CN115068694A - 一种活性可注射骨水泥修复材料的制备方法 - Google Patents
一种活性可注射骨水泥修复材料的制备方法 Download PDFInfo
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Abstract
本发明公开一种活性可注射骨水泥修复材料的制备方法,将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须混合均匀,得到固相;将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相;将液相添加至固相中,并搅拌成糊状物,得到活性可注射骨水泥修复材料;本发明材料可用于骨、软骨、口腔等病损组织精准修复,具有可注射、原位固化、力学性能可控、抗感染和良好的生物学激发效应,能有效解决外科手术创伤大、修复慢以及手术适应证范围窄、并发症发生率高等难点问题,本发明制备工艺简单,成本低廉,产量稳定,具有良好的临床应用前景和广阔的市场潜力。
Description
技术领域
本发明涉及一种活性可注射骨水泥修复材料的制备方法,属于生物医用材料技术领域。
背景技术
微创治疗是近年来医学领域的新方向,临床上外科医生主要透过内窥镜及各种显像技术在无需对患者造成巨大伤口的情况下施行。与传统手术相比,微创治疗具有伤口小、瘢痕细、手术中出血少、术后病人疼痛轻、恢复快等特征,受到社会各界的高度关注。
椎弓根螺钉固定是微创治疗的一个分支,已被广泛应用于多种适应症的胸腰椎稳定,如促进骨融合、矫正畸形和固定椎体骨折。但随着人口老龄化,骨质疏松症病例增多,椎弓根螺钉固定术面临挑战,因为骨质疏松患者伴随骨密度降低,螺钉界面的机械力受到不利影响,导致松动、断裂、或退离椎弓根螺钉。因此,为了改善椎弓根螺钉在骨质疏松脊柱中的附着,使用骨水泥注射空心椎弓根螺钉(CICPSs)进行骨水泥加固已被证明是一种有效的方法。在这种方法中,骨水泥是影响椎弓根螺钉扩增手术临床结果的关键因素。尽管只有聚甲基丙烯酸甲酯(PMMA)水泥被美国食品和药物管理局(FDA)批准用于CICPSs的临床应用,但使用PMMA进行增强有许多缺点,包括渗漏、单体毒性、高热生成、高刚度和不可降解性。所有这些在临床实践中都被证明会造成严重的副作用。最重要的是,由于其不可降解性和缺乏生物活性,PMMA既不能与骨形成生物结合,也不能诱导骨长入或骨结合。然而,PMMA水泥与螺钉形成过度粘结,这导致在翻修手术中取出或拆卸螺钉极其困难。此外,在考虑术后感染的情况下,不可降解PMMA成为深部感染和浅表感染的另一个高危因素。
因此,基于微创技术与材料原位激发组织再生相结合,制备出一种具有类似于PMMA的生物力学和处理性能,但能够克服PMMA缺点的活性骨水泥修复材料,对于腰椎退行性疾病患者来说显得尤为重要。一直是生物医用材料技术领域研究的热点问题之一。
磷酸钙(CaP)生物陶瓷长期以来被用作增强和促进新骨形成的骨修复材料。因为CaP化合物约占骨无机相的70%,使得这类材料具有优异的骨传导性和生物活性,被认为是最适合的骨修复材料。Brown和Chow首次报道了一种自凝磷酸钙骨水泥(CalciumPhosphate Cement,CPC)。近30年来,CPC因其优异的生物相容性、良好的骨传导性、自整固性、可注射性和填充复杂形状缺损的能力而被广泛研究,并被证明磷酸钙骨水泥材料强化椎弓根螺钉后,能够增加椎弓根螺钉的抗拔出强度。
但是磷酸钙骨水泥是比PMMA脆弱的材料,这种较低的内在机械强度限制了磷酸钙骨水泥在承重骨修复中的应用。而且磷酸钙骨水泥容易被手术部位可能存在的多余液体分解。从CPC分离出来的固体颗粒可进入血管,引起严重的炎症反应、肺栓塞和心血管疾病。可注射CPC抗溃散能力差,极大地限制了其广泛应用。此外,手术部位感染在骨科手术中的频繁发生,目前临床上主要使用抗生素治疗手术部位感染。然而,长期重复使用这些药物会导致多药耐药细菌突变。因此,开发有效的抗菌骨水泥也已成为当务之急。
为了解决磷酸钙骨水泥存在的问题,近年来活性骨水泥修复材料成为研究的热点。如何使其具有可注射、原位固化、力学性能可控、抗感染和良好的生物学激发效应是目前研究的难点,这对强化椎弓根螺钉的应用具有重要的意义。
考虑到CPC在强度、脆性和可靠性方面的力学性能;人们提出了两种主要的策略来克服这些限制。首先,制备更致密的由更小的晶体组成的CPC,可以增强其内在的力学性能,尽管不能保证骨长入和其他生物性能的关键因素能够安全地保持。其次,将增强纤维如碳纤维、玻璃纤维、硅灰石、聚酰胺、、胶原蛋白和壳聚糖加入CPC基体中,该纤维通过纤维桥接、裂纹挠度和摩擦滑动等机理增强CPC基体。然而,尽管这些纤维可能会为CPC基体引入特定的结构或力学性能,但它们中的大多数并不能同时提供适当的生物相容性、生物吸收性和高的内在机械强度。
氧化锌具有良好的热稳定性、抗菌活性和生物相容性等优点,是一种很有前途的抗菌剂。更重要的是氧化锌对广泛的细菌均具有优良的抗菌活性如金黄色葡萄球菌和大肠杆菌。另外纳米氧化锌已被证明对细菌有选择性毒性,但对人体正常细胞的影响可以忽略不计,氧化锌纳米粒子与细菌的相互作用在氧化锌颗粒减小到纳米级时更有效,而细菌大多是有毒的,纳米氧化锌是无毒的,与人体细胞具有生物相容性。因其独特的性能被认为是目前最有前途的抗菌纳米材料,并且纳米氧化锌已被认为是安全、经济的抗菌候选者。
发明内容
本发明基于微创技术与材料原位激发组织再生相结合,设计一种微创治疗用活性可注射骨水泥修复材料用于CICPS增强,能够满足骨修复工程所需结构、成分及性能需求,其制备方法简单可控,具有临床应用优势。
本发明提供一种活性可注射骨水泥修复材料的制备方法,成分为磷酸钙盐复合物,可用于骨、软骨、口腔等病损组织精准修复,具有可注射、原位固化、力学性能可控、抗感染和良好的生物学激发效应。
一种活性可注射骨水泥修复材料的制备方法,具体步骤包括:
(1)将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须按一定的质量比混合均匀,得到固相;
(2)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相;
(3)将步骤(2)所得的液相添加至步骤(1)所制备的固相中,并搅拌成糊状物,得到可注射骨水泥修复材料。
优选地,步骤(1)所述的掺镁羟基磷灰石晶须采用水热法合成,镁对钙的原子取代度为1%-5%。
优选地,步骤(1)所述的磷酸三钙可为α-磷酸三钙、β-磷酸三钙或双相磷酸三钙,磷酸三钙粒径为7-20μm。
优选地,步骤(1)所述的掺镁羟基磷灰石晶须量可以调控组织修复材料的力学强度,磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须的质量比为5:0.75:0.03-0.12。
优选地,步骤(2)所述的纳米氧化锌溶于磷酸氢二钠溶液中,纳米氧化锌的浓度根据临床应用改变,一般,液相中纳米氧化锌的浓度为0.5-1.5mol/L,磷酸氢二钠的浓度为0.25mol/L。
优选地,步骤(3)的固液比可调控,步骤(1)所制备的固相和步骤(2)所得的液相的固液比为0.8-1.5mL/g。
本发明的有益效果:
(1)本发明活性可注射骨水泥修复材料的成分,其与人体组织类似的成分能够提供足够的生物活性及抗菌性,有利于其在骨修复工程领域的应用。
(2)本发明所设计的活性可注射骨水泥修复材料的制备方法可用于微创精准治疗,能满足增强椎弓根螺钉(CICPSs)固定要求。
附图说明
图1为实施例1制备的掺镁羟基磷灰石晶须(Mg-HAw)形貌图和能谱图((a)SEM图,(b)元素质量谱图,(c)EDS能谱图);
图2为实施例1制备的活性可注射骨水泥修复材料形貌图和能谱图((a)SEM图像,(b)元素质量谱图,(c)EDS能谱图);
图3为实施例1制备的活性可注射骨水泥修复材料XRD图;
图4为实施例1制备的活性可注射骨水泥修复材料的注射性能结果图;
图5为实施例1制备的活性可注射骨水泥修复材料的抗菌试验结果图(左图:大肠杆菌抗菌实验,右图:金色葡萄球菌抗菌实验);
图6对比例1制备的活性可注射骨水泥修复材料与实施例1制备的活性可注射骨水泥修复材料的三点弯曲强度;
图7对比例1制备的活性可注射骨水泥修复材料与实施例1制备的活性可注射骨水泥修复材料的抗压强度。
具体实施方式
下面结合附图和具体实施对本发明作进一步详细说明,但本发明的保护范围并不限于所述内容。
实施例1
一种微创治疗用活性可注射骨水泥修复材料的制备方法,具体步骤包括:
(1)掺镁羟基磷灰石晶须的制备
1)精确称量药品:硝酸钙(Ca(NO3).4H2O)15.6138g、硝酸镁(Mg(NO3)2.6H2O)0.1713g、尿素(H2NCONH2)18g、磷酸氢二铵((NH4)H2PO4)5.2824g、山梨醇(C6H14O6)0.8036g、籽晶(Ca10(PO4)6(OH)2)0.06g;市售质量分数68%的浓硝酸3mL;
2)将硝酸钙、尿素、磷酸氢二铵、山梨醇、籽晶依次加入到装有400mL去离子水的烧杯中,每次加入一种药品,搅拌5min,待所有药品加完后再滴加浓硝酸3mL;
3)30min后把烧杯放入鼓风干燥箱中,7小时时间内由常温加热到90℃,在90℃温度下反应24h;
4)反应后,将制备的掺镁羟基磷灰石晶须取出,用蒸馏水清洗数次,直至盛有晶须的溶液pH达到7,进行抽滤;
5)抽滤的掺镁羟基磷灰石晶须,置于恒温干燥箱,直至晶须干燥完全;所得掺镁羟基磷灰石晶须中镁对钙的原子取代度为1%;
(2)将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须按质量比为5:0.75:0.03的比例混合均匀,得到固相;磷酸三钙为β-磷酸三钙,其粒径为7-20μm;
(3)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相,液相中纳米氧化锌的浓度为0.5mol/L,磷酸氢二钠的浓度为0.25mol/L;
(4)将步骤(3)所得的液相添加至步骤(2)所制备的固相中,液固比为0.8mL/g,并搅拌成糊状物,得到活性可注射骨水泥修复材料。
实施例2
一种微创治疗用活性可注射骨水泥修复材料的制备方法,具体步骤包括:
(1)掺镁羟基磷灰石晶须的制备:
1)精确称量药品:硝酸钙(Ca(NO3).4H2O)15.2983g、硝酸镁(Mg(NO3)2.6H2O)0.5138g、尿素(H2NCONH2)18g、磷酸氢二铵((NH4)H2PO4)5.2824g、山梨醇(C6H14O6)0.8036g、籽晶(Ca10(PO4)6(OH)2)0.06g;市售质量分数68%的浓硝酸3mL;
2)将硝酸钙、尿素、磷酸氢二铵、山梨醇、籽晶依次加入到装有400mL去离子水的烧杯中,每次加入一种药品,搅拌5min,待所有药品加完后再滴加浓硝酸3mL;
3)30min后把烧杯放入鼓风干燥箱中,7小时时间内由常温加热到90℃,在90℃温度下反应24h;
4)反应后,将制备的掺镁羟基磷灰石晶须取出,用蒸馏水清洗数次,直至盛有晶须的溶液pH达到7,进行抽滤;
5)抽滤的掺镁羟基磷灰石晶须,置于恒温干燥箱,直至晶须干燥完全;所得掺镁羟基磷灰石晶须中镁对钙的原子取代度为3%;
(2)将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须按质量比为5:0.75:0.06的比例混合均匀,得到固相;磷酸三钙为α-磷酸三钙,其粒径为7-20μm;
(3)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相,液相中纳米氧化锌的浓度为1.25mol/L,磷酸氢二钠的浓度为0.25mol/L;
(4)将步骤(3)所得的液相添加至步骤(2)所制备的固相中,液固比为1mL/g,并搅拌成糊状物,得到活性可注射骨水泥修复材料。
实施例3
一种微创治疗用活性可注射骨水泥修复材料的制备方法,具体步骤包括:
(1)掺镁羟基磷灰石晶须的制备。
1)精确称量药品:硝酸钙(Ca(NO3).4H2O)15.1406g、硝酸镁(Mg(NO3)2.6H2O)0.6897g、尿素(H2NCONH2)18g、磷酸氢二铵((NH4)H2PO4)5.2824g、山梨醇(C6H14O6)0.8036g、籽晶(Ca10(PO4)6(OH)2)0.06g;市售质量分数68%的浓硝酸3mL;
2)将硝酸钙、尿素、磷酸氢二铵、山梨醇、籽晶依次加入到装有400mL去离子水的烧杯中,每次加入一种药品,搅拌5min,待所有药品加完后再滴加浓硝酸3mL;
3)30min后把烧杯放入鼓风干燥箱中,7小时时间内由常温加热到90℃,在90℃温度下反应24h;
4)反应后,将制备的掺镁羟基磷灰石晶须取出,用蒸馏水清洗数次,直至盛有晶须的溶液pH达到7,进行抽滤;
5)抽滤的掺镁羟基磷灰石晶须,置于恒温干燥箱,直至晶须干燥完全;所得掺镁羟基磷灰石晶须中镁对钙的原子取代度为4%;
(2)将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须按质量比为5:0.75:0.09的比例混合均匀,得到固相;磷酸三钙为双相磷酸三钙,其粒径为7-20μm;
(3)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相,液相中纳米氧化锌的浓度为1mol/L,磷酸氢二钠的浓度为0.25mol/L;
(4)将步骤(3)所得的液相添加至步骤(2)所制备的固相中,液固比为1.2mL/g,并搅拌成糊状物,得到活性可注射骨水泥修复材料。
实施例4
一种微创治疗用活性可注射骨水泥修复材料的制备方法,具体步骤包括:
(1)掺镁羟基磷灰石晶须的制备:
1)精确称量药品:硝酸钙(Ca(NO3).4H2O)14.9829g、硝酸镁(Mg(NO3)2.6H2O)0.8564g、尿素(H2NCONH2)18g、磷酸氢二铵((NH4)H2PO4)5.2824g、山梨醇(C6H14O6)0.8036g、籽晶(Ca10(PO4)6(OH)2)0.06g;市售质量分数68%的浓硝酸3mL;
2)将硝酸钙、尿素、磷酸氢二铵、山梨醇、籽晶依次加入到装有400mL去离子水的烧杯中,每次加入一种药品,搅拌5min,待所有药品加完后再滴加浓硝酸3mL;
3)30min后把烧杯放入鼓风干燥箱中,7小时时间内由常温加热到90℃,在90℃温度下反应24h;
4)反应后,将制备的掺镁羟基磷灰石晶须取出,用蒸馏水清洗数次,直至盛有晶须的溶液pH达到7,进行抽滤;
5)抽滤的掺镁羟基磷灰石晶须,置于恒温干燥箱,直至晶须干燥完全;所得掺镁羟基磷灰石晶须中镁对钙的原子取代度为5%;
(2)将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须按质量比为5:0.75:0.12的比例混合均匀,得到固相;磷酸三钙可为β-磷酸三钙,其粒径为7-20μm;
(3)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相,液相中纳米氧化锌的浓度为1.5mol/L,磷酸氢二钠的浓度为0.25mol/L;
(4)将步骤(3)所得的液相添加至步骤(2)所制备的固相中,液固比为1.5mL/g,并搅拌成糊状物,得到活性可注射骨水泥修复材料。
对比例1
(1)将磷酸三钙、魔芋葡甘聚糖按质量比为5:0.75的比例混合均匀,得到固相;磷酸三钙为β-磷酸三钙,其粒径为7-20μm;
(2)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相,液相中纳米氧化锌的浓度为0.5mol/L,磷酸氢二钠的浓度为0.25mol/L;
(3)将步骤(2)所得的液相添加至步骤(1)所制备的固相中,液固比为0.8mL/g,并搅拌成糊状物,得到可注射骨水泥。
实施例1所制备的掺镁羟基磷灰石晶须(Mg-HAw)形貌图和能谱图如图1所示,(a)SEM图,(b)元素质量谱图,(c)EDS能谱图,由图可知,镁离子成功掺杂进入羟基磷灰石晶须。
实施例1所制备的活性可注射骨水泥修复材料形貌图如图2所示,(a)SEM图,(b)元素质量谱图,(c)EDS能谱图,由图可知,掺镁羟基磷灰石晶须混合进入到活性骨水泥修复材料基体中。
图3所示为活性可注射骨水泥修复材料XRD成分分析结果图,由图可知,XRD图谱在2θ约为10°~40°时,存在馒头峰,这是由于高分子有机物魔芋葡甘聚糖造成,其中结晶成分为羟基磷灰石与β磷酸三钙的复合,结果符合实施例成分预期。
图4所示为制备的活性可注射骨水泥修复材料的注射性能结果图,说明注射性能极好,骨水泥修复材料符合微创治疗用。
图5所示为制备的活性可注射骨水泥修复材料的抗菌试验结果图,由结果可知,骨水泥修复材料对大肠杆菌和金色葡萄球菌有好的抑菌效果,说明本实施例所制备的骨水泥修复材料在微创治疗用的过程中能抗感染。
图6对比例1制备的可注射活性骨水泥修复材料与实施例1制备的可注射活性骨水泥修复材料的三点弯曲强度对比,图7对比例1制备的活性可注射骨水泥修复材料与实施例1制备的活性可注射骨水泥修复材料的抗压强度对比,由图可知,对比例1可注射骨水泥修复材料的抗弯性能和抗压性能比实施例1活性可注射骨水泥修复材料的抗弯性能和抗压性能差,表明掺镁羟基磷灰石晶须的加入可极大提高可注射活性骨水泥修复材料的抗弯曲和抗压缩性能。
Claims (6)
1.一种活性可注射骨水泥修复材料的制备方法,其特征在于,具体步骤包括:
(1)将磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须混合均匀,得到固相;
(2)将纳米氧化锌溶于磷酸氢二钠溶液中,得到液相;
(3)将步骤(2)所得的液相添加至步骤(1)所制备的固相中,并搅拌成糊状物,得到活性可注射骨水泥修复材料。
2.根据权利要求1所述活性可注射骨水泥修复材料的制备方法,其特征在于,步骤(1)掺镁羟基磷灰石晶须中镁对钙的原子取代度为1%~5%。
3.根据权利要求1所述活性可注射骨水泥修复材料的制备方法,其特征在于,步骤(1)磷酸三钙为α-磷酸三钙、β-磷酸三钙或双相磷酸三钙,磷酸三钙粒径为7-20μm。
4.根据权利要求1所活性可注射骨水泥修复材料的制备方法,其特征在于,步骤(1)磷酸三钙、魔芋葡甘聚糖、掺镁羟基磷灰石晶须的质量比为5:0.75:0.03-0.12。
5.根据权利要求1所述活性可注射骨水泥修复材料的制备方法,其特征在于,步骤(2)液相中纳米氧化锌的浓度为0.5-1.5mol/L,磷酸氢二钠的浓度为0.25mol/L。
6.根据权利要求1所述活性可注射骨水泥修复材料的制备方法,其特征在于,步骤(3)中液相和固相的液固比为0.8-1.5mL/g。
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