CN113694013A - 一种软骨修复水凝胶、制备方法及其应用 - Google Patents
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Abstract
本发明属于生物医学材料领域,具体涉及一种软骨修复水凝胶、制备方法及其应用。本发明提供的软骨修复水凝胶为胆红素接枝聚赖氨酸、β‑环糊精接枝透明质酸、丝素蛋白之间通过多种复合作用结合形成的可用于骨或软骨的修复。该水凝胶所有的成分均为天然来源,具有良好的生物相容性,且制备简单,成本低廉。从制剂学角度,该软骨修复水凝胶具有良好的机械性能、可注射性和自愈合性,可用于关节腔注射。从功效上来说,该软骨修复水凝胶具有良好的抗氧化、抗炎、抗菌性,对于细胞具有良好的保护性,这都有利于其直接作为软骨修复剂或协同细胞递送实现软骨修复治疗。
Description
技术领域
本发明属于生物医学材料领域,具体涉及一种软骨修复水凝胶、制备方法及其应用。
背景技术
目前,关节内注射药物是临床治疗骨相关疾病的有效手段之一,可以提高局部药物浓度,同时减少全身不良反应,但多数药物关节腔内递送效率不高,关节内保留时间短,需要反复、多次给药,严重削弱了药物疗效,增加了潜在的出血、感染风险。通过原位注射水凝胶,可以模拟自然的组织环境,为损伤组织提供结构支撑。目前用于骨相关疾病治疗的关节腔用水凝胶多以透明质酸为主。透明质酸钠作为一种独特的线性黏多糖,是构成关节软骨和滑液的主要成分。许多动物实验与临床应用研究已证明,关节内应用透明质酸对于骨关节疾病治疗有比较好的效果。理想的用于骨相关疾病治疗的水凝胶体系应具有良好的生物相容性、可注射性、自愈合性,且自身具有一定的生物活性,能协助包载药物或干细胞实现骨相关疾病的治疗。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足,而提供一种软骨修复水凝胶、制备方法及其应用。
本发明所采取的技术方案如下:一种软骨修复水凝胶,该水凝胶由胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白组成。
所述胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白的质量比为3-5:4-8:5。
所述胆红素接枝聚赖氨酸的接枝率为20~25%,所述β-环糊精接枝透明质酸的接枝率为5~10%。
所述聚赖氨酸为ε-聚赖氨酸。
如上所述的软骨修复水凝胶,其特征在于包括以下步骤:
(1)将β-环糊精接枝透明质酸和丝素蛋白共同溶于水中形成溶液I;
(2)将胆红素接枝聚赖氨酸溶解于水中形成溶液II;
(3)临用前,将溶液II缓慢滴入溶液I中,混合均匀后使用。
步骤(1)和步骤(2)中采用的水均为去离子水。
如上所述的软骨修复水凝胶用于制备细胞递送系统的应用。
所述细胞递送系统中的细胞为胚胎干细胞、间充质干细胞、脂肪干细胞、成骨细胞、软骨细胞中的一种或多种。
如上所述的软骨修复水凝胶用于制备治疗软骨细胞损伤的关节腔注射药物中的应用。
如上所述的软骨修复水凝胶用于制备治疗骨关节炎关节腔注射药物中的应用。
本发明的有益效果如下:本发明提供的软骨修复水凝胶为胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白之间通过多种复合作用结合形成的可用于骨或软骨的修复。该水凝胶具有以下效果:
(1)该水凝胶所有的成分均为天然来源,具有良好的生物相容性;
(2) 该水凝胶具有良好的可注射性,可在原位形成凝胶,使用便利;
(3)该水凝胶具有良好的自愈合性,能自动修复破损、恢复材料性能,提高了水凝胶在体耐用性;
(4)该水凝胶具有良好的抗菌性能,能降低关节腔给药过程中出现的感染概率;
(5)该水凝胶具有良好的抗氧化、抗炎、促修复性能,单独使用即对软骨细胞具有修复作用;
(6)该水凝胶具有良好的细胞递送和保护性能,可与细胞联合使用治疗骨关节相关疾病;
(7)该水凝胶制备简单、成本较低,具有良好的应用前景。
综上所述,本发明提供的水凝胶可以直接作为软骨修复剂或协同细胞递送实现软骨修复治疗。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将对本发明作进一步地详细描述。
本发明提供一种软骨修复水凝胶,该水凝胶由胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白组成。
在本发明的一些实施例中,所述胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白的质量比为1-8:2-10:5,均可成功制备得到红色凝胶。其中优选胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白的质量比为3-5:4-8:5,上述比例范围的多组实施例的自愈合性、可注射性、抗菌性、抗炎性的评分均较优,而其它实施例,则相比明显欠缺许多。
所述胆红素接枝聚赖氨酸的接枝率为20~25%,所述β-环糊精接枝透明质酸的接枝率为5~10%。在本发明的一些实施例中,采用接枝率20%的胆红素接枝聚赖氨酸和接枝率为10%的β-环糊精接枝透明质酸作为原料,还有的实施例采用接枝率25%的胆红素接枝聚赖氨酸和接枝率为5%的β-环糊精接枝透明质酸作为原料,均成功制备得到红色凝胶,且各方面性能较佳。
在本发明的一些实施例中,所述聚赖氨酸为ε-聚赖氨酸。
本发明提供如上所述的软骨修复水凝胶,包括以下步骤:
(1)将β-环糊精接枝透明质酸和丝素蛋白共同溶于水中形成溶液I;
(2)将胆红素接枝聚赖氨酸溶解于水中形成溶液II;
(3)临用前,将溶液II缓慢滴入溶液I中,混合均匀后使用。
在本发明的一些实施例中,采用的水为去离子水,实验室中处理后去离子水整体呈微酸性。
在本发明的一些实施例中,在体评价软骨修复水凝胶对骨关节炎的治疗效果,可以发现,所制备得到的水凝胶具有较好的软骨修复功能,且能改善大鼠关节滑膜情况,因此,本发明提供的软骨修复水凝胶用于制备治疗软骨细胞损伤的关节腔注射药物以及治疗骨关节炎关节腔注射药物。结合干细胞治疗后,取得了最佳的治疗效果。因此,本发明提供的软骨修复水凝胶用于制备细胞递送系统,所述细胞为胚胎干细胞、间充质干细胞、脂肪干细胞、成骨细胞、软骨细胞中的一种或多种。实现更好的治疗效果。
以下结合具体实例进一步说明本发明。
实施例1:
根据表1的处方,制备本发明所述的软骨修复水凝胶。具体将组分1(无另有说明,即β-环糊精接枝透明质酸,接枝率10%)和组分2(无另有说明,即丝素蛋白)溶解于5mL去离子水中,缓慢将组分3(无另有说明,即胆红素接枝聚赖氨酸,接枝率20%)溶液5mL滴入其中,并在冰水浴中搅拌均匀形成水凝胶溶液。在37℃条件下静置30分钟后,对制备后所得产物进行外观描述。
实施例2 针对上述实施例1的成功制备得到的软骨修复水凝胶,进行自愈合性、可注射性、抗菌性和抗炎性进行评价。
(1)自愈合性能测试:为了表征该水凝胶自愈合行为,将该水凝胶样本进行切断后,拼合在一起,然后4小时后对其进行压力测试,与未切断的水凝胶样本进行比较。
(2)可注射性评价:将软骨修复水凝胶在配置好5分钟内,将其通过注射器注射到模具中,静置30分钟,观察凝胶的注塑性和可成型性。
(3)抗菌性评价;将细菌浓度为5000CFU的金黄色葡萄球菌均匀涂布在培养皿上,干燥后将直径为6 mm的软骨修复水凝胶置于培养皿表面;并以市售抗生素药物作为阳性对照得到抑菌效果。
(4)抗炎性能评价:将水凝胶适量与LPS激活的巨噬细胞共培养后,用ELISA法测TNF-α和IL-1β指标。
基于以上结果,采用双盲法评价各组水凝胶的体外性能效果评价,给出评分(每个单项20分,满分80分),分数越高代表综合效果越好。
实验结果:各组骨修复水凝胶的实验结果见表2。从表2数据可见,各个实验组的自愈合性、可注射性,抗炎性较好,验证了实验组的水凝胶用于关节腔注射的可行性和优越性。若调整组分比例超出范围或替换部分组分,其自愈合性、可注射性、抗菌性和抗炎性等综合评分明显区低于实验组结果。由上可知,各实验组比例范围内可成功制备具有自愈合性、可注射性、抗菌性和较好的抗炎性的骨修复水凝胶。
实施例3 在体评价软骨修复水凝胶对骨关节炎的治疗效果
骨髓干细胞负载的软骨修复水凝胶的制备:在软骨修复水凝胶中,加入骨髓干细胞(BMSCs)混悬液迅速搅拌均匀,使细胞浓度约为5×106/mL。静置后,得到骨髓干细胞负载的软骨修复水凝胶。
采用手术法断裂前交叉韧带结合跑步的方法构建小鼠骨关节炎模型。其中假手术组作为阳性对照。将大鼠骨关节炎模型随机分为生理盐水组、水凝胶1、水凝胶14、水凝胶19、BMSCs、BMSCs-水凝胶1、BMSCs水凝胶17。
造模2周后,将生理盐水或其他治疗因子于膝关节内给予注射样品,每3天给药1次,持续给药10次。在术后10周后,处死所有大鼠,取膝关节组织,固定、脱钙后制成组织蜡块,进行组织学safranin-O固绿(S-O)染色。对S-O染色后的组织切片进行评分。
通过OARSI评分系统评估大鼠关节软骨的退变情况。0分:表面完整,软骨完好无损;1分:表面完整;2分:表面不连续;3分:垂直裂缝;4分:侵蚀;5分:剥蚀;6分:变形。
采用滑膜评分来评估大鼠关节滑膜的改变。0分:光滑正常,半透明的滑膜组织,血管稀疏清晰;1分:局灶性受累,轻微变色,可见增生/纤维化/增厚,血管明显增加;2分:弥散性受累,轻微变色,可见增生/纤维化/增厚,血管显著扩张;3分:中度弥漫性浸润,严重变色,明显增生/纤维化/增厚,中度血管增生;4分:显著弥漫性浸润,严重变色,显著的增生/纤维化/增厚,弥漫性血管过度增生;5分:严重弥漫性浸润,严重变色,严重的增生/纤维化/增厚,组织纤维化和严重的血管过度增生。
将内侧股骨、胫骨的OARSI评分和关节滑膜评分结合进行综合评价大鼠骨关节炎的软骨病变情况结果见表3所示。
由表3结果可知,软骨修复水凝胶1具有较好的软骨修复功能,且能改善大鼠关节滑膜情况。软骨修复水凝胶1结合干细胞治疗后,取得了最佳的治疗效果。对照组水凝胶14和对照组水凝胶19对大鼠骨关节炎的软骨修复性远不如本发明的水凝胶1,说明本发明软骨修复水凝胶其具有的自愈合性、可注射性、抗菌性和抗炎性有助于其对大鼠骨关节炎的治疗。此外,BMSCs具有一定的治疗效果,但是由于其在骨关节腔的滞留时间有限、且单独使用不易存活,所以其效果有限,结合水凝胶1的凝胶作用后,其作用效果最佳。
以上所揭露的仅为本发明较佳实施例而已,当然不能以此来限定本发明之权利范围,因此依本发明权利要求所作的等同变化,仍属本发明所涵盖的。
Claims (10)
1.一种软骨修复水凝胶,其特征在于:该水凝胶由胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白组成。
2.根据权利要求1所述的软骨修复水凝胶,其特征在于:所述胆红素接枝聚赖氨酸、β-环糊精接枝透明质酸、丝素蛋白的质量比为3-5:4-8:5。
3.根据权利要求1所述的软骨修复水凝胶,其特征在于:所述胆红素接枝聚赖氨酸的接枝率为20~25%,所述β-环糊精接枝透明质酸的接枝率为5~10%。
4.根据权利要求1所述的软骨修复水凝胶,其特征在于:所述聚赖氨酸为ε-聚赖氨酸。
5.如权利要求1-4任一项所述的软骨修复水凝胶,其特征在于包括以下步骤:
(1)将β-环糊精接枝透明质酸和丝素蛋白共同溶于水中形成溶液I;
(2)将胆红素接枝聚赖氨酸溶解于水中形成溶液II;
(3)临用前,将溶液II缓慢滴入溶液I中,混合均匀后使用。
6.根据权利要求5所述的软骨修复水凝胶,其特征在于:步骤(1)和步骤(2)中采用的水均为去离子水。
7.如权利要求1-4任一项所述的软骨修复水凝胶用于制备细胞递送系统的应用。
8.根据权利要求7所述的应用,其特征在于:所述细胞递送系统中的细胞为胚胎干细胞、间充质干细胞、脂肪干细胞、成骨细胞、软骨细胞中的一种或多种。
9.如权利要求1-4任一项所述的软骨修复水凝胶用于制备治疗软骨细胞损伤的关节腔注射药物中的应用。
10.如权利要求1-4任一项所述的软骨修复水凝胶用于制备治疗骨关节炎关节腔注射药物中的应用。
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CN114835917A (zh) * | 2022-04-13 | 2022-08-02 | 西南大学 | 再生丝素蛋白/ε-聚赖氨酸复合水凝胶的制备方法及其产品和应用 |
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CN114835917A (zh) * | 2022-04-13 | 2022-08-02 | 西南大学 | 再生丝素蛋白/ε-聚赖氨酸复合水凝胶的制备方法及其产品和应用 |
CN114835917B (zh) * | 2022-04-13 | 2024-03-19 | 西南大学 | 再生丝素蛋白/ε-聚赖氨酸复合水凝胶的制备方法及其产品和应用 |
CN114984244A (zh) * | 2022-05-30 | 2022-09-02 | 浙江大学 | 一种含超支化聚赖氨酸水凝胶载体材料及其制备方法 |
CN114984244B (zh) * | 2022-05-30 | 2023-09-29 | 浙江大学 | 一种含超支化聚赖氨酸水凝胶载体材料及其制备方法 |
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