CN113929448B - 一种梯度结构磷酸钙颗粒及其制备方法和制备装置 - Google Patents
一种梯度结构磷酸钙颗粒及其制备方法和制备装置 Download PDFInfo
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- CN113929448B CN113929448B CN202111434226.9A CN202111434226A CN113929448B CN 113929448 B CN113929448 B CN 113929448B CN 202111434226 A CN202111434226 A CN 202111434226A CN 113929448 B CN113929448 B CN 113929448B
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Abstract
本发明公开了一种梯度结构磷酸钙颗粒及其制备方法和制备装置,涉及陶瓷材料制备技术领域,所述梯度结构磷酸钙颗粒中含有磷酸钙和活性金属氧化物,所述梯度结构磷酸钙颗粒呈球形,颗粒平均直径为2~3mm,颗粒的外层和内层含不同的活性金属氧化物。本发明制备的羟基磷灰石颗粒内外层可根据临床骨缺损需求构建不同活性金属氧化物,可以在球形羟基磷灰石颗粒外层构建具有抗菌活性外层,在植入初期,颗粒表面快速与人体组织接触,达到快速抗菌的效果;在球形羟基磷灰石颗粒内层构建促进骨修复的活性内层,可以在移植后慢慢释放活性离子,促进组织生长,从而解决了现有技术无法实现人体在移植骨修复材料后不同阶段对于材料功能的要求的技术问题。
Description
技术领域
本发明涉及陶瓷材料制备技术领域,具体涉及一种梯度结构磷酸钙颗粒及其制备方法和制备装置。
背景技术
随着医疗技术以及经济的发展,人们对生活品质要求也越来越高,包括一些因骨肿瘤疾病、交通意外创伤、人口老龄化等原因导致的骨缺损病人,他们都迫切寻求骨修复以恢复至正常生活水平,这就使得临床上对骨修复材料的需求日益增大。
羟基磷灰石(HA)是哺乳动物骨骼的主要矿物成分,因其良好的生物相容性、生物活性和骨诱导能力,在生物医学应用中很受青睐。另外,HA表面在体液中可作为骨矿物质的成核位点,且HA在确定的生理环境(温度、pH值、体液)中溶解度较低,是最稳定的磷酸钙。但受HA材料自身限制,一方面其脆性大,加工成型困难,另一方面骨诱导活性和生物活性不足。因此,HA常与其他其他大分子和活性离子形成复合材料,进而表现出更好的抗菌效果和成骨能力,满足理想的骨填充材料的要求。对于复杂骨缺损的修复,颗粒状骨移植物由于其可移动性和易于操作的性质,能满足不同部位和不同形状骨缺损的填充,比大块支架更适合。此外,与不规则粒子(棱角边缘)相比,球形颗粒引起的炎症反应较小;此外,高比表面积的颗粒还能促进细胞的粘附和增殖。由于大的粒间空间对血管的生长至关重要,相较于纳米/微米球形颗粒,大的球形颗粒更适合作为骨填料(>1mm)。基于此,公开号为CN104548213B、专利名称为《一种多孔球形磷酸钙骨填充材料及其制备方法》的专利文件,就公开了一种利用磷酸钙、海藻酸钠以及粘接剂等组分组成的浆料滴加在可溶性钙盐溶液中形成凝胶微球,再烘干、烧结而得到的多孔球形磷酸钙骨填充材料,该材料由于加入了海藻酸钠,在复合凝胶微球预烧和后续的烧结过程中,海藻酸钠的分解脱离会在球形颗粒基体内部留下丰富的微孔。此种多孔结构的磷酸钙颗粒植入体内后有利于体液的循环以及营养和氧的供给,生物活性更高,可提高骨填充材料植入的成功率。
但是骨修复是一个复杂和长期的过程,这个过程可能会受到细菌感染、骨愈合缓慢的阻碍,上述方法并不能解决以上问题。传统的治疗方法是通过给药系统对抗生素进行局部和系统的注射,这种治疗方式往往耗时长,且伴随着潜在的细菌耐药性。为了克服这些问题,一些金属离子,如Cu2+,Zn2+在骨组织修复过程中显示出良好的抗菌效果。锶则被报道为骨再生的载体,锶可以增加破骨细胞凋亡,促进前成骨细胞增殖和胶原合成,从而抑制骨吸收,来调节骨转换以有利于新骨形成。二价钴(Co2+)和镍(Ni2+)则可以在不影响骨传导性能的前提下增强血管生成能力。因此,含金属离子的磷酸钙骨填充材料也进入了人们的实现,比如公开号为CN101628124、专利名称为《一种锶羟基磷灰石的制备方法及其应用》的专利申请文件,就公开了一种含锶-钙的羟基磷灰石材料,该不仅具有生物相容性,而且在人体的体液中能形成纳米锶羟基磷灰石,具有生物活性,更重要的是在人体体液中,最终可以完全溶解,具有其它生物玻璃不具备的生物降解和吸收作用。此类可溶性玻璃材料,可以作为组织工程中骨细胞生长的主要支架材料。但以离子形式掺入HA晶格内,离子掺入量有限,难以形成多种离子掺杂形式,且离子释放难以有效控释。
尽管各种具有精细结构的纳米/微米HA球已被制备出来,但目前采用的制备方法为油包水乳液、滴灌等传统制备方法,此类方法由于成本高、效率低的特点,仍难以满足规模化生产的需要。同时,因为人体在移植骨修复材料后所处的阶段不同,对材料的要求也就不同,譬如移植初期,需要抗感染;移植后期,需要促进骨修复,上述现有技术都只能解决单一的技术问题,无法实现人体在移植骨修复材料后不同阶段对于材料功能的要求。
发明内容
针对现有技术中的上述问题,本发明提供一种梯度结构磷酸钙颗粒及其制备方法和制备装置,以解决现有技术无法实现人体在移植骨修复材料后不同阶段对于材料功能的要求的技术问题。
本发明采用的技术方案如下:
一种梯度结构磷酸钙颗粒,所述梯度结构磷酸钙颗粒中含有磷酸钙和活性金属氧化物,所述梯度结构磷酸钙颗粒呈球形,颗粒平均直径为2~3mm,颗粒的外层和内层含不同的活性金属氧化物。
作为优选地,所述活性金属氧化物为Cu2+、Zn2+、Sr2+、Ca2+、Co2+、Ni2+氧化物中的一种或多种。
更进一步地,所述梯度结构磷酸钙颗粒内层为Ca2+、Sr2+、Co2+、Ni2+氧化物的中的一种或多种。
更进一步地,所述梯度结构磷酸钙颗粒外层为Ca2+、Cu2+、Zn2+氧化物的中的一种或多种。
一种梯度结构磷酸钙颗粒的制备方法,包括如下步骤:
(1)将1~2质量份的海藻酸钠、15~20质量份的磷酸钙粉体置于去离子水中,形成混合浆料备用,浆料中,所述海藻酸钠质量浓度为1~2%;
(2)配制由上层可溶性二价阳离子乙醇溶液、中层油相以及下层可溶性二价阳离子水溶液组成的三层溶液体系备用,其中,所述可溶性二价阳离子乙醇溶液的摩尔浓度为0.0125~0.1mol/L,下层可溶性二价阳离子水溶液的摩尔浓度为0.05~0.3mol/L;
(3)将步骤(1)所得混合浆料自上层滴加至三层溶液体系,混合浆料滴入上层可溶性二价阳离子乙醇溶液即形成复合凝胶陶瓷球,然后自上而下落入下层可溶性二价阳离子水溶液,将复合凝胶陶瓷球在下层中继续浸泡至完全固化,然后将固化后的复合陶瓷球用去离子水洗涤、干燥;
(4)将步骤(3)所得复合凝胶陶瓷球在马弗炉中,以5~20℃/min的升温速率升至900~1200℃,保温烧结0.5~5h,烧结结束后冷却至室温即得到梯度结构磷酸钙颗粒。
进一步地,步骤(1)中所用磷酸钙粉体中钙、磷原子摩尔比为1.50~1.70:1。
进一步地,步骤(3)中,所述复合凝胶陶瓷球干燥条件为40~50℃,干燥时间为4小时~12小时。
进一步地,步骤(4)中,烧结结束后的降温速率为5℃/min~100℃/min。
进一步地,步骤(4)中,使用马弗炉烧结时,以5℃/min的升温速率升至900~1200℃,保温烧结2h。
一种梯度结构磷酸钙颗粒的制备装置,其特征在于,所述制备装置包括水相反应主体,所述水相反应主体的侧边靠近底部的位置斜向上连通有乙醇相反应主体,水相和乙醇相中间用油相间隔,所述乙醇相反应主体设置成葫芦状,乙醇相反应主体的顶部设置加料的瓶口和控制乙醇相上下流通的活动塞阀。
综上所述,相比于现有技术,本发明具有如下优点及益效果:
1.本发明制备的球形羟基磷灰石颗粒内外层可根据临床植入的需要内外包含不同的二价阳离子对应的氧化物,可以在球形羟基磷灰石颗粒外层具有抗菌效果的离子,从而在植入初期,具有抗菌效果的离子快速与人体组织接触,达到快速抗菌的效果;在球形羟基磷灰石颗粒内层包含促进骨修复的二价阳离子,因不直接接触人体组织,这些阳离子可以在移植后慢慢释放离子,促进组织生长,外部的抗菌离子在移植初期快速消散也避免了抗菌离子对组织的伤害作用,进一步促进生长,从而解决了现有技术无法实现人体在移植骨修复材料后不同阶段对于材料功能的要求的技术问题;
2、本发明提供的制备方法,采用三层体系,使得制备过程中实现内外两种不同阳离子的交联过程,上层乙醇相交联颗粒表面,下层水相主要交联颗粒微孔内壁,油相起到分隔作用,还可以通过改变上层交联液的浓度和液面高度,很容易就达到调整球形羟基磷灰石颗粒的外层厚度的目的;
3、本发明提供的制备装置,设置了活动塞阀,还能控制复合凝胶陶瓷球在上层溶液的停留时间,进一步控制球形羟基磷灰石颗粒的外层厚度;
4、本发明所述方法工艺简单,成型容易,工序少,易于操作。
附图说明
本发明将通过例子并参照附图的方式说明,其中:
图1为本发明提供的梯度结构磷酸钙颗粒的制备装置结构示意图,图中标号分别为:1、活动塞阀;2、瓶口;3、乙醇相;4、油相;5、网勺;6、水相;
图2为本发明制备的梯度结构磷酸钙颗粒及其断面光镜图;
图3为本发明制备的梯度结构磷酸钙颗粒表面及断面内部SEM及元素扫描图,图中编号分别为:a1、颗粒表面微观形貌及放大图;a2、颗粒表面元素扫描;b1、颗粒内部微观形貌及放大图;a2、颗粒内部元素扫描。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。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,即所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
本发明提供一种梯度结构磷酸钙颗粒的制备方法和制备装置,其制备方法包括如下步骤:
(1)将1~2质量份的海藻酸钠、15~20质量份的磷酸钙粉体置于去离子水中,形成混合浆料备用,浆料中,所述海藻酸钠质量浓度为1~2%;
(2)配制由上层可溶性二价阳离子乙醇溶液、中层油相以及下层可溶性二价阳离子水溶液组成的三层溶液体系备用,其中,所述可溶性二价阳离子乙醇溶液的摩尔浓度为0.0125~0.1mol/L,下层可溶性二价阳离子水溶液的摩尔浓度为0.05~0.3mol/L;
(3)将步骤(1)所得混合浆料自上层滴加至三层溶液体系,混合浆料滴入上层可溶性二价阳离子乙醇溶液即形成凝胶陶瓷球,经油相自上而下落入下层可溶性二价阳离子水溶液,在下层中继续浸泡至完全固化得到复合凝胶陶瓷球,然后将固化后的复合陶瓷球用去离子水洗涤、干燥;
(4)将步骤(3)所得复合凝胶陶瓷球在马弗炉中,以5~20℃/min的升温速率升至900~1200℃,保温烧结0.5~5h,烧结结束后冷却至室温即得到梯度结构磷酸钙颗粒,以铜离子乙醇溶液作为外层交联液,锶离子水溶液做为内层交联液为例,制得的梯度结构磷酸钙颗粒及其断面实物图如图2,其SEM及元素扫描图如图3。
其制备装置如图1所示,包括水相6的反应主体,所述水相6的反应主体的侧边靠近底部的位置斜向上连通有乙醇相3的反应主体,所述乙醇相3的反应主体设置成葫芦状,乙醇相反应主体的顶部设置加料的瓶口2和控制乙醇相上下流通的活动塞阀1,乙醇相3的反应主体的下端装有分隔水相6和乙醇相3的油相4。制备梯度结构磷酸钙颗粒时,将混合浆料自瓶口2滴加至乙醇相3中,设置了活动塞阀1,还能控制复合凝胶陶瓷球在上层溶液的停留时间,进一步控制球形羟基磷灰石颗粒的外层厚度;随后复合凝胶陶瓷球经油相4落入水相6中,继续浸泡至完全固化即可捞出进行后续操作,为了便于捞出复合凝胶陶瓷球,还在水相6的反应主体底部放置有一网勺5,网勺5的手柄延伸至水相6的反应主体外部。
本发明利用上述制备装置和方法,提供下述实施例:
实施例1
本实施例中梯度结构羟基磷灰石骨填充材料的制备工艺如下:
(1)将15g具有纳米结构的羟基磷灰石(钙、磷原子摩尔比Ca/P=1.67)粉体、1g海藻酸钠和100mL去离子水混合均匀,得到混合浆料;
(2)将步骤(1)所得混合浆料用注射泵经制备装置瓶口2均匀滴加到上层摩尔浓度为0.05mol/l的氯化铜乙醇溶液,中间为油相,下层摩尔浓度为0.1mol/l的氯化锶溶液中,形成复合凝胶球,所述氯化铜乙醇溶液的量为40ml左右,油相量为20ml左右,所述氯化锶溶液的量以能将形成的复合凝胶球完全浸没为限,滴加结束后,形成的复合凝胶球继续在所述氯化锶溶液中浸泡3小时以固化,将固化后的复合凝胶球用去离子水洗涤,洗涤至硝酸银滴进去不产生沉淀为止,在40℃烘干8小时。
(3)将步骤(2)所得的复合凝胶球在马弗炉中,以5℃/min的升温速率升至1150℃保温烧结2h,保温结束后以10℃/min的的降温速率降至室温;即得到梯度结构羟基磷灰石骨填充材料,颗粒形貌为球形,颗粒平均直径为2.61mm,为毫米级的骨填充材料,能承受的最大压力平均值为44.5N。
实施例2
本实施例中梯度结构羟基磷灰石骨填充材料的制备工艺如下:
(1)将15g具有纳米结构的羟基磷灰石(钙、磷原子摩尔比Ca/P=1.67)粉体、1g海藻酸钠和100mL去离子水混合均匀,混合均匀得到混合浆料;
(2)将步骤(1)所得混合浆料用注射泵经制备装置瓶口2均匀滴加到上层摩尔浓度为0.025mol/l的氯化锌乙醇溶液,中间为油相,下层为摩尔浓度为0.1mol/l的六水氯化锶溶液中,形成复合凝胶球,所述氯化铜乙醇溶液的量为40ml左右,油相量为20ml左右,所述六水氯化锶溶液的量以能将形成的复合凝胶球完全浸没为限,滴加结束后,形成的复合凝胶球继续在所述六水氯化锶溶液中浸泡3小时以固化,将固化后的复合凝胶球用去离子水洗涤,洗涤至硝酸银滴进去不产生沉淀为止,在40℃烘干8小时。
(3)将步骤(2)所得的复合凝胶球在马弗炉中,以5℃/min的升温速率升至1150℃保温烧结2h,保温结束后以10℃/min的的降温速率降至室温;即得到梯度结构羟基磷灰石骨填充材料,颗粒形貌为球形,颗粒平均直径为2.417mm,为毫米级别的骨填充材料,能承受的最大压力平均值为44.6N。
实施例3
本实施例中梯度结构羟基磷灰石骨填充材料的制备工艺如下:
(1)将15g具有纳米结构的羟基磷灰石(钙、磷原子摩尔比Ca/P=1.67)粉体、1g海藻酸钠和100mL去离子水混合均匀,混合均匀得到混合浆料;
(2)将步骤(1)所得混合浆料用注射泵经制备装置瓶口2均匀滴加到上层摩尔浓度为0.05mol/l的氯化铜乙醇溶液,中间为油相,下层为摩尔浓度为0.05mol/l的六水氯化锶溶液中,形成复合凝胶球,所述氯化铜乙醇溶液的量为40ml左右,油相量为20ml左右,所述六水氯化锶溶液的量以能将形成的复合凝胶球完全浸没为限,滴加结束后,形成的复合凝胶球继续在所述六水氯化锶溶液中浸泡3小时以固化,将固化后的复合凝胶球用去离子水洗涤,洗涤至硝酸银滴进去不产生沉淀为止,在40℃烘干8小时。
(3)将步骤(2)所得的复合凝胶球在马弗炉中,以5℃/min的升温速率升至1150℃保温烧结2h,保温结束后以10℃/min的的降温速率降至室温;即得到梯度结构羟基磷灰石骨填充材料,颗粒形貌为球形,颗粒平均直径为2.788mm,毫米级别的骨填充材料,能承受的最大压力平均值为43.9N。
实施例4
本实施例中梯度结构羟基磷灰石骨填充材料的制备工艺如下:
(1)将15g具有纳米结构的羟基磷灰石(钙、磷原子摩尔比Ca/P=1.67)粉体、1g海藻酸钠和100mL去离子水混合均匀,混合均匀得到混合浆料;
(2)将步骤(1)所得混合浆料用注射泵经制备装置瓶口2均匀滴加到上层摩尔浓度为0.05mol/l的氯化铜乙醇溶液,中间为油相,下层为摩尔浓度为0.01mol/l的六水氯化锶溶液中,形成复合凝胶球,所述氯化铜乙醇溶液的量为40ml左右,油相量为20ml左右,所述六水氯化锶溶液的量以能将形成的复合凝胶球完全浸没为限,滴加结束后,形成的复合凝胶球继续在所述六水氯化锶溶液中浸泡3小时以固化,将固化后的复合凝胶球用去离子水洗涤,洗涤至硝酸银滴进去不产生沉淀为止,在40℃烘干8小时。
(3)将步骤(2)所得的复合凝胶球在马弗炉中,以5℃/min的升温速率升至1150℃保温烧结2h,保温结束后以10℃/min的降温速率降至室温;即得到梯度结构羟基磷灰石骨填充材料,颗粒形貌为球形,颗粒平均直径为2.527mm,毫米级别的骨填充材料,能承受的最大压力平均值为44.7N。
应用例1
为验证制备的梯度结构羟基磷灰石(HA)骨填充材料的生物活性,采用实施例1~4制备的材料进行间充质干细胞成骨活性研究和抗菌活性研究,以钙离子溶液交联制备的普通HA颗粒作为对照。两种羟基磷灰石颗粒采用高压蒸汽法灭菌后,分别进行细胞成骨活性测定和抗菌活性研究。
细胞成骨活性测定:根据国家标准GB/T 16886.5-2017分别对两组样品进行的细胞毒性和分化性能测定。五组样品分别各取15颗置于24孔板内,接种大鼠骨髓间充质干细胞,接种密度1*105个/孔,采用a-MEM诱导培养基培养,隔天换液,用MTT方法测定1、4、7天细胞数量,并在14天测定反映细胞成骨分化指标碱性磷酸酶(ALP)活性。各组实验设置5个平行。实验结果表明:梯度结构HA颗粒(实施例1~4)和对照HA颗粒对细胞均无毒性,随培养时间延长细胞数量增加;ALP活性,梯度结构HA(实施例1~4)活性均显著高于对照HA颗粒(p<0.01)。
抗菌活性测定:根据国家标准GB/T 21510-2008分别对两组样品进行的抗菌性能测试,结果表明梯度结构HA(实施例1~4)颗粒均对大肠杆菌、金黄色葡萄球菌具有90%以上的抑菌效果,而普通HA颗粒仅有22%抗菌效果。
以上所述实施例仅表达了本申请的具体实施方式,其描述较为具体和详细,但并不能因此而理解为对本申请保护范围的限制,比如滴加使用的滴加装置除了注射泵,还可以为为蠕动泵、注射器、移液枪等装置中的一种,只要能实现滴加即可。应当指出的是,对于本领域的普通技术人员来说,在不脱离本申请技术方案构思的前提下,还可以做出若干变形和改进,这些都属于本申请的保护范围。
Claims (9)
1.一种梯度结构磷酸钙颗粒的制备方法,其特征在于,所述梯度结构磷酸钙颗粒中含有磷酸钙和活性金属氧化物,所述梯度结构磷酸钙颗粒呈球形,颗粒平均直径为2~3mm,颗粒的外层和内层含不同的活性金属氧化物,其制备过程包括如下步骤:
(1)将1~2质量份的海藻酸钠、15~20质量份的磷酸钙粉体置于去离子水中,形成混合浆料备用,浆料中,所述海藻酸钠质量浓度为1~2%;
(2)配制由上层可溶性二价阳离子乙醇溶液、中层油相以及下层可溶性二价阳离子水溶液组成的三层溶液体系备用,其中,所述可溶性二价阳离子乙醇溶液的摩尔浓度为0.0125~0.1mol/L,下层可溶性二价阳离子水溶液的摩尔浓度为0.05~0.3mol/L;
(3)将步骤(1)所得混合浆料自上层滴加至三层溶液体系,混合浆料滴入上层可溶性二价阳离子乙醇溶液即形成复合凝胶陶瓷球,然后自上而下落入下层可溶性二价阳离子水溶液,将复合凝胶陶瓷球在下层中继续浸泡至完全固化,然后将固化后的复合陶瓷球用去离子水洗涤、干燥;
(4)将步骤(3)所得复合凝胶陶瓷球在马弗炉中,以5~20℃/min的升温速率升至900~1200℃,保温烧结0.5~5h,烧结结束后冷却至室温即得到梯度结构磷酸钙颗粒。
2.如权利要求1所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,所述活性金属氧化物为Cu2+、Zn2+、Sr2+、Ca2+、Co2+、Ni2+氧化物中的一种或多种。
3.如权利要求1所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,所述梯度结构磷酸钙颗粒内层为Ca2+、Sr2+、Co2+、Ni2+氧化物的中的一种或多种。
4.如权利要求1所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,所述梯度结构磷酸钙颗粒外层为Ca2+、Cu2+、Zn2+氧化物的中的一种或多种。
5.如权利要求1~4任意一项所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,步骤(1)中所用磷酸钙粉体中钙、磷原子摩尔比为1.50~1.70:1。
6.如权利要求1~4任意一项所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,步骤(3)中,所述复合凝胶陶瓷球干燥条件为40~50℃,干燥时间为4小时~12小时。
7.如权利要求1~4任意一项所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,步骤(4)中,烧结结束后的降温速率为5℃/min~100℃/min。
8.如权利要求1~4任意一项所述的梯度结构磷酸钙颗粒的制备方法,其特征在于,步骤(4)中,使用马弗炉烧结时,以5℃/min的升温速率升至900~1200℃,保温烧结2h。
9.一种如权利要求1所述的梯度结构磷酸钙颗粒的制备方法所用的装置,其特征在于,制备装置包括水相反应主体,所述水相反应主体的侧边靠近底部的位置斜向上连通有乙醇相反应主体,水相和乙醇相中间用油相间隔,所述乙醇相反应主体设置成葫芦状,乙醇相反应主体的顶部设置加料的瓶口和控制乙醇相上下流通的活动塞阀。
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