CN106312050A - 一种具有活性夹层的抗菌型功能梯度多孔HA‑Ag骨填充支架的制备方法 - Google Patents
一种具有活性夹层的抗菌型功能梯度多孔HA‑Ag骨填充支架的制备方法 Download PDFInfo
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Abstract
本发明公开一种具有活性夹层的抗菌型功能梯度多孔HA‑Ag骨填充支架,属于生物医用材料制备技术领域。本发明所述生物材料将羟基磷灰石HA、Ag粉末按成分配比称取后进行球磨;将混合粉末与碳酸氢铵造孔剂按孔隙率配比称取并混合;制备出三种粉末后将粉末梯度铺放,并机械压制成块体压坯,再置入放电等离子烧结炉中,系统真空抽至2~6 Pa后进行烧结,升温速率为50~100min/℃,在800~1000℃下保温5~10 min,随炉冷却至室温即可得具有活性夹层的功能梯度多孔HA‑Ag骨填充支架材料。该材料能够主动诱导骨细胞在其表面粘附增殖,具有很好的成骨活性和抗菌性,此外具有高孔隙率的同时还具有高的力学稳定性,可作为良好的人造骨填充材料。
Description
技术领域
本发明涉及一种具有活性夹层的抗菌型功能梯度多孔HA-Ag骨填充支架的制备方法,属于生物医用材料制备技术领域。
背景技术
羟基磷灰石(HA)因具有与人骨相似的化学结构和优秀的生物活性而被认为是当前骨修复领域的首选支架或填充材料。银(Ag)因具有良好的抗菌性(葡萄球菌和大肠杆菌)和生物活性而作为合金元素广泛用于生物材料中。锶(Sr)由于其在骨质疏松中特有的治疗效果可以有效促进骨愈合及新骨生长,增加骨形成的同时,减少骨吸收。细胞实验已经证明,Sr的融和能够有效的促进成骨细胞的增殖及分化。此外,预临床实验也证实,Sr离子的释放可以增强不同部位的骨密度,包括腰椎、股骨颈和髋关节,可以有效阻止骨质酥松(见文献:Yamaguchi S, Nath S, Matsushita T, et al. Controlled release ofstrontium ions from a bioactive Ti metal with a Ca-enriched surface layer[J].Acta Biomaterialia, 2014, 10(5):2282-2289.)。与此同时,很多学者在上述两种骨填充材料中引入孔隙结构,制成多孔HA材料,以此来增加材料的比表面积,更容易使骨细胞在其表面粘附生长,使得材料在填充骨缺损部位后与骨组织形成长期稳定的生物锁合。
但是,原本力学性能较差的HA,再引入孔隙结构,无疑更加使其力学性能进一步受到破坏,无法在临床上满足其力学性能的基本要求,而且,文献表明,若要引入骨细胞在其表面粘附生长,还需要高的孔隙率(30%-50%)和大的孔径(300-500μm),然而,问题是越高的孔隙参量(孔隙率和孔隙尺度),就会导致越差的力学性能。另一方面,目前制备多孔HA生物陶瓷的方法有模板法、溶胶凝胶法、泡沫法等,这些制备方法不但容易引入杂质,而且在制备过程中为了材料的力学稳定性往往需要添加像聚乙烯醇的粘结剂,而这些添加剂可能在制备过程中无法完全去除,而残留的聚乙烯醇已被证明具有肝胆毒性,无法用在生物医用领域。
基于上述原因,十分有必要设计一种功能梯度一体化的多孔骨填充支架,在成分上,将HA与Ag掺杂,制备成既有成骨活性和抗菌性,引入骨细胞生长增加材料的骨整合性能,内层又有Sr作为诱导因子,促进骨细胞增殖分化;在结构上,采取梯度结构设计,与骨组织接触的一层(最外层)设计为高孔隙率、大孔径的多孔层,可以为骨细胞提供稳定生长增殖平台,中间层,设计为功能型的诱导平台,既诱导外接骨组织向材料中心长入,促进骨生长,中心层,设计为高致密度的强度层,主要为整体的骨支架提供力学稳定性,使整体材料既具有高孔隙率、大孔径的同时还具有好的力学性能,使三者的结合不再矛盾。
放电等离子烧结(Spark Plasma Sintering, SPS)是一种粉末快速固结的新型技术。SPS利用强电流的脉冲电源来激发和促进材料的固结和反应烧结过程。相较于传统技术,SPS在加工过程中,对各类导体、非导体以及复合材料的密度值均可调节至任意需求值。SPS最大程度的缩短了实验时间及能耗,同时又完美的保持了材料的微纳结构。
基于此,本发明通过采用梯度功能一体化的设计思路结合放电等离子烧结技术烧结温度低、升温速度快、制备过程洁净的优点,制备一种具有活性夹层的抗菌型功能梯度多孔HA-Ag骨填充支架材料。
发明内容
本发明针对目前HA骨修复支架材料存在的问题,提供了一种具有抗菌型活性夹层的功能梯度多孔HA-Ag骨填充支架的制备方法;目的在于进一步提高骨填充支架的生物活性、成骨活性和抗菌性,同时解决支架材料的高孔隙结构与高力学性能无法共存的问题,有效提高骨填充支架在骨缺损部位植入的长期稳定性。
具体包括以下步骤:
(1)按羟基磷灰石(HA) 97%~80%、Ag 3~20%的质量百分比,分别称取100 nm的羟基磷灰石(HA)粉末和Ag粉末,将两种粉末放入玛瑙球磨罐中进行球磨,用酒精密封后抽真空至20~30Pa,然后球磨50~100 h,所得混合粉末仍置于酒精中,备用;
(2)将步骤(1)中得到的HA-Ag粉末与NH4HCO3粉末在混料机内混合120~240min得到混合粉末A;混合粉末中HA-Ag粉末的质量百分比为95%~75%,NH4HCO3粉末的质量百分比为5%~25%,筛分粒径100~700μm。
(3)按Sr 95%~90%、NH4HCO3粉末5%~10%的质量百分比,分别称取Sr粉末和NH4HCO3粉末在混料机内混合30~60min得到混合粉末B。
(4)称取10~20g ,纯度超过99.7%,粒度为100nm的HA粉末,记为粉末C,备用。
(5)将步骤(2)、步骤(3)和步骤(4)得到的粉末梯度铺放装入镀Cr的合金钢模具中,首先装混合粉末A,再装混合粉末B作为活性夹层,再装粉末C,最后装混合粉末B和混合粉末A,形成中心层为羟基磷灰石,次层为混合粉末B,最外层是混合粉末A的夹层结构;。将装好粉末的模具在50~100MPa的单项压力下冷压成型,退模后得到块体压坯。
(6)将步骤(5)得到的块体压坯装入石墨模具中,再置入放电等离子烧结炉中,系统真空抽至2~6 Pa后进行烧结,升温速率为50~100min/℃,在800~1000℃下保温5~10min,随炉冷却至室温即可得抗菌型功能梯度多孔HA-Ag骨填充支架材料。
与现有技术相比,本发明的优点在于:
(1)生物活性,成骨活性好。其材料中成分主要为外层HA掺杂Ag元素,内层为多孔Sr,能够主动诱导骨细胞的粘附,促进骨细胞增殖,成骨活性好,还具有有效抗菌作用。
(2)孔隙参量可控,生物相容性好。所制备的多孔支架在满足高孔隙率、大孔径的同时还不会破坏材料本身的力学强度,使得材料在保持力学稳定性的同时能够为周围的骨细胞提供良好的生长增殖平台。
(4)采用本发明方法制备的抗菌型功能梯度多孔HA-Ag骨填充支架可以作为理想的人骨组织替换材料,同时本发明方法工艺简单、操作方便、成本低廉,易于实现工业化生产。
附图说明
图1为本发明实施例多孔HA-Ag骨填充支架的结构简图。
图2为本发明实施例Ag粉末原料的扫描电镜图片。
图3为本发明实施例多孔HA-Ag骨填充支架与兔骨髓间充质干细胞的细胞增殖率(MTT)图。
具体实施方式
下面结合附图和具体实施例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
(1)按羟基磷灰石(HA) 97%、Ag 3%的质量百分比,分别称取100 nm的羟基磷灰石(HA)粉末和Ag粉末,将上述两种粉末放入玛瑙球磨罐中进行球磨,用酒精密封后抽真空至20Pa,然后球磨50 h,所得HA-Ag混合粉末仍置于酒精中,备用;
(2)将步骤(1)中得到的HA-Ag粉末与NH4HCO3粉末在混料机内混合120min得到混合粉末A;混合粉末A中HA-Ag粉末的质量百分比为95%,NH4HCO3粉末的质量百分比为5%,筛分平均粒径100μm。
(3)按Sr粉末 95%、NH4HCO3粉末5%的质量百分比,分别称取Sr粉末和NH4HCO3粉末在混料机内混合30min得到混合粉末B。
(4)称取10 g ,纯度超过99.7%,粒度为100nm的羟基磷灰石HA粉末,记为粉末C,备用。
(5)将步骤(2)步骤(3)和步骤(4)得到的粉末梯度铺放装入镀Cr的合金钢模具中,首先装混合粉末A,再装混合粉末B作为活性夹层,再装粉末C,最后装混合粉末B和混合粉末A,形成中心层是羟基磷灰石,次层为混合粉末B,最外层是混合粉末A的夹层结构。将装好粉末的模具在50MPa的单项压力下冷压成型,退模后得到块体压坯。
(6)将步骤(5)得到的块体压坯装入石墨模具中,再置入放电等离子烧结炉中,系统真空抽至2 Pa后进行烧结,升温速率为50min/℃,在800℃下保温5 min,随炉冷却至室温即可得功能梯度多孔HA-Sr骨填充支架材料。
按HA95%、Ag5%,HA90%、Ag10%的质量百分比,分别称取100 nm的HA粉末和Ag粉末,连同本例按HA 97%、Ag 3%配比的粉末A,再按本例中相同的工艺条件烧结得到不同掺Ag比的抗菌型功能梯度多孔HA-Ag骨填充支架材料,其结构简图如图1所示。其中Ag颗粒的扫描电镜图片如图2所示。将本发明一个实施例获得的抗菌型功能梯度多孔HA-Ag骨填充支架材料连同HA支架一起进行对比的生物毒性MTT实验,如图3所示。将两种材料与兔骨髓间充值干细胞分别共培养1到2天后,发现细胞数量逐渐升高,多孔HA-Ag骨填充支架材料的细胞增殖率超过对照组,且其数据具有统计学意义,说明材料无细胞毒性。
实施例2
(1)按羟基磷灰石HA 80%、Ag 20%的质量百分比,分别称取100 nm的羟基磷灰石HA粉末和Ag粉末,将两种粉末放入玛瑙球磨罐中进行球磨,用酒精密封后抽真空至30Pa,然后球磨100 h,所得HA-Ag混合粉末仍置于酒精中,备用;
(2)将步骤(1)中得到的HA-Ag混合粉末与NH4HCO3粉末在混料机内混合240min得到混合粉末A;混合粉末中HA-Ag粉末的质量百分比为75%,NH4HCO3粉末的质量百分比为25%,筛分平均粒径700μm。
(3)按Sr粉末 90%、NH4HCO3粉末10%的质量百分比,分别称取Sr粉末和NH4HCO3粉末在混料机内混合60min得到混合粉末B。
(4)称取20g ,纯度超过99.7%,粒度为100nm的HA粉末,记为粉末C,备用。
(5)将步骤(2)步骤(3)步骤(4)得到的粉末梯度铺放装入镀Cr的合金钢模具中,首先装混合粉末A,再装混合粉末B作为活性夹层,再装粉末C,最后装混合粉末B和混合粉末A;形成中心层是羟基磷灰石,次层为混合粉末B,最外层是混合粉末A的夹层结构。将装好粉末的模具在100MPa的单项压力下冷压成型,退模后得到块体压坯。
(6)将步骤(5)得到的块体压坯装入石墨模具中,再置入放电等离子烧结炉中,系统真空抽至6 Pa后进行烧结,升温速率为100min/℃,在800℃下保温10 min,随炉冷却至室温即可得抗菌型功能梯度多孔HA-Ag骨填充支架材料。
按本例中相同的工艺条件,获得块体压坯后,置入放电等离子烧结炉中,分别按850℃、900℃、950℃、1000℃烧结,连同本例在800℃下烧结获得的不同烧结温度的抗菌型功能梯度多孔HA-Ag骨填充支架材料。利用阿基米德法对不同烧结温度的支架材料进行测量,并通过计算获得该材料的孔隙率。结果表明随温度从800℃到1000℃不断升高,其外层孔径逐渐减小,孔隙率从65%到30%不断降低。将材料与成年兔骨髓间充质细胞共培养2周后,发现五种材料都具有优异的生物活性。
实施例3
(1)按羟基磷灰石HA 85%、Ag 15%的质量百分比,分别称取100 nm的羟基磷灰石HA粉末和Ag粉末,将上述两种粉末放入玛瑙球磨罐中进行球磨,用酒精密封后抽真空至25Pa,然后球磨80 h,所得HA-Ag混合粉末仍置于酒精中,备用;
(2)将步骤(1)中得到的HA-Ag粉末与NH4HCO3粉末在混料机内混合200min得到混合粉末A;混合粉末A中HA-Ag粉末的质量百分比为80%,NH4HCO3粉末的质量百分比为20%,将混合粉末A筛分平均粒径500μm。
(3)按Sr粉末 90%、NH4HCO3粉末10%的质量百分比,分别称取Sr粉末和NH4HCO3粉末在混料机内混合55min得到混合粉末B。
(4)称取15g ,纯度超过99.7%,粒度为100nm的羟基磷灰石HA粉末,记为粉末C,备用。
(5)将步骤(2)步骤(3)步骤(4)得到的粉末梯度铺放装入镀Cr的合金钢模具中,首先装混合粉末A,再装混合粉末B作为活性夹层,再装粉末C,最后装混合粉末B和混合粉末A;形成中心层是羟基磷灰石,次层为混合粉末B,最外层是混合粉末A的夹层结构;将装好粉末的模具在60 MPa的单项压力下冷压成型,退模后得到块体压坯。
(6)将步骤(5)得到的块体压坯装入石墨模具中,再置入放电等离子烧结炉中,系统真空抽至5 Pa后进行烧结,升温速率为80min/℃,在900℃下保温8 min,随炉冷却至室温即可得抗菌型功能梯度多孔HA-Ag骨填充支架材料。
按本例中相同的工艺条件,将HA-Ag粉末与筛分的200μm、300μm 400μm、600μm、的不同粒径的NH4HCO3粉末混合,连同本例在烧结得到的抗菌型功能梯度多孔HA-Ag骨填充支架材料,用相对密度法进行测量,并通过计算得到抗菌型功能梯度多孔HA-Ag骨填充支架材料的平均孔隙率和平均孔隙尺度分别在40%和500μm左右,这样的孔隙结构有利于成骨细胞的长入和体液的传输,加快骨组织缺损处的愈合过程。
Claims (1)
1.一种具有活性夹层的抗菌型功能梯度多孔HA-Ag骨填充支架的制备方法,其特征在于工艺步骤如下:
(1)按羟基磷灰石(HA )97%~80%、Ag 3~20%的质量百分比,分别称取100 nm的羟基磷灰石(HA )粉末和Ag粉末,将两种粉末放入玛瑙球磨罐中进行球磨,用酒精密封后抽真空至20~30Pa,然后球磨50~100 h,所得混合粉末仍置于酒精中,备用;
(2)将步骤(1)中得到的HA-Ag粉末与NH4HCO3粉末在混料机内混合120~240min得到混合粉末A;其中以质量百分比计在混合粉末A中,HA-Ag粉末为95%~75%,NH4HCO3粉末为5%~25%,混合粉末A筛分粒径100~700μm;
(3)以质量百分比计,按Sr粉末占 95%~90%,NH4HCO3粉末占5%~10%,分别称取Sr粉末和NH4HCO3粉末在混料机内混合30~60min后得到混合粉末B;
(4)称取10~20g ,纯度超过99.7%,粒度为100nm的羟基磷灰石(HA)粉末,记为粉末C,备用;
(5)将步骤(2)、步骤(3)和步骤(4)分别获得到的粉末梯度铺放装入镀Cr的合金钢模具中,首先装混合粉末A,再装混合粉末B作为活性夹层,再装粉末C,最后装混合粉末B和混合粉末A,形成中心层是羟基磷灰石,次层为混合粉末B,最外层是混合粉末A的夹层结构;将装好上述三种粉末的模具在50~100MPa的单项压力下冷压成型,退模后得到块体压坯;
(6)将步骤(5)得到的块体压坯装入石墨模具中,再置入放电等离子烧结炉中,系统真空抽至2~6 Pa后进行烧结,升温速率为50~100min/℃,在800~1000℃下保温5~10 min,随炉冷却至室温即可得抗菌型功能梯度多孔HA-Ag骨填充支架材料。
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