CN110025822A - 一种具有抗感染特性的骨支架的制备方法 - Google Patents
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Abstract
本发明提出一种具有抗感染特性的骨支架的制备方法,以介孔纳米羟基磷灰石作为万古霉素的载体,利用介孔纳米羟基磷灰石的高万古霉素负载能力以及万古霉素的抑制细菌生长和预防感染的功能,结合羧甲基壳聚糖和纳米银不同程度的抗感染作用,以载有万古霉素的介孔纳米羟基磷灰石和银‑羧甲基壳聚糖混合粉末为基体材料,采用三维打印快速成型技术制备具有抗感染特性的骨支架,并在制作过程中用I型胶原蛋白对支架进行改性,改善支架生物相容性。
Description
技术领域
本发明涉及医用人工骨移植材料的技术领域,具体涉及一种具有抗感染特性的骨支架的制备方法。
背景技术
在骨科领域,由于严重创伤、骨肿瘤、骨髓炎等多种原因所致的骨缺损十分常见。创伤性骨缺损修复过程中,极易引发感染,替代骨移植成功与否与是否感染密切相关。感染性骨缺损的治疗由于既要对骨缺损部位进行修复,又要防治感染,一直以来是骨科临床上所面临的难题。感染之后细菌在植入体表面形成生物膜而使单纯的植骨术因感染不易控制而失败,因此患者往往不能进行一期植骨,而须彻底清创,待感染因素消除、伤口愈合、血管重建后再进行二期植骨修复骨缺损。这种治疗方法既增加了患者的痛苦,也延长了治疗时间。考虑到骨支架所需的抗感染特性,将抗生素加入纳米骨中可以有效降低感染的风险。人工骨作为成骨细胞的载体,起着为成骨细胞生长提供充足的营养物质和生存空间的重要作用,具有抗感染特性的载药人工骨可以减少患者感染风险,依靠纳米材料和有机高分子材料的特性,在满足高效负载药物的条件下,既可保证骨支架的力学性能,又能改善骨支架的生物相容性。
理想的人工骨修复材料概括起来应具备的特性有:(1)良好的生物相容性与弱的免疫排斥反应;(2)与人工骨相似的力学性能;(3)良好的骨诱导再生性;(4)生物降解性,其降解速度不超过新骨长入的骨组织修复速度;(5)适当的孔径与孔隙率。
介孔纳米羟基磷灰石(MHA)不仅具有优良的生物相容性、骨传导性和生物可降解性,同时具有高比表面积和孔道结构,其具有高效的药物负载能力;但机械强度和断裂韧性差。万古霉素是糖肽抗生素,对许多革兰阳性细菌,如金黄色葡萄球菌,具有很强的杀菌作用,并且已经应用与多个临床领域。同时羟基磷灰石晶体和万古霉素分子存在的OH基团间的氢键相互作用可促进万古霉素分子的吸附。纳米银是近年来抗菌药物的研究热点,其抗菌能力强且对人体细胞相对无毒,广谱杀菌且无耐药性,能够促进细胞的生长和受损细胞的修复,是最新一代的天然抗菌剂。羧甲基壳聚糖(CMC)是一种水溶性壳聚糖衍生物,具有良好的生物相容性,生物降解性、力学稳定性和一定程度的抗感染作用,同时由于氨基的存在,使得羧甲基壳聚糖对金属离子有较好的吸附能力。
聚乙烯醇(PVA),具有优良的生物相容性、粘接性、化学稳定性和水溶性,其在人体内可以缓慢降解且降解产物无毒副作用,因此PVA已经作为粘结材料在生物医学领域得到广泛应用。I型胶原是哺乳动物结缔组织主要存在的化合物,具有良好的生物相容性、生物活性和粘接性,被广泛应用于生物医学中。
目前尚无报道利用载有万古霉素的介孔纳米羟基磷灰石和银-羧甲基壳聚糖混合粉末为基体材料,并结合胶原-聚乙烯醇粘结剂混合制备具有抗感染特性的人工骨支架,该支架在满足骨支架的力学性能和生物相容性的条件下,有效的保证了骨支架的抗感染特性。
发明内容
本发明的目的是提供一种具有抗感染特性的人工骨支架制备方法。该支架以介孔纳米羟基磷灰石作为万古霉素的载体,利用介孔纳米羟基磷灰石的高万古霉素负载能力以及万古霉素的抑制细菌生长和预防感染的功能,结合羧甲基壳聚糖和纳米银不同程度的抗感染作用,以载有万古霉素的介孔纳米羟基磷灰石和银-羧甲基壳聚糖混合粉末为基体材料,采用三维打印快速成型技术制备具有抗感染特性的骨支架,并在制作过程中用I型胶原蛋白对支架进行改性,改善支架生物相容性。
本发明的技术方案为:
所述一种具有抗感染特性的骨支架的制备方法,其特征在于:包括以下步骤:
步骤1:获取待打印骨组织的三维模型,并对骨组织三维模型进行分层切片处理,获取分层截面数据;
步骤2:制备质量分数为0.5~1.5%的聚乙烯醇溶液,并将一定质量的I型胶原蛋白粉末加入所制备的聚乙烯醇溶液中,其中混合溶液中I型胶原蛋白的质量分数为1.5~2.5%;待混合溶液中I型胶原蛋白完全溶解后,将其置于3~5℃的无菌环境下静置保存,并作为粘结剂备用;
步骤3:将介孔纳米羟基磷灰石粉末与万古霉素按5:1的质量比加入到无菌去离子水中,搅拌后得到悬浮液,将悬浮液密封并在37℃±1℃温度下振荡至少24小时;然后对所制备的悬浮液进行离心处理,离心后用孔径500nm的微孔过滤器过滤并干燥,得到载有万古霉素的介孔纳米羟基磷灰石载药微球;
步骤4:通过液相化学还原法制备银-羧甲基壳聚糖Ag-OCMC复合微粒,将质量分数为8~12%的Ag-OCMC复合微粒与步骤3所制备的载药微球均匀混合,得到混合粉末材料,加入生物三维成型机粉仓中;
步骤5:将步骤2所得的聚乙烯醇-I型胶原蛋白粘结剂装入生物三维成型机的储液腔,向生物三维成型机导入三维模型数据,根据分层数据,进行具有抗感染特性人工骨支架的分层打印制备;每一层打印过程为:在成型工作台上均匀铺一层步骤4制备的混合粉末材料,然后由生物三维成型机在混合粉末上喷洒步骤2制备的粘结剂;
步骤6:将制备好的骨支架在干燥箱中干燥后,储存在无菌环境中备用。
进一步的优选方案,所述一种具有抗感染特性的骨支架的制备方法,其特征在于:步骤2中聚乙烯醇溶液的浓度为1%。
进一步的优选方案,所述一种具有抗感染特性的骨支架的制备方法,其特征在于:步骤4中通过液相化学还原法制备银-羧甲基壳聚糖Ag-OCMC复合微粒的过程为:
将羧甲基壳聚糖OCMC溶于乙酸水溶液,使羧甲基壳聚糖完全溶解,向上述溶液中缓慢滴加硝酸银溶液,并在30℃的水浴中搅拌至少30min;而后缓慢滴加香草醛溶液,继续搅拌得到Ag-OCMC复合胶乳,将胶乳置于烘箱中于60℃烘干至恒重,得到Ag-OCMC复合微粒。
有益效果
(1)本发明利用介孔纳米羟基磷灰石生物可降解性、高比表面积和孔道结构,以介孔纳米羟基磷灰石作为药物载体,负载抗生素,使骨支架具有一定的抗感染性,有效减少或者避免了二次感染的可能。
(2)本发明利用介孔纳米羟基磷灰石负载万古霉素,前期可实现快速释放保证了在短时间内达到治疗浓度并防止细菌菌株产生抗药性,随后平缓释放,长期保持局部有效抗菌浓度,抑制细菌生长。
(3)通过液相化学还原法制备银-羧甲基壳聚糖(Ag-OCMC)复合微粒,结合了银的广谱抑菌作用和羧甲基壳聚糖的抑菌杀菌功能,同时与载有万古霉素的介孔纳米羟基磷灰石作为基体材料,使支架具有更好的抑菌效果。
(4)本发明考虑自然骨的成分组成,将I型胶原蛋白-聚乙烯醇混合溶液作为粘结剂对骨支架进行改性处理,满足仿生骨支架的材料与自然骨成分的相似性,在不影响支架孔隙率的情况下,增加了支架的抗压强度并改善了骨支架的生物相容性。
(5)本发明解决了传统制备方法上人工骨支架与生物体相容性、可降解性的问题,同时载万古霉素的介孔羟基磷灰石的加入解决了植骨环节中易感染的问题。植入后,生物组织能更快依附植骨生长。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
具体实施方式
下面详细描述本发明的实施例,所述实施例是示例性的,旨在用于解释本发明,而不能理解为对本发明的限制。
本发明提供的具有抗感染特性的人工骨支架以介孔纳米羟基磷灰石作为万古霉素的载体,利用介孔纳米羟基磷灰石的高万古霉素负载能力以及万古霉素的抑制细菌生长和预防感染的功能,结合羧甲基壳聚糖和纳米银不同程度的抗感染作用,以载有万古霉素的介孔纳米羟基磷灰石和银-羧甲基壳聚糖混合粉末为基体材料,采用三维打印快速成型技术制备具有抗感染特性的骨支架,并在制作过程中用I型胶原蛋白对支架进行改性,改善支架生物相容性。
制备的具体步骤为:
步骤1:采用Micro-CT扫描人体损伤处骨组织,获取损伤骨组织图像数据;将获取的损伤处骨组织图像数据导入Mimics软件,重构人体损伤部分的骨骼三维模型,以STL格式导入3D骨成型系统;计算机处理人工骨支架三维CAD模型,将其从下至上顺序分割成间距0.1mm的二维界面图形N份,并将数据导入三维打印机中。
步骤2:制备质量分数为1%的聚乙烯醇溶液,并将一定质量的I型胶原蛋白粉末加入所制备的聚乙烯醇溶液中,其中混合溶液中I型胶原蛋白的质量分数为2%;待混合溶液中I型胶原蛋白完全溶解后,将其置于4℃的无菌环境下静置保存,并作为粘结剂备用。
这里优选聚乙烯醇溶液的浓度为1%。聚乙烯醇浓度较小会导致粘结剂粘度变小,打印过程中液滴在粉床表面过度分散影响成型精度;浓度过高会导致喷嘴堵塞,无法进行喷洒;浓度为1%时,粘结剂浸润性能最佳,粘结效率最高,可以保证支架成型精度。
步骤3:将介孔纳米羟基磷灰石粉末与万古霉素按5:1的质量比加入到无菌去离子水中,搅拌后得到悬浮液,将悬浮液密封并在37℃温度下振荡24小时;然后对所制备的悬浮液进行离心处理(600rmp),离心后用微孔(孔径500nm)过滤器过滤并干燥,得到载有万古霉素的介孔纳米羟基磷灰石载药微球。
步骤4:通过液相化学还原法制备银-羧甲基壳聚糖(Ag-OCMC)复合微粒,将质量分数为10%的Ag-OCMC复合微粒与步骤3所制备的载药微球均匀混合,得到混合粉末材料,加入生物三维成型机粉仓中。
液相化学还原法制备银-羧甲基壳聚糖(Ag-OCMC)复合微粒过程为:
将1.2g羧甲基壳聚糖(OCMC)溶于40ml 2wt%的乙酸水溶液,使羧甲基壳聚糖完全溶解,向上述溶液中缓慢滴加2mL 0.1mol/L的硝酸银溶液,并在30℃的水浴中搅拌30min;缓慢滴加20ml 0.05mol/L香草醛溶液(溶剂为水和乙醇体积比为1:1的混合液),继续搅拌3h,得到Ag-OCMC复合胶乳。将胶乳置于烘箱中于60℃烘干至恒重,得到Ag-OCMC复合微粒。
步骤5:将步骤2所得的聚乙烯醇-I型胶原蛋白粘结剂装入生物三维成型机的储液腔,向生物三维成型机导入三维模型数据,根据分层数据,进行具有抗感染特性人工骨支架的分层打印制备;每一层打印过程为:在成型工作台上均匀铺一层步骤4制备的混合粉末材料,然后由生物三维成型机在混合粉末上喷洒步骤2制备的粘结剂;其中粘结剂的喷洒量为0.3L/m2。
步骤6:将制备好的骨支架置于干燥箱中,在40℃下干燥两小时,而后储存在无菌环境中备用。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (3)
1.一种具有抗感染特性的骨支架的制备方法,其特征在于:包括以下步骤:
步骤1:获取待打印骨组织的三维模型,并对骨组织三维模型进行分层切片处理,获取分层截面数据;
步骤2:制备质量分数为0.5~1.5%的聚乙烯醇溶液,并将一定质量的I型胶原蛋白粉末加入所制备的聚乙烯醇溶液中,其中混合溶液中I型胶原蛋白的质量分数为1.5~2.5%;待混合溶液中I型胶原蛋白完全溶解后,将其置于3~5℃的无菌环境下静置保存,并作为粘结剂备用;
步骤3:将介孔纳米羟基磷灰石粉末与万古霉素按5:1的质量比加入到无菌去离子水中,搅拌后得到悬浮液,将悬浮液密封并在37℃±1℃温度下振荡至少24小时;然后对所制备的悬浮液进行离心处理,离心后用孔径500nm的微孔过滤器过滤并干燥,得到载有万古霉素的介孔纳米羟基磷灰石载药微球;
步骤4:通过液相化学还原法制备银-羧甲基壳聚糖Ag-OCMC复合微粒,将质量分数为8~12%的Ag-OCMC复合微粒与步骤3所制备的载药微球均匀混合,得到混合粉末材料,加入生物三维成型机粉仓中;
步骤5:将步骤2所得的聚乙烯醇-I型胶原蛋白粘结剂装入生物三维成型机的储液腔,向生物三维成型机导入三维模型数据,根据分层数据,进行具有抗感染特性人工骨支架的分层打印制备;每一层打印过程为:在成型工作台上均匀铺一层步骤4制备的混合粉末材料,然后由生物三维成型机在混合粉末上喷洒步骤2制备的粘结剂;
步骤6:将制备好的骨支架在干燥箱中干燥后,储存在无菌环境中备用。
2.根据权利要求1所述一种具有抗感染特性的骨支架的制备方法,其特征在于:步骤2中聚乙烯醇溶液的浓度为1%。
3.根据权利要求1所述一种具有抗感染特性的骨支架的制备方法,其特征在于:步骤4中通过液相化学还原法制备银-羧甲基壳聚糖Ag-OCMC复合微粒的过程为:
将羧甲基壳聚糖OCMC溶于乙酸水溶液,使羧甲基壳聚糖完全溶解,向上述溶液中缓慢滴加硝酸银溶液,并在30℃的水浴中搅拌至少30min;而后缓慢滴加香草醛溶液,继续搅拌得到Ag-OCMC复合胶乳,将胶乳置于烘箱中于60℃烘干至恒重,得到Ag-OCMC复合微粒。
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