CN113476660A - 一种模拟肌腱-骨界面的高仿生复合支架的制备方法 - Google Patents
一种模拟肌腱-骨界面的高仿生复合支架的制备方法 Download PDFInfo
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Abstract
本发明为一种模拟基于腱骨界面的高仿生复合支架的制备方法，属于组织工程骨支架材料的制备技术领域。本发明中，结合腱骨界面连续渐变结构和组织工程方法特点构建高仿生复合支架，于不同模拟相负载不同生长因子，并种植骨髓间质干细胞促进修复。其中第一层采用负载BMP‑2‑明胶微球的多孔支架模拟腱骨界面的骨相，促进骨组织再生；第二层采用载TGF‑β3的海藻酸钠和胶原的复合水凝胶模拟腱骨界面渐变相；最外层采用聚乳酸定向纳米纤维模拟腱骨界面肌腱相，并具防止组织粘连和抗菌作用。本方法所制备的复合支架实现了腱骨界面异型细胞群体和基质的特异性变化，并表现出分级的力学特性和组织诱导特性，在骨组织工程中具有应用前景。
Description
技术领域
本发明为一种基于肌腱-骨界面的组织构成和组织工程方法特点的复合支架，属于组织工 程骨支架材料的制备技术领域，特别是模拟肌腱-骨界面连续渐变结构构建一种高仿生支架， 有望用于腱-骨组织的再生修复。
背景技术
由创伤、感染、肿瘤等引起的大段骨缺损修复与重建是临床医疗的常见问题，而大尺寸 骨缺损往往伴随着严重肌腱和韧带组织损伤。肌腱-骨界面是软组织向骨转化的特殊移行区域， 由肌腱、未钙化纤维软骨、钙化纤维软骨和骨共四层组织构成，由于腱-骨界面复杂的组成结 构和特殊的生物力学功能，其重建和修复缓慢而困难。临床上，传统的保守治疗或手术由于 缺乏修复肌腱到骨的过渡区而不能有效地实现肌腱愈合和再生。采用组织工程方法构建复合 种子细胞、支架材料和生长因子的生物活性人工骨被认为是腱骨组织再生修复最有效的方法 之一。然而目前，能够用于临床的组织工程产品种类和数量都非常有限，行使的功能和结构 也相对简单，尤其缺乏一种能够模拟腱-骨界面组织结构连续渐变且细胞分化多样的高仿生组 织工程支架材料，因此现有技术方法无法对其进行有效重建和整合。我们旨在制备一种模拟 肌腱-骨界面连续渐变结构的多层生物活性支架，能够实现结构和功能的高度仿生化，从而迅 速有效地实现肌腱和骨组织的再生修复。
本发明的目的：提供一种模拟肌腱-骨界面连续渐变结构的高仿生多层生物活性支架的制 备方法。
本发明的构思：基于肌腱-骨界面的组织构成和组织工程方法的特点，构建的支架材料主 要包括三层：第一层为骨相，采用聚乳酸-羟基乙酸共聚物(PLGA)和纳米羟基磷灰石(nHA) 制备，同时加入负载BMP-2的明胶微球并种植骨髓间充值干细胞(BMSCs)，可为大段骨缺 损提供力学支撑同时诱导细胞成骨分化，促进骨再生；第二层为肌腱相，采用胶原和海藻酸 钠制备的复合凝胶材料并负载TGF-β，为种植的肌腱细胞的生长分化提供细胞外基质和诱导 因子；最外层拟采用定向排列的左旋聚乳酸(PLLA)纳米纤维膜，诱导诱导肌腱细胞的定向 分化，并具有防止组织粘连和抗菌的作用。最后，将上述三层复合，构建一种模拟肌腱-骨界 面连续渐变结构的多层生物活性支架，使其能够从结构和功能等全面促进的肌腱-骨界面的修 复和再生。
发明内容
本发明的目的主要是通过以下技术路线实现的：
(1)肌腱-骨界面模拟骨相的制备：首先制备载BMP-2明胶微球，在室温下将明胶溶解在 去离子水中，使用氢氧化钠调节溶液pH值至中性。搅拌条件下加入乙醇梯度置换出水以形 成明胶颗粒，再加入乙二醛进行交联，并在反应结束后使用12％的焦亚硫酸钠水溶液除去未 反应的醛基。通过离心收集到的明胶颗粒用去离子水洗涤两次后进行冷冻干燥。将明胶颗粒 置于活化液中活化1h。将活化的明胶颗粒在去离子水中透析过夜后离心且冷冻干燥，再于已 加入的BMP-2水溶液的PBS中溶胀以装载BMP-2。最后将载BMP-2的明胶微球离心收集并 冷冻干燥后保存备用。使用氯仿溶解PLGA，待聚合物完全溶解后，将预定质量的已过筛氯 化钠和羟磷灰石分散在溶液中,并加入一定量的载BMP-2明胶微球混合均匀。将混合物注入 支架模具，室温静置24小时后脱模，干燥24小时。用去离子水浸泡支架2天，每4小时换 一次水并不断搅拌。最后将样品取出，干燥24小时，再真空干燥24小时，即得载BMP-2明 胶微球的PLGA/nHA多孔支架。将BMSCs细胞悬液接种到支架上，置于37℃、5％CO2的加湿培养箱中培养。
(2)肌腱-骨界面模拟肌腱-骨渐变相的制备：通过涡旋混合器将一定浓度海藻酸钠与I型 胶原溶液混匀，并在低温的条件下加入TGF-β3溶液。将混合液于旋涡状态下滴加氯化钙溶 液使其胶凝，样品在4℃下放置过夜，制得海藻酸钠/I型胶原水凝胶。将复合水凝胶冻干后 置于细胞培养基，将肌腱细胞(TCs)悬液接种到水凝胶上。置于37℃、5％CO2的加湿培养 箱中培养。
(3)肌腱-骨界面模拟肌腱相的制备：将PLLA溶解于氯仿中形成PLLA-氯仿溶液，装入装 有钝端针头的10mL注射器中。通过静电纺丝装置进行纺丝得到的PLLA取向的微纤维膜。
(4)不同模拟相材料的复合：将载BMP-2微球的PLGA/nHA多孔支架外部涂抹一层海藻 酸钠/I型胶原混合液，通过混合液的粘性将静电纺丝膜包裹在最外部，滴加氯化钙溶液使其 交联成胶，静置后翻转支架，再于水凝胶层滴加氯化钙交联，静置，即得三层复合支架。
本发明的用途：本发明主要用于制备一种模拟肌腱-骨界面连续渐变结构的高仿生复合支 架，使其能够从结构和功能等全面促进的肌腱-骨界面的修复和再生。
本发明的优点：本方法制备过程简单，绿色环保高度仿生。所制备的模拟肌腱-骨界面连 续渐变结构的高仿生复合支架每一层使用不同的生物材料制成不同的性质，以模拟肌腱-骨界 面的结构和组成梯度，这使得支持界面异型细胞群体和基质的相特异性变化成为可能，并且 表现出分级的机械性质。
附图说明
附图1.PLGA/nHA多孔支架形貌电镜观察
附图2.海藻酸钠/I型胶原复合水凝胶形貌电镜观察
附图3.PLLA定向微纤维形貌电镜观察
附图4.载BMP-2明胶微球形貌电镜观察
附图5.摘要附图
具体实施方式
以下结合发明人给出的具体实例，对所发明的高仿生组织工程支架作进一步的详细阐述。但 本发明并不仅限于如下实施例的范围。
实例一复合支架骨相的制备：
(1)取5ml氯仿溶解0.5g PLGA(分子量为10万)制备得到10％(w/v)PLGA-氯仿溶液。
(2)将2.5g已过筛(200μm)氯化钠(氯化钠与PLGA体积比为5:1)和纳米羟磷灰石0.1g分散 在氯仿-PLGA溶液中,并加入一定量的BMP-2载药微球高速搅拌5分钟，直至混合均匀。
(3)将混合物注入支架模具，注模时间不易过快，完成注模后于室温静置24小时。
(4)脱模，继续干燥24小时，挥发有机溶剂。
(5)用去离子水浸泡支架2天，每4小时换一次水并不断搅拌。
(6)最后将样品取出，于鼓风干燥机37℃干燥24小时，然后置于真空干燥箱37℃干燥24小 时，即得载BMP-2明胶微球的PLGA/nHA多孔支架。
(7)将支架放入超净台进行紫外灯照射灭菌1小时，加入生长培养基1ml。1小时后，将BMSCs 细胞悬液(10μl，1×105个细胞)接种到多孔支架上。1小时后，加入1ml生长培养基，放入37℃、 5％CO2的培养箱中培养。
实例二复合支架肌腱-骨渐变相的制备：
(1)称取海藻酸钠以去离子水溶解制成9.1mg/ml的海藻酸钠溶液
(2)称取I型胶原以0.02N醋酸溶液溶解制成9.1mg/ml的I型胶原溶液
(3)通过涡旋混合器将海藻酸钠与I型胶原溶液混匀(海藻酸钠与I型胶原溶液体积比为3:2)， 并使用NaOH(1mol/L)调节pH至7.4。
(4)在低温的条件下(4℃)加入TGF-β3，并混匀。
(5)将混合液于旋涡状态下滴加氯化钙溶液(0.1mol/L)使其胶凝。
(6)样品在4℃下放置过夜，将制得的I型胶原/海藻酸钠水凝胶于细胞接种前冻干。
(7)将冻干后的水凝胶放入超净台进行紫外灯照射灭菌后，将TCs细胞悬液(10μl，1×105个细 胞)接种到水凝胶上，加入培养基，放入37℃、5％CO2培养箱中培养。
实例三复合支架肌腱相的制备：
(1)称取1.3gPLLA(分子量为30万)溶解于10ml氯仿中形成13％(w/v)PLLA-氯仿溶液，
(2)将PLLA-氯仿溶液装入配有21号钝端针头的10mL注射器中，并将注射器安装于静电纺 丝设备上。
(3)设置静电纺丝机制备参数为：温度37℃，电压20kV，流速1.5mL/h，针尖到电动旋转靶距 离10cm，电动旋转靶转速2000rpm。
(4)开启静电纺丝装置进行纺丝10分钟，使用电动旋转靶接收PLLA纺丝。停止机器，得到定 向PLLA纳米纤维膜。
实例四复合支架的制备：
(1)将载BMP-2微球PLGA/nHA多孔支架外部涂抹一层厚度约1mm的海藻酸钠/I型胶原混 合液，通过水凝胶的粘性将PLLA静电纺丝膜包裹在最外部。
(2)于海藻酸钠/I型胶原水凝胶层滴加氯化钙溶液(0.8mol/L)进行交联，静置5min。
(3)翻转支架，再于海藻酸钠/I型胶原水凝胶层滴加氯化钙(0.8mol/L)交联，静置5min。
(4)将复合支架浸泡于氯化钙溶液2min。
(5)取出支架，吸干表面多余氯化钙溶液，即得。
实例五载BMP-2明胶微球的制备：
(1)将200mg明胶溶解在20ml去离子水中，直至得到澄清溶液。使用0.2mol/L氢氧化钠调节 溶液pH值至7.00。
(2)搅拌条件下加入乙醇梯度置换出水以形成明胶颗粒，最终洗脱混合液为100ml，乙醇与水 的体积比分别为65：35、50：50、35：65。
(3)加入乙二醛进行交联，室温下搅拌10h。反应结束后使用12％的焦亚硫酸钠水溶液除去乙 二醛中未反应的醛基。在14000rpm下离心90min，将离心收集到的明胶颗粒用去离子水洗涤 两次后冷冻干燥。
(4)将明胶颗粒置于已添加N-乙基-N`-(3-二甲氨基丙基)碳二酰亚胺盐酸盐(EDC，4mg/ml)和 N-羟基磺基琥珀酰亚胺钠(NHS，4mg/mL)的MES缓冲液(100mM，pH 6)中活化1h。
(5)活化的明胶颗粒在去离子水中透析过夜后离心并冷冻干燥，再于已加入的BMP-2水溶液 的PBS中反应10h以装载BMP-2。
(6)将载BMP-2的明胶微球离心收集并冷冻干燥，即得。
Claims (9)
1.一种模拟肌腱-骨界面的高仿生复合支架制备方法，其特征在于，所述方法包括下述步骤：
(1)肌腱-骨界面模拟骨相的制备：使用氯仿溶解PLGA，待聚合物完全溶解后，将预定质量的已过筛氯化钠和纳米羟磷灰石分散在溶液中,并加入一定量的载BMP-2明胶微球混合均匀。将混合物注入聚四氟乙烯支架模具。完成注模后于室温静置24小时后脱模，继续干燥24小时。使用去离子水浸泡支架2天，每4小时换一次水并不断搅拌。将多孔支架取出，在鼓风干燥机中干燥24小时，然后置于真空干燥箱中干燥24小时，保存在真空干燥器中，以避免降解。将支架放入超净台照紫外灯，将骨髓间质干细胞(BMSCs)细胞悬液接种到支架上。置于37℃、5％CO2培养箱中培养。
(2)肌腱-骨界面模拟肌腱-骨渐变相的制备：通过涡旋混合器将同浓度海藻酸钠与I型胶原溶液混匀，并在保持低温的条件下加入TGF-β3。将混合液于旋涡状态下滴加氯化钙溶液使其胶凝，样品在4℃下过夜，制得I型胶原/海藻酸钠水凝胶。将冻干后的水凝胶放入超净台照紫外灯，将肌腱细胞(TCs)细胞悬液接种到水凝胶上，置于37℃、5％CO2培养箱中培养。
(3)肌腱-骨界面模拟肌腱相的制备：将PLLA溶解于氯仿中形成PLLA-氯仿溶液，装入装有钝端针头的10mL注射器中，通过使用静电纺丝设备进行纺丝。将收集到的定向PLLA的纳米纤维膜60℃加热处理2小时。
(4)不同模拟相材料的复合：将载BMP-2微球的PLGA/nHA多孔支架外部涂抹一层海藻酸钠/I型胶原混合液，通过混合液的粘性将静电纺丝膜包裹在最外部。于水凝胶层滴加氯化钙溶液进行交联，静置5min。翻转支架，再于水凝胶层滴加氯化钙交联，静置5min。将复合支架浸泡于氯化钙溶液2min后取出支架，吸干表面多余氯化钙溶液，即得。
2.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤1中，采用粒子沥滤法制备PLGA/nHA多孔支架时所述室温范围为5～40℃，真空干燥箱温度30～40℃，压强为(0.08±0.01)MPa.，鼓风干燥机中干燥温度30～40℃。
3.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤1中，采用粒子沥滤法制备PLGA/nHA多孔支架时：PLGA的分子量为5～15万，用量为0.1～1.0g，PLGA溶液的浓度为5～15％(w/v)，氯仿的用量为1.0～10.0mL，NaCl的粒径为100～200um用量为0.3～9.0g，PLGA与NaCl的质量比为1:3～1:9
4.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤1中，载BMP-2明胶微球的制备方法为：在室温下将200mg明胶溶解在20ml去离子水中，直至得到澄清溶液。使用0.2mol/L氢氧化钠调节溶液pH值至7.00。搅拌条件下加入乙醇梯度置换出水以形成明胶颗粒，再加入乙二醛进行交联，室温下搅拌10h。反应结束后使用12％的焦亚硫酸钠水溶液除去乙二醛中未反应的醛基。在14000rpm下离心90min，将离心收集到的明胶颗粒用去离子水洗涤两次后进行冷冻干燥。BMP-2明胶微球的制备，明胶的羧基在添加N-乙基-N`-(3-二甲氨基丙基)碳二酰亚胺盐酸盐(EDC，4mg/ml)和N-羟基磺基琥珀酰亚胺钠(NHS，4mg/mL)的MES缓冲液(100mM，pH 6)中活化1h。将活化的明胶颗粒在去离子水中透析过夜后离心且冷冻干燥，再于已加入的BMP-2水溶液的PBS中溶胀10h以装载BMP-2。最后将载BMP-2的明胶微球离心收集并冷冻干燥。其中，在100ml的最终洗脱混合液中，乙醇与水的体积比为13：7～7：13，载药微球的用量为10～40mg。
5.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤2中，海藻酸钠/I型胶原水凝胶浓度为8.0～10.0mg/ml，体积比为体积比2:3～3:2，通过加入盐酸或氢氧化钠，将混合物的pH值调节到7.0-7.6。实验温度为0-10℃，氯化钙浓度为0.2～1.0mol/L，TGF浓度为10～1000ng/ml。
6.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤1、2中，细胞悬液的使用量为100～1000μl，内含1×105～2×106个细胞。
7.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤3中，采用同轴静电纺丝法制备定向纳米纤维膜的工艺参数为：温度30～40℃，电压差10～30kV，针头为17～25号，流速为1.0～2.0mL/h，针尖到电动旋转靶距离为8～30cm，电动旋转靶转速为1000～7000rpm。
8.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤3中，采用同轴静电纺丝法制备定向纳米纤维膜时：PLLA的分子量为10～30万，PLLA-氯仿溶液浓度为10～20％(w/v)。
9.根据权利要求1所述的一种模拟肌腱-骨界面的高仿生复合支架的制备方法，其特征在于，步骤4中，不同模拟相材料的复合中所使用的海藻酸钠/I型胶原混合液体积为50～200μl，静电纺丝膜的长度为20～60mm，宽度为5～10mm，厚度为0.1～2mm，氯化钙溶液浓度为0.6～1.0mol/L。
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| CN114732949A (zh) * | 2022-03-25 | 2022-07-12 | 上海工程技术大学 | 具有取向结构的肩袖补片及其制备方法 |
| CN115068687A (zh) * | 2022-07-08 | 2022-09-20 | 重庆科技学院 | 梯度纳/微纤维支架及其制备方法与应用 |
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| CN114306743A (zh) * | 2021-11-19 | 2022-04-12 | 中南大学湘雅医院 | 三相仿生套筒支架及制备方法 |
| CN114732949A (zh) * | 2022-03-25 | 2022-07-12 | 上海工程技术大学 | 具有取向结构的肩袖补片及其制备方法 |
| CN114732949B (zh) * | 2022-03-25 | 2023-01-24 | 上海工程技术大学 | 具有取向结构的肩袖补片及其制备方法 |
| CN115068687A (zh) * | 2022-07-08 | 2022-09-20 | 重庆科技学院 | 梯度纳/微纤维支架及其制备方法与应用 |
| CN115068687B (zh) * | 2022-07-08 | 2023-12-12 | 重庆科技学院 | 梯度纳/微纤维支架及其制备方法与应用 |
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| CN115282335A (zh) * | 2022-08-05 | 2022-11-04 | 河北医科大学口腔医院 | 骨修复支架的制备方法 |
| CN115400265A (zh) * | 2022-08-05 | 2022-11-29 | 河北医科大学口腔医院 | 仿生化梯度支架及其制备方法 |
| CN115282335B (zh) * | 2022-08-05 | 2023-08-29 | 河北医科大学口腔医院 | 骨修复支架的制备方法 |
| CN115607740A (zh) * | 2022-12-21 | 2023-01-17 | 北京德益达美医疗科技有限公司 | 一种生长因子复合肌腱及其制备方法 |
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