CN109758262A - 力学降解性能可调的编织状蚕丝支架及制备方法和应用 - Google Patents

力学降解性能可调的编织状蚕丝支架及制备方法和应用 Download PDF

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CN109758262A
CN109758262A CN201811637878.0A CN201811637878A CN109758262A CN 109758262 A CN109758262 A CN 109758262A CN 201811637878 A CN201811637878 A CN 201811637878A CN 109758262 A CN109758262 A CN 109758262A
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silk
stent
pedestal
preparation
mechanics
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郐学先
汪燕艳
赵洪石
陈隆坤
王芳
余锦有
宣铁锋
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ZHEJIANG XINGYUE BIOTECHNOLOGY CO Ltd
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ZHEJIANG XINGYUE BIOTECHNOLOGY CO Ltd
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Priority to CN202310323367.6A priority patent/CN116510084A/zh
Publication of CN109758262A publication Critical patent/CN109758262A/zh
Priority to PCT/CN2019/107710 priority patent/WO2020134241A1/zh
Priority to US16/767,687 priority patent/US11660374B2/en
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Abstract

本发明公开了一种力学降解性能可调的编织状蚕丝支架及制备方法和应用。制备方法包括将至少一股蚕丝股编织形成蚕丝内芯；将1～6束蚕丝内芯置于编织机中，并将至少一层蚕丝包壳编织在蚕丝内芯表面，形成蚕丝基架；去除蚕丝基架的丝胶蛋白；将蚕丝基架浸泡于浓度为3～20mg/ml的胶原溶液中，将蚕丝基架在真空热交联机中交联，得到蚕丝支架。本发明公开了一种力学降解性能可调的编织状蚕丝支架及制备方法和应用，具有良好的力学性能以及生物相容性，埋入体内以后可以在较长的时间内维持支架的力学性能，可以通过改变支架的编织方式调控支架的粗细及体内降解的时间，此编织蚕丝支架可以应用于肌腱或韧带的修复。

Description

力学降解性能可调的编织状蚕丝支架及制备方法和应用
技术领域
本发明涉及肌腱/韧带修复的三维支架材料领域，尤其涉及一种力学降解性能可调的编织状蚕丝支架及制备方法和应用。
背景技术
随着我国经济的不断发展和人民生活水平的日渐提高，国人参加体育锻炼和竞赛活动的热情明显提高，运动损伤的发病率也明显增加，其中肌腱/韧带损伤占运动损伤的一半以上。运动系统损伤尤其是肌腱/韧带损伤病程缓慢，目前治疗效果大都不佳，不仅严重影响病人的生活质量，也给社会带来了沉重的经济负担。
当前，临床上主要靠直接缝合、自体移植、同种异体移植、异种移植和假体材料修复术来修复韧带和肌腱损伤。然而，这些手术或重建再生技术都有其固有的缺陷，例如复发性撕裂、供体缺乏、供体部位并发症、免疫排斥和较差的支架整合性等。
目前临床治疗方法存在的缺点促使肌腱/韧带修复的研究转向可降解生物材料和组织工程方法。蚕丝作为FDA批准的天然生物材料，由于其优良的力学性能、低廉的价格、良好的生物相容性，被广泛的应用于组织工程领域，并且有许多相关研究着力于应用蚕丝支架复合其他材料促进肌腱/韧带的再生。蚕丝作为自然界中存在的生物力学性能最强的天然的生物大分子材料，其力学强度完全可以满足人体肌腱/韧带的日常活动所需，但是这种蚕丝支架在植入体内以后力学性能下降极为迅速，在体内原位修复以后很快就会因为力学性能过低，低于生理的力学要求而发生断裂，导致韧带重建的失败。而且力学降低的速度在关节腔内韧带(如前交叉韧带)更为明显(8周时候力学丢失75％-85％)。这种埋入以后力学丢失的现象极大的限制了编织状蚕丝组织工程韧带的临床应用。
尽管目前有很多研究采用各种不同类型的蚕丝支架进行了前交叉韧带的重建，并且通过组织学、基因等水平证明了蚕丝支架可以作为细胞长入的支架，促进细胞向肌腱方向分化。但是现存的几乎所有的蚕丝支架在植入体内以后力学丢失极为迅速，力学性能差，极大的限制了蚕丝支架的临床应用及临床转化。构建一种在体内可以长期维持力学，有实际临床转化前景的人工蚕丝肌腱/韧带仍面临巨大挑战。
发明内容
为了克服现有技术的不足，本发明的目的在于提供一种力学降解性能可调的编织状蚕丝支架及制备方法和应用，具有良好的力学性能以及生物相容性，埋入体内以后可以在较长的时间内维持支架的力学性能，可以通过改变支架的编织方式调控支架的粗细及体内降解的时间，此编织蚕丝支架可以应用于肌腱或韧带的修复。
本发明的目的采用如下技术方案实现：
本发明提供一种力学降解性能可调的编织状蚕丝支架的制备方法，所述制备方法包括以下步骤：步骤S1：将至少一股蚕丝股置于编织机中编织形成蚕丝内芯，所述蚕丝股由多束2～6根的蚕丝并成一股形成；步骤S2：将1～6束所述步骤S1中的所述蚕丝内芯置于所述编织机中，并将至少一层蚕丝包壳编织在所述蚕丝内芯表面，形成蚕丝基架，所述蚕丝包壳由8～16束的2～8根的蚕丝并成的蚕丝股编织形成，；步骤S3：去除所述蚕丝基架的丝胶蛋白；步骤S4：将所述步骤S3中的所述蚕丝基架浸泡于浓度为3～20mg/ml的胶原溶液中，超声分散20～120min，使得胶原溶液充分进入蚕丝基架的孔隙中，然后将蚕丝基架取出，-15～-25℃冰箱储存3～5h，-70～-90℃冰箱储存8～12h；步骤S5：将步骤S4中的所述蚕丝基架真空干燥，并在真空热交联机中交联，得到蚕丝支架。
进一步地，所述蚕丝股由8束～16束2～6根的蚕丝并成一股形成。
进一步地，所述蚕丝纤度为40～44den或20～22den。
进一步地，所述蚕丝内芯的直径为0.1～2mm；所述蚕丝基架的直径为0.5～3mm。
进一步地，所述步骤S3中去除所述蚕丝基架的丝胶蛋白的方法包括：碳酸钠溶液煮沸去除法、去污剂煮沸去除法、硼酸煮沸去除法、直接加热去除法。
进一步地，所述碳酸钠煮沸去除法为：将步骤2中的所述蚕丝基架浸没于0.2％wt的Na2CO3水溶液中，煮沸60～150min，并在搅拌器中2000～6000rpm的转速搅拌,中间换水2～5次，30～80℃干燥。
本发明还提供一种根据以上任一制备方法形成的蚕丝支架，包括至少一束蚕丝内芯以及包绕在所述蚕丝内芯外的至少一层蚕丝包壳。
进一步地，所述蚕丝内芯的直径为0.1～2mm；蚕丝支架的直径为0.5～3mm。
本发明还提供一种根据以上任一实施例所述的力学降解性能可调的编织状蚕丝支架作为生物支架应用于肌腱或韧带的修复。
相比现有技术，本发明的有益效果在于：
本发明力学降解性能可调的蚕丝支架由机器编织而成，单根蚕丝支架的粗细可根据蚕丝的根数以及并股的蚕丝数量及其组成的蚕丝内芯的数量、以及蚕丝包壳的数量来调整蚕丝支架的粗细以及在体内的降解时间，可以适用于人体几乎所有的肌腱/韧带的修复。
本发明力学降解性能可调的蚕丝支架生物相容性好，引起的炎症反应极低，并且埋入体内以后支架周围以及内部间隙有再生组织形成。
本发明力学降解性能可调的蚕丝支架力学性能调节范围宽，可以满足人体不同肌腱或韧带所需的力学，在体内力学丢失速率可控，早期可以提供力学，晚期可以适时降解以利于肌腱韧带结构重塑。
本发明力学降解性能可调的蚕丝支架性状与自体肌腱韧带相似，前交叉韧带重建时可以直接套用临床手术技术以及器械，有较好的临床转化前景。
本发明力学降解性能可调的蚕丝支架可以作为基架提供力学，后期可以在其基础上被覆胶原，可以被覆其他生长因子，小分子，以及特殊细胞等，促进局部组织修复。
附图说明
图1：编织状蚕丝支架图片；
图2：编织状蚕丝支架脱胶前后的表面以及横截面的扫描电镜图片；
图3：编织状蚕丝支架复合胶原后扫描电镜图片；
图4：皮下埋入以后不同时间点的最大载荷力学强度图片；
图5：皮下埋入8周组织学图片。
具体实施方式
下面，结合附图以及具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
本发明提供一种力学降解性能可调的编织状蚕丝支架的制备方法，制备方法包括以下步骤：
步骤S1：将至少一股蚕丝股置于高速绳带编织机中(如张家港市加成纺织机械有限公司，16/4)，编织形成蚕丝内芯，可选地，蚕丝股由8束～16束的2～6根的蚕丝并成一股形成，蚕丝内芯有至少一股蚕丝股编织形成，形成的蚕丝内芯的直径为0.1～2mm。其中，蚕丝股为多束2～6根的蚕丝并成一股形成。
步骤S2：将1～6束步骤S1中的蚕丝内芯置于高速绳带编织机中，并将至少一层蚕丝包壳编织在蚕丝内芯表面形成蚕丝基架，形成的蚕丝基架的直径为0.5～3mm。蚕丝包壳由8～16束的2～8根的蚕丝并成的蚕丝股编织形成。应当理解的是，可以重复步骤S2，增加蚕丝包壳的层数来增加蚕丝基架的直径。
步骤S3：去除蚕丝基架的丝胶蛋白。去除蚕丝基架的丝胶蛋白的方法包括：碳酸钠溶液煮沸去除法、去污剂煮沸去除法、硼酸煮沸去除法、直接加热去除法。进一步地，碳酸钠煮沸去除法为：将步骤2中的蚕丝基架浸没于0.2％wt的Na2CO3水溶液中，煮沸60～150min，并在搅拌器中2000～6000rpm的转速搅拌,中间换水2～5次，30～80℃干燥。
步骤S4：将步骤S3中的蚕丝基架浸泡于浓度为3～20mg/mL的胶原溶液中，超声分散20～120min，使得胶原溶液充分进入蚕丝基架的孔隙中，然后将蚕丝基架取出，-15～-25℃冰箱储存3～5h，-70～-90℃冰箱储存8～12h，优选，-20℃冰箱储存4h，-80℃冰箱储存8～12h或一晚上。
步骤S5：将步骤S4中蚕丝基架从-80℃的冰箱中取出，冷冻干燥机抽真空48h之后，在将蚕丝基架放于真空干燥箱中，干燥温度为20～120℃，干燥时间为4天，干燥完成后再放入在真空热交联机中交联，得到蚕丝支架。
优选地，本发明采用5A级及以上蚕丝编织而成，所选的蚕丝纤度为40～44den或20～22den。此外其他类型的蚕丝如柞蚕丝等，都适合本发明。
本发明所述的编织状蚕丝支架为基础支架，除了被覆胶原基质，还可以被覆透明质酸、壳聚糖、多肽以及生长因子、小分子，以及细胞等。
本发明还提供一种根据上述制备方法形成的蚕丝支架，蚕丝支架包括至少一束蚕丝内芯以及包绕在所述蚕丝内芯外的至少一层蚕丝包壳。进一步地，蚕丝内芯的直径为0.1～2mm；蚕丝支架的直径为0.5～3mm。
也就是说，单根蚕丝支架的粗细可根据蚕丝的根数以及并股的蚕丝数量及其组成的蚕丝内芯的数量、以及蚕丝包壳的数量来调整蚕丝支架的粗细以及在体内的降解时间，可以适用于人体几乎所有的肌腱/韧带的修复。
本发明力学降解性能可调的蚕丝支架由机器编织而成，单根蚕丝支架的粗细可根据蚕丝的根数以及并股的蚕丝数量及其组成的蚕丝内芯的数量、以及蚕丝包壳的数量来调整蚕丝支架的粗细以及在体内的降解时间，可以适用于人体几乎所有的肌腱或韧带的修复。
本发明力学降解性能可调的蚕丝支架力学性能调节范围宽，可以满足人体不同肌腱或韧带所需的力学，在体内力学丢失速率可控，早期可以提供力学，晚期可以适时降解以利于肌腱韧带结构重塑。
本发明力学降解性能可调的蚕丝支架性状与自体肌腱韧带相似，前交叉韧带重建时可以直接套用临床手术技术以及器械，有较好的临床转化前景。
本发明还提供一种根据上述实施例所述的力学降解性能可调的编织状蚕丝支架作为生物支架应用于肌腱或韧带的修复。
本发明力学降解性能可调的蚕丝支架生物相容性好，引起的炎症反应极低，并且埋入体内以后支架周围以及内部间隙有再生组织形成。本发明力学降解性能可调的蚕丝支架可以作为基架提供力学，后期可以在其基础上被覆胶原，可以被覆其他生长因子，小分子，以及特殊细胞等，促进局部组织修复。
实施例1：
将桑蚕生丝放置于高速绳带编织机器上，采用8束4根蚕丝并股，编织蚕丝内芯，得到直径为0.2mm的蚕丝内芯a(一共32根蚕丝纤维)，参考图1。将桑蚕生丝放置于高速绳带编织机器上，采用16束5根蚕丝并股，在蚕丝内芯外层直接编织蚕丝包壳，一共编织两层芯包壳，得到直径为1mm的编织状蚕丝基架b(一共192根蚕丝纤维)，参考图1。将6根蚕丝内芯或者1根蚕丝支架并联，分别得到支架一(8x4x6＝192根蚕丝纤维)和支架二(16x5+16x5+8x4＝192根蚕丝纤维)，使用的蚕丝纤维的根数完全相同。参考图2，蚕丝支架扫描电子显微镜下观察支架一(如图2b)、支架二(如图2a)。蚕丝基架浸没于0.2％Na2CO3水溶液中，煮沸60min，同时搅拌器3000rpm搅拌，中间换水4次，45℃干燥，脱胶后蚕丝支架扫描电子显微镜下观察支架一(如图2d)、支架二(如图2c)。
将支架一以及支架二浸泡于胶原溶液中，4℃超声20min，抽真空2h，重复5次以上步骤使得胶原溶液充分进入支架内部间隙，然后将支架取出，-20℃冰箱储存4h，-80℃冰箱储存过夜，冷冻干燥箱冻干48小时，真空热交联机22℃一天，110℃两天，65℃一天，蚕丝支架扫描电子显微镜下观察，参考图3，支架一状态(如图3b)，支架二状态(如图3a)。
实施例2：
力学降解性能可调蚕丝支架在前交叉韧带损伤中的应用。
(1)建立动物模型：将5只约2500g的雌性兔子，经过静脉麻醉后，切开皮肤、筋膜及打开关节腔，去除关节腔内的脂肪垫，将前交叉韧带充分暴露，完全切断前交叉韧带，去除前交叉韧带残端。
(2)支架植入：同一只兔子左右对照，实验组应用支架二重建前叉韧带，对照组应用支架一重建前叉韧带。使用直径为2mm的钻头在股骨与胫骨端分别打出直径为2mm的骨性隧道，分别将水化以后支架一和支架二穿过骨隧道，支架两端分别使用直径为2mm的界面骨螺钉固定。
(3)组织修复能力：术后8周，取出兔子前交叉韧带，检测前交叉韧带的力学水平。力学检测结果：参考图4，实验组8周时力学基本上没有下降(如图4a)，而对照组在8周时力学降低达到80％以上(如图4b)，说明采用支架二的编织方法可以明显延缓力学降低。进行HE染色结果显示：参考图5，细胞在支架二周围生长(如图5a)，细胞长入支架一内部(如图5b)。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。

Claims (9)

1.一种力学降解性能可调的编织状蚕丝支架的制备方法，其特征在于，所述制备方法包括以下步骤：
步骤S1：将至少一股蚕丝股置于编织机中编织形成蚕丝内芯，其中，所述蚕丝股由多束2～6根的蚕丝并成一股形成；
步骤S2：将1～6束所述步骤S1中的所述蚕丝内芯置于所述编织机中，并将至少一层蚕丝包壳编织在所述蚕丝内芯表面，形成蚕丝基架，其中，所述蚕丝包壳由8～16束的2～8根的蚕丝并成的蚕丝股编织形成；
步骤S3：去除所述蚕丝基架的丝胶蛋白；
步骤S4：将所述步骤S3中的所述蚕丝基架浸泡于浓度为3～20mg/ml的胶原溶液中，超声分散20～120min，使得胶原溶液充分进入蚕丝基架的孔隙中，然后将蚕丝基架取出，-15～-25℃冰箱储存3～5h，-70～-90℃冰箱储存8～12h；
步骤S5：将步骤S4中的所述蚕丝基架真空干燥，并在真空热交联机中交联，得到蚕丝支架。
2.根据权利要求1所述的力学降解性能可调的编织状蚕丝支架的制备方法，其特征在于，所述蚕丝股由8束～16束2～6根的蚕丝并成一股形成。
3.根据权利要求1或2所述的力学降解性能可调的编织状蚕丝支架的制备方法，其特征在于，所述蚕丝纤度为40～44den或20～22den。
4.根据权利要求3所述的力学降解性能可调的编织状蚕丝支架的制备方法，其特征在于，所述蚕丝内芯的直径为0.1～2mm；所述蚕丝基架的直径为0.5～3mm。
5.根据权利要求1或2中任一项所述的力学降解性能可调的编织状蚕丝支架的制备方法，其特征在于，所述步骤S3中去除所述蚕丝基架的丝胶蛋白的方法包括：碳酸钠溶液煮沸去除法、去污剂煮沸去除法、硼酸煮沸去除法、直接加热去除法。
6.根据权利要求5所述的力学降解性能可调的编织状蚕丝支架的制备方法，其特征在于，所述碳酸钠煮沸去除法为：将步骤2中的所述蚕丝基架浸没于0.2％wt的Na2CO3水溶液中，煮沸60～150min，并在搅拌器中2000～6000rpm的转速搅拌,中间换水2～5次，30～80℃干燥。
7.一种根据权利要求1至6中任一项所述制备方法形成的蚕丝支架，其特征在于，包括至少一束蚕丝内芯以及包绕在所述蚕丝内芯外的至少一层蚕丝包壳。
8.根据权利要求7所述蚕丝支架，其特征在于，所述蚕丝内芯的直径为0.1～2mm；蚕丝支架的直径为0.5～3mm。
9.根据权利要求1-8中任一项所述的力学降解性能可调的编织状蚕丝支架作为生物支架应用于肌腱或韧带的修复。
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