MES缓冲液(0.1mol/L，p H＝5.5)中；量取2mL0.3mg/mL的SVVYGLR多肽，依次加入654μL 2.8mM的EDC、132μL 2.8mM的NHS活化羧基基团，之后加入上述氨基化介孔硅酸钙的MES缓冲液中，常温避光反应12小时，所得产物离心、水洗3次，于37℃下干燥，得到载药介孔硅酸钙；
(3)明胶包覆处理
将载药介孔硅酸钙按固液比g/mL为0.1-1：1的比例加入固液g/mL比为1％明胶水溶液中，高速搅拌10min，用液氮冰冻，进行冷冻干燥，干燥后产物粉碎，得到明胶包覆的载药介孔硅酸钙粉末；
(4)改性PMMA骨水泥制备
PMMA骨水泥固相粉末按质量百分比计由明胶包覆载药介孔硅酸钙94％、引发剂显影剂硫酸钡5％，引发剂过氧化苯甲酰1％组成；将PMMA骨水泥粉末与固化液按固液比1.5-2g/mL进行混合，得到载药介孔硅酸钙改性PMMA骨水泥。
实施例2
其他步骤及配比与实施例1相同，只是SVVYGLR多肽替换为丝素蛋白，制备得到载药介孔硅酸钙改性PMMA骨水泥。
实施例3
其他步骤及配比与实施例1相同，只是SVVYGLR多肽替换为VEGF，制备得到载药介孔硅酸钙改性PMMA骨水泥。
实施例4
其他步骤及配比与实施例1相同，只是SVVYGLR多肽替换为bmp-2，制备得到载药介孔硅酸钙改性PMMA骨水泥。

Claims (9)

  1. 一种载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，包括以下步骤：
    (1)介孔硅酸钙的制备：
    将摩尔比1:1的正硅酸四乙酯、四水硝酸钙加入溶有硝酸、表面活性剂的水溶液中，38℃水浴搅拌下反应24小时；60℃旋转蒸发干溶剂后，产物置于马弗炉中600℃煅烧6小时，之后自然冷却的产物用乙醇为介质进行湿法球磨，转速为400rpm，球磨2-4小时，45℃旋蒸干燥，之后过300目筛网，得到介孔硅酸钙粉末；
    (2)载药介孔硅酸钙的制备
    将介孔硅酸钙加入80℃的乙醇回流溶液中，加入APTES，继续回流24小时，离心收集沉淀并用乙醇清洗3次，得到氨基化介孔硅酸钙；将氨基化介孔硅酸钙分散于0.1mol/L、pH＝5.5的MES缓冲液中；配制药物溶液，加入EDC、NHS活化羧基基团，之后加入上述氨基化介孔硅酸钙的MES缓冲液中，常温避光反应12小时，产物离心，水洗3次，于37℃下干燥，得到载药介孔硅酸钙；
    (3)明胶包覆处理
    将载药介孔硅酸钙按固液比g/mL为0.1-1：1的比例加入固液g/mL比为1％明胶水溶液中，高速搅拌10min，用液氮冰冻，进行冷冻干燥，干燥后产物粉碎，得到明胶包覆的载药介孔硅酸钙粉末；
    (4)改性PMMA骨水泥制备
    PMMA骨水泥固相粉末按质量百分比计由明胶包覆载药介孔硅酸钙94％、引发剂显影剂硫酸钡5％，引发剂过氧化苯甲酰1％组成；将PMMA骨水泥粉末与固化液按固液比1.5-2g/mL进行混合，得到载药介孔硅酸钙改性PMMA骨水泥。
  2. 根据权利要求1所述载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，步骤(1)所述的表面活性剂包括P123、聚乙二醇、硬质酸钠、十二烷基苯磺酸钠。
  3. 根据权利要求1所述载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，步骤(2)所述的MES缓冲溶液的配制方法为称取4.875g MES溶于200mL超纯水中，逐滴加入1mol/L的NaOH溶液至pH5.5，然后，定容至250mL，4℃保存。
  4. 根据权利要求1所述载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，步骤(2)所述的药物包括包含羧基基团的生物活性促血管化、促骨生长、抗肿瘤药物。
  5. 根据权利要求1所述载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，步骤(4)所述的骨水泥固相粉末的配制方式为将粉末用干法球混合，转速为120rpm。
  6. 根据权利要求1至5任一项所述载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征 在于，按以下步骤制备：
    (1)介孔硅酸钙的制备：
    将390mL去离子水、60mL硝酸、9g表面活性剂P123混合，搅拌至溶液澄清得水溶液；在上述水溶液中加入25.5g正硅酸四乙酯、28.8g四水硝酸钙，38℃水浴搅拌下反应24小时；反应完后，60℃旋转蒸发干溶剂后，产物置于马弗炉中600℃煅烧6小时，之后自然冷却的产物用乙醇为介质进行湿法球磨，转速为400rpm，球磨2-4小时，45℃旋蒸干燥，之后过300目筛网，得到介孔硅酸钙粉末；
    (2)载药介孔硅酸钙的制备
    将500mg介孔硅酸钙粉末分散于150mL乙醇中，加入加热至80℃回流，加入1.5mL硅烷偶联剂APTES，继续回流24小时，离心收集沉淀，并用乙醇清洗3次，得到氨基化介孔硅酸钙；将该氨基化介孔硅酸钙产物分散于0.1mol/L，pH＝5.5的MES缓冲液中；量取2mL 0.3mg/mL的SVVYGLR多肽，依次加入654μL 2.8mM的EDC、132μL 2.8mM的NHS活化羧基基团，之后加入上述氨基化介孔硅酸钙的MES缓冲液中，常温避光反应12小时，所得产物离心、水洗3次，于37℃下干燥，得到载药介孔硅酸钙；
    (3)明胶包覆处理
    将载药介孔硅酸钙按固液比g/mL为0.1-1：1的比例加入固液g/mL比为1％明胶水溶液中，高速搅拌10min，用液氮冰冻，进行冷冻干燥，干燥后产物粉碎，得到明胶包覆的载药介孔硅酸钙粉末；
    (4)改性PMMA骨水泥制备
    PMMA骨水泥固相粉末按质量百分比计由明胶包覆载药介孔硅酸钙94％、引发剂显影剂硫酸钡5％，引发剂过氧化苯甲酰1％组成；将PMMA骨水泥粉末与固化液按固液比1.5-2g/mL进行混合，得到载药介孔硅酸钙改性PMMA骨水泥。
  7. 根据权利要求6所述载药介孔硅酸钙改性的PMMA骨水泥的制备方法，其特征在于，所述的SVVYGLR多肽替换为丝素蛋白、VEGF或bmp-2。
  8. 一种载药介孔硅酸钙改性的PMMA骨水泥，其特征在于根据权利要求1-7任一所述方法制备得到。
  9. 根据权利要求8所述骨水泥在制备载药介孔硅酸钙改性的PMMA骨水泥材料中的应用。
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