CN116271211A - 一种载药人工骨材料的制备方法与应用 - Google Patents
一种载药人工骨材料的制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种载药人工骨材料的制备方法与应用，载药人工骨材料包括以下重量份组分：羟基磷灰石28‑40份、壳聚糖20‑30份、改性海藻酸钠18‑35份、负载药物0.1‑5份，其制备方法包括以下步骤：S1、配置改性海藻酸钠溶液，然后加入负载药物，搅拌后超声分散得到混合液A；S2、将混合液A滴加到氯化钙溶液中，低速搅拌后静置，洗涤、真空冷冻干燥得到载药海藻酸钠微球；S3、将羟基磷灰石和载药海藻酸钠微球加入壳聚糖醋酸溶液中充分搅拌，得到载药人工骨材料，本发明通过改性海藻酸钠对药物进行包覆，显著提高了其对药物的负载量并增强其体外缓释性能，采用纳米羟基磷灰石与载药的改性海藻酸纳、壳聚糖复合，增加了骨诱导能力，使其适用于骨组织工程。
Description
技术领域
本发明涉及人工骨骼材料技术领域，具体是一种载药人工骨材料的制备方法与应用。
背景技术
因外伤、先天畸形、肿瘤切除或骨髓炎等导致的骨缺损在骨科临床中十分常见。骨缺损的临床修复往往需要人工骨替代材料对缺损部位加以填充，提供永久性或短期的支架来减少缺损的尺寸，帮助组织修复重建。近年来，载药人工骨受到越来越多的研究者和临床医生的关注。一方面，它可作为人工骨材料对骨缺损进行填充修复，另一方面；还可充当局部药物缓释系统，对创伤部位进行局部治疗。
羟基磷灰石(HAP)是一类多孔的无机材料，因具有优良的生物相容性以及与蛋白质分子的高亲和性被广泛用于蛋白缓释药物载体，但其质地脆、韧性差、强度低、抗弯曲度和断裂韧性指标均低于人体密质骨，与其他生物材料相比，并不是高强度的材料。羟基磷灰石(HAP)与人体骨组织成分更接近，具有更加良好的生物学性能，在机械强度、细胞亲和性、体内降解速率、骨诱导活性等方面优势明显，可良好填充骨缺损并起到骨传导的作用，可逐渐被骨组织取代，作为一种可吸收的人工骨材料。HAP虽然比表面积大，具有较高的载药量，但用作药物载体时，由于所载药物前期突释现象明显，主要可能是吸附在HAP表面的药物快速被吸收的原因。这样就难以形成长期、稳定有效的药物浓度，使其应用在一定程度上受到限制。
因此，亟需开发一种基于HAP的人工骨载药系统，在保证复合材料具有良好的生物相容性及性质稳定的前提下，获得复合材料载药量高，释放稳定，降解速度与机体组织生长相匹配等综合性能高的复合材料。
发明内容
本发明的目的在于提供一种载药人工骨材料的制备方法与应用，本发明方法制备的载药人工骨材料显著提高了其对药物的负载量并增强其体外缓释性能，支架的骨诱导强，适合被应用于骨组织工程。
本发明的目的可以通过以下技术方案实现：
本发明公开了一种载药人工骨材料的制备方法，所述载药人工骨材料包括以下重量份组分：羟基磷灰石28-40份、壳聚糖20-30份、改性海藻酸钠18-35份、负载药物0.1-5份；
所述改性海藻酸钠由海藻酸钠通过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与N-羟基琥珀酰亚胺活化后与端氨基化聚乳酸发生酰胺化反应制得；
所述载药人工骨材料制备方法包括以下步骤：
S1、于无菌超净台内将改性海藻酸钠溶解在去离子水中，配置成浓度为2wt％的改性海藻酸钠溶液，然后将负载药物加入上述改性海藻酸钠溶液中，充分搅拌后超声分散5～15min，得到混合液A；
S2、将混合液A滴加到0.2mol/L的氯化钙溶液中，低速搅拌10～20min后静置2～4h，然后用去离子水冲洗3～5遍，真空冷冻干燥得到载药海藻酸钠微球；
S3、将壳聚糖加入浓度为2wt％的醋酸溶液中，充分搅拌至壳聚糖溶解，然后将纳米羟基磷灰石和载药海藻酸钠微球加入壳聚糖醋酸溶液中充分搅拌，得到所述载药人工骨材料。
进一步优选地，羟基磷灰石的粒径为20-425微米。
进一步优选地，负载药物为抗生素类、促骨愈合类或抗肿瘤类药物的一种。
进一步优选地，改性海藻酸钠的制备方法具体包括以下步骤：
(1)将海藻酸钠溶于去离子水中，滴加HCl调节溶液pH至6.0，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，搅拌10～20min，得到活化海藻酸钠溶液；
(2)将端氨基聚乳酸加入四氢呋喃溶液中，40℃搅拌溶解，再加入一定量的N，N-二甲基甲酰胺，充分搅拌，得到端氨基聚乳酸溶液；
(3)将端氨基聚乳酸溶液缓慢滴加到活化海藻酸钠溶液中，滴加完毕后将混合液置于40℃搅拌反应18～24h，离心洗涤后冷冻干燥，得到改性海藻酸钠。
进一步优选地，步骤(3)中端氨基聚乳酸和活化海藻酸钠的摩尔比为1:2～4。
本发明还公开了一种载药人工骨材料在骨骼修复中的应用，所述载药人工骨材料由上述制备方法制得，将所述载药人工骨材料装入气动凝胶纤维打印机中，根据待修复的骨骼模型，打印出所需的人工骨骼支架。
本发明的有益效果：
本发明采用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与N-羟基琥珀酰亚胺形成的催化体系来活化海藻酸钠中的羧基，与端氨基聚乳酸发生酰胺化反应实现疏水性聚乳酸的接枝，通过端氨基聚乳酸疏水改性后的海藻酸钠对药物进行包覆后形成核壳结构载药微球，显著提高了其对药物的负载量并增强其体外缓释性能。而羟基磷灰石颗粒复合到改性海藻酸纳、壳聚糖凝胶中可以显著改善凝胶的力学性能，增加支架的骨诱导能力，使其更适合被应用于骨组织工程。当然，实施本发明的任一产品并不一定需要同时达到以上所述的所有优点。
具体实施方式
下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，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。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实施例1
一种载药人工骨材料的制备方法，其特征在于，所述载药人工骨材料包括以下重量份组分：羟基磷灰石30份、壳聚糖30份、改性海藻酸钠20份、环丙沙星1.5份；
所述载药人工骨材料制备方法包括以下步骤：
S1、于无菌超净台内将改性海藻酸钠溶解在去离子水中，配置成浓度为2wt％的改性海藻酸钠溶液，然后将环丙沙星加入上述改性海藻酸钠溶液中，充分搅拌后超声分散8min，得到混合液A；
S2、将混合液A滴加到0.2mol/L的氯化钙溶液中，低速搅拌10min后静置4h，然后用去离子水冲洗3～5遍，真空冷冻干燥得到载药海藻酸钠微球；
S3、将壳聚糖加入浓度为2wt％的醋酸溶液中，充分搅拌至壳聚糖溶解，然后将羟基磷灰石和载药海藻酸钠微球加入壳聚糖醋酸溶液中充分搅拌，得到所述载药人工骨材料。
其中，改性海藻酸钠的制备方法具体包括以下步骤：
(1)将海藻酸钠溶于去离子水中，滴加HCl调节溶液pH至6.0，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，搅拌10min，得到活化海藻酸钠溶液；
(2)将端氨基聚乳酸加入四氢呋喃溶液中，40℃搅拌溶解，再加入一定量的N，N-二甲基甲酰胺，充分搅拌，得到端氨基聚乳酸溶液；
(3)将端氨基聚乳酸溶液缓慢滴加到活化海藻酸钠溶液中，端氨基聚乳酸和活化海藻酸钠的摩尔比为1:2，滴加完毕后将混合液置于40℃搅拌反应18h，离心洗涤后冷冻干燥，得到改性海藻酸钠。
一种载药人工骨材料在骨骼修复中的应用，将上述载药人工骨材料装入气动凝胶纤维打印机中，根据待修复的骨骼模型，打印出所需的人工骨骼支架，该人工骨骼支架可以缓慢释放抗生素环丙沙星，起到抗感染的作用。
实施例2
一种载药人工骨材料的制备方法，其特征在于，所述载药人工骨材料包括以下重量份组分：羟基磷灰石40份、壳聚糖20份、改性海藻酸钠35份、淫羊藿苷5份；
所述载药人工骨材料制备方法包括以下步骤：
S1、于无菌超净台内将改性海藻酸钠溶解在去离子水中，配置成浓度为2wt％的改性海藻酸钠溶液，然后将淫羊藿苷加入上述改性海藻酸钠溶液中，充分搅拌后超声分散15min，得到混合液A；
S2、将混合液A滴加到0.2mol/L的氯化钙溶液中，低速搅拌15min后静置3h，然后用去离子水冲洗3～5遍，真空冷冻干燥得到载药海藻酸钠微球；
S3、将壳聚糖加入浓度为2wt％的醋酸溶液中，充分搅拌至壳聚糖溶解，然后将羟基磷灰石和载药海藻酸钠微球加入壳聚糖醋酸溶液中充分搅拌，得到所述载药人工骨材料。
其中，改性海藻酸钠的制备方法具体包括以下步骤：
(1)将海藻酸钠溶于去离子水中，滴加HCl调节溶液pH至6.0，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，搅拌15min，得到活化海藻酸钠溶液；
(2)将端氨基聚乳酸加入四氢呋喃溶液中，40℃搅拌溶解，再加入一定量的N，N-二甲基甲酰胺，充分搅拌，得到端氨基聚乳酸溶液；
(3)将端氨基聚乳酸溶液缓慢滴加到活化海藻酸钠溶液中，端氨基聚乳酸和活化海藻酸钠的摩尔比为1:3，滴加完毕后将混合液置于40℃搅拌反应20h，离心洗涤后冷冻干燥，得到改性海藻酸钠。
一种载药人工骨材料在骨骼修复中的应用，将上述载药人工骨材料装入气动凝胶纤维打印机中，根据待修复的骨骼模型，打印出所需的人工骨骼支架，该人工骨骼支架可以缓慢释放淫羊藿苷，从而促进骨折愈合，也可治疗骨质疏松。
实施例3
一种载药人工骨材料的制备方法，其特征在于，所述载药人工骨材料包括以下重量份组分：羟基磷灰石30份、壳聚糖20份、改性海藻酸钠25份、蟾毒灵0.2份；
所述载药人工骨材料制备方法包括以下步骤：
S1、于无菌超净台内将改性海藻酸钠溶解在去离子水中，配置成浓度为2wt％的改性海藻酸钠溶液，然后将蟾毒灵加入上述改性海藻酸钠溶液中，充分搅拌后超声分散10min，得到混合液A；
S2、将混合液A滴加到0.2mol/L的氯化钙溶液中，低速搅拌20min后静置2～4h，然后用去离子水冲洗3～5遍，真空冷冻干燥得到载药海藻酸钠微球；
S3、将壳聚糖加入浓度为2wt％的醋酸溶液中，充分搅拌至壳聚糖溶解，然后将羟基磷灰石和载药海藻酸钠微球加入壳聚糖醋酸溶液中充分搅拌，得到所述载药人工骨材料。
其中，改性海藻酸钠的制备方法具体包括以下步骤：
(1)将海藻酸钠溶于去离子水中，滴加HCl调节溶液pH至6.0，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，搅拌10min，得到活化海藻酸钠溶液；
(2)将端氨基聚乳酸加入四氢呋喃溶液中，40℃搅拌溶解，再加入一定量的N，N-二甲基甲酰胺，充分搅拌，得到端氨基聚乳酸溶液；
(3)将端氨基聚乳酸溶液缓慢滴加到活化海藻酸钠溶液中，端氨基聚乳酸和活化海藻酸钠的摩尔比为1:4，滴加完毕后将混合液置于40℃搅拌反应24h，离心洗涤后冷冻干燥，得到改性海藻酸钠。
一种载药人工骨材料在骨骼修复中的应用，将上述载药人工骨材料装入气动凝胶纤维打印机中，根据待修复的骨骼模型，打印出所需的人工骨骼支架，该人工骨骼支架可以缓慢释放蟾毒灵，从而抑制骨肉瘤细胞增殖。
性能测试
将实施例1-实施例3制备的载药人工骨材料浸没于装有PBS缓冲溶液的离心管中，分别于2h、4h、6h、8h和10h取出缓释液，然后通过液相色谱法检测缓释液中的环丙沙星、淫羊藿苷和蟾毒灵的含量并计算累计释放率，得到数据表1所示。
表1载药人工骨材料缓释性能测试结果
由表1可以看出，通过端氨基聚乳酸疏水改性后的海藻酸钠对药物进行包覆后形成核壳结构载药微球，显著增强了药物的体外缓释性能。
以上内容仅仅是对本发明的构思所作的举例和说明，所属本技术领域的技术人员对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离发明的构思或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。
Claims (6)
1.一种载药人工骨材料的制备方法，其特征在于，所述载药人工骨材料包括以下重量份组分：羟基磷灰石28-40份、壳聚糖20-30份、改性海藻酸钠18-35份、负载药物0.1-5份；
所述改性海藻酸钠由海藻酸钠通过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐与N-羟基琥珀酰亚胺活化后与端氨基化聚乳酸发生酰胺化反应制得；
所述载药人工骨材料制备方法包括以下步骤：
S1、于无菌超净台内将改性海藻酸钠溶解在去离子水中，配置成浓度为2wt％的改性海藻酸钠溶液，然后将负载药物加入上述改性海藻酸钠溶液中，充分搅拌后超声分散5～15min，得到混合液A；
S2、将混合液A滴加到0.2mol/L的氯化钙溶液中，低速搅拌10～20min后静置2～4h，然后用去离子水冲洗3～5遍，真空冷冻干燥得到载药海藻酸钠微球；
S3、将壳聚糖加入浓度为2wt％的醋酸溶液中，充分搅拌至壳聚糖溶解，然后将羟基磷灰石和载药海藻酸钠微球加入壳聚糖醋酸溶液中充分搅拌，得到所述载药人工骨材料。
2.如权利要求1所述的载药人工骨材料的制备方法，其特征在于，所述羟基磷灰石的粒径为20-450微米。
3.如权利要求1所述的载药人工骨材料的制备方法，其特征在于，所述负载药物为抗生素类、促骨愈合类或抗肿瘤类药物的一种。
4.根据权利要求1所述的载药人工骨材料的制备方法，其特征在于，所述改性海藻酸钠的制备方法具体包括以下步骤：
(1)将海藻酸钠溶于去离子水中，滴加HCl调节溶液pH至6.0，再加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，搅拌10～20min，得到活化海藻酸钠溶液；
(2)将端氨基聚乳酸加入四氢呋喃溶液中，40℃搅拌溶解，再加入一定量的N，N-二甲基甲酰胺，充分搅拌，得到端氨基聚乳酸溶液；
(3)将端氨基聚乳酸溶液缓慢滴加到活化海藻酸钠溶液中，滴加完毕后将混合液置于40℃搅拌反应18～24h，离心洗涤后冷冻干燥，得到改性海藻酸钠。
5.根据权利要求4所述的载药人工骨材料的制备方法，其特征在于，所述步骤(3)中端氨基聚乳酸和活化海藻酸钠的摩尔比为1:2～4。
6.一种载药人工骨材料在骨骼修复中的应用，其特征在于，所述载药人工骨材料由权利要求1～5任一项所述制备方法制得，将所述载药人工骨材料装入气动凝胶纤维打印机中，根据待修复的骨骼模型，打印出所需的人工骨骼支架。
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