CN114569793A - 一种海绵体损伤修复组织工程支架及其制备方法 - Google Patents
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Abstract
本发明公开了一种海绵体损伤修复组织工程支架及其制备方法，包括支架基底层与表面功能化层，所述支架基底层由生物相容性水凝胶经3D打印工艺制造，主要在组织修复过程中提供力学强度与细胞生长的支持；所述表面功能化层包括生物活性因子与种子细胞，主要提供更好的促血管再生和组织修复效果。本发明的海绵体损伤修复组织工程支架生物安全性好、原料来源广泛、可定制化加工、具有与组织适配的力学和结构特性。可用于外伤、阴茎手术等疾病造成的海绵体损伤，促进患者生殖功能的恢复。
Description
技术领域
本发明涉及生物医用材料与组织工程技术领域，尤其是指一种海绵体损伤修复组织工程支架及其制备方法。
背景技术
阴茎是男性重要的器官，具有排尿、性交和射精等重要的生理功能。然而，多种先天性疾病，癌症或外伤等均可能导致阴茎严重受损，情况严重时甚至完全丧失功能。无论从生理还是伦理角度来说，阴茎都是男子气概的重要象征，阴茎组织的缺损及其对泌尿、生殖功能的影响往往对患者的心理健康造成严重影响，并可能由此引发一系列的社会问题。
为了从根本上恢复患者的生殖功能，最终需要进行外科手术，对受损的阴茎结构进行修复或替换。但是，当前的临床治疗方案极为有限，这些技术包括使用自体组织移植(来自患者皮肤，胃肠或其他身体部位的粘膜)，同种异体移植(尸体筋膜或供体阴茎直接移植)，异源组织修复(牛胶原)或合成材料假体填充(有机硅，聚氨酯或聚四氟乙烯)等方式重建受损的器官。但由于阴茎海绵体复杂的结构和特殊的功能，这些治疗方案难以解决美学、功能性或伦理道德方面的挑战，很难得到满意的治疗效果。
通过3D打印技术与组织工程技术结合，可以开发出用于替代受损组织或器官的生物替代品，其来源广泛，成本可控，且可能恢复患者正常的生理功能。
发明内容
本发明的第一目的在于克服现有技术的不足，提供一种可降解、来源广泛、制备简单、生物安全性好、可修复复杂缺损、具有促血管再生功能的海绵体损伤修复组织工程支架。
本发明的第二目的在于提供一种海绵体损伤修复组织工程支架的制备方法。
本发明的第一目的通过下述技术方案实现：一种海绵体损伤修复组织工程支架，包括支架基底层与表面功能化层，所述支架基底层由生物相容性水凝胶经3D打印工艺制造，主要在组织修复过程中提供力学强度与细胞生长的支持；所述表面功能化层包括生物活性因子与种子细胞，主要提供更好的促血管再生和组织修复效果。
进一步，所述支架基底层包括未改性及化学改性后的高分子基体材料，该高分子基体材料包括明胶、透明质酸、葡聚糖、壳聚糖、丝胶蛋白、弹性蛋白中的一种或两种，该高分子基体材料改性的方法包括接枝双键化改性、接枝胺基化改性、接枝醛基化改性中的一种或几种。
进一步，所述高分子基体材料的质量百分数为9.5％～29.5％。
进一步，所述生物活性因子包括肝素、干细胞外泌体、VEGF蛋白中的一种或几种，所述生物活性因子的质量百分数为0.5％～3％。
进一步，所述种子细胞包括骨髓间充质干细胞、脂肪间充质干细胞、肌源性干细胞、血管平滑肌细胞、血管上皮细胞中的一种或几种，所述种子细胞接种密度为1万-100万个/cm2。
进一步，所述支架基底层的整体厚度为1-80mm，局部出丝直径为 100-500μm，整体孔隙率为30-70％。
进一步，所述表面功能化层厚度为1-10μm。
本发明的第二目的通过下述技术方案实现：一种海绵体损伤修复组织工程支架的制备方法，包括以下步骤：
1)将高分子基体材料溶解在PBS溶液或细胞培养基中，得到3D打印墨水；
2)将步骤1)所得的3D打印墨水装入3D打印机料筒中，按照预设的结构进行打印，打印完成后再经过清洗、脱模得到支架基底层；
3)往步骤1)所得的3D打印墨水中掺入生物活性因子及种子细胞，得到生物活性溶液；
4)步骤2)所得的支架基底层通过接枝方法接枝步骤3)所得的生物活性溶液，得到带有表面功能化层的支架基底层，将该带有表面功能化层的支架基底层在特定条件下进行培养一段时间，即可得到海绵体损伤修复组织工程支架。
进一步，在步骤4)中，所述接枝方法包括静电吸附作用层层自组装、光引发交联、氢键交联、氨基醛基反应中的一种或两种。
进一步，在步骤4)中，带有表面功能化层的支架基底层的培养条件为37℃， 5％CO2，培养时间1-72小时。
本发明与现有技术相比，具有如下优点与有益效果：
1、本发明提供一种生物安全性好、可降解、制备简单、可以实现患者勃起功能修复的3D打印海绵体损伤修复组织工程支架，填补了临床相关领域的空白。
2、可根据不同患者具体情况进行支架外形和功能化的个性化定制，可用于割伤、刺伤类外型急性创伤，以及生殖器相关肿瘤治疗造成海绵体缺损的个性化修复，具有广泛的适用性。
3、通过引入表面功能化层，实现了缺损部位原位促血管修复，从而进一步实现海绵体缺损的修复与功能再生。
附图说明
图1为海绵体损伤修复组织工程支架的实物图。
图2为海绵体损伤修复组织工程支架的局部剖视图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
如图1和图2所示，本发明提供了一种海绵体损伤修复组织工程支架，包括支架基底层1与表面功能化层2，所述支架基底层1由生物相容性水凝胶经 3D打印工艺制造，主要在组织修复过程中提供力学强度与细胞生长的支持；所述表面功能化层2包括生物活性因子与种子细胞，主要提供更好的促血管再生和组织修复效果。
在一个具体示例中，所述支架基底层包括未改性及化学改性后的高分子基体材料，该高分子基体材料包括明胶、透明质酸、葡聚糖、壳聚糖、丝胶蛋白、弹性蛋白中的一种或两种。
在一个具体示例中，所述高分子基体材料的改性方法包括接枝双键化改性、接枝胺基化改性、接枝醛基化改性中的一种或几种。
在一个具体示例中，所述生物活性因子包括肝素、干细胞外泌体、VEGF 蛋白中的一种或几种。
在一个具体示例中，所述种子细胞包括骨髓间充质干细胞、脂肪间充质干细胞、肌源性干细胞、血管平滑肌细胞、血管上皮细胞中的一种或几种。
在一个具体示例中，所述支架基底层的整体厚度为1-80mm，局部出丝直径为100-500μm，整体孔隙率为30-70％。
在一个具体示例中，所述表面功能化层厚度为1-10μm，所述种子细胞接种密度为1万-100万个/cm2。
本发明还提供了上述海绵体损伤修复组织工程支架的制备方法，包括如下制备步骤：
1)将高分子基体材料溶解在PBS溶液或细胞培养基中，得到3D打印墨水；
2)将步骤1)所得的3D打印墨水装入3D打印机料筒中，按照预设的结构进行打印，打印完成后再经过清洗、脱模得到支架基底层；
3)往步骤1)所得的3D打印墨水中掺入生物活性因子及种子细胞，得到生物活性溶液；
4)步骤2)所得的支架基底层通过接枝方法接枝步骤3)所得的生物活性溶液，得到带有表面功能化层的支架基底层，将该带有表面功能化层的支架基底层在特定条件下进行培养一段时间，即可得到海绵体损伤修复组织工程支架。
在一个具体示例中，所述高分子基体材料的质量百分数为9.5％～29.5％，所述生物活性因子的质量百分数为0.5％～3％，所述种子细胞接种密度为1万-100 万个/cm2，其余质量为水。
在一个具体示例中，所述适宜的接枝方法包括静电吸附作用层层自组装、光引发交联、氢键交联、氨基醛基反应中的一种或两种。
在一个具体示例中，所述带有表面功能化层的支架基底层的培养条件为 37℃，5％CO2，培养时间1-72小时。
在一个具体示例中，所述支架基底层的整体厚度为1-80mm，局部出丝直径为100-500μm，整体孔隙率为30-70％。
在一个具体示例中，所述表面功能化层厚度为1-100μm。
以下结合多个实施例和对比例对本发明上述海绵体损伤修复组织工程支架进行更详细说明。
实施例1
1)将明胶、透明质酸接枝双键改性，随后配置成较粘稠的水溶液，其中质量分数分别为10％和2％，加入光引发剂I2959(质量分数0.5％)，制成3D打印墨水。
2)将所得3D墨水装入无菌3D打印机料筒，挤出式打印得到正交网格支架，每打印完一层后使用365nm波长紫外光交联15s，所得支架基底层整体厚度为1mm，局部出丝直径为100μm，整体孔隙率为30％。
3)将打印得到的支架基底层浸泡在细胞培养基中，包被聚赖氨酸后，利用静电吸附作用表面吸附外泌体，制成10μm厚的表面功能化层，随后在支架表面接种肌源性干细胞，接种密度为1万个/cm2，在37℃，5％CO2浓度条件下培养，培养时间72小时，得到海绵体损伤修复组织工程支架。
实施例2
与实施例1不同的是本实施例的步骤1)中，所用高分子基体材料为丝胶蛋白、弹性蛋白，质量分数分别为6.5％、3％；所得支架基底层整体厚度为5mm，局部出丝直径为150μm，整体孔隙率为40％；步骤3)中，所用生物活性因子为 VEGF蛋白；所得表面功能化层厚度为50μm；所用种子细胞为骨髓间充质干细胞，接种密度为10万个/cm2；接种细胞后培养时间为48小时。
实施例3
与实施例1不同的是本实施例的步骤1)中，所用高分子基体材料为进行醛基化改性的透明质酸，与氨基化改性的葡聚糖，质量分数分别为20％、9.5％；所得支架基底层整体厚度为20mm，局部出丝直径为260μm，整体孔隙率为50％；步骤2)中所用的交联方法是直接将两组分混合成胶。
实施例4
与实施例1不同的是本实施例的步骤1)中，所用高分子基体材料为进行壳聚糖、丝胶蛋白，质量分数分别为5％、15％。所得支架基底层整体厚度为40mm，局部出丝直径为410μm，整体孔隙率为60％；步骤3)中，所得表面功能化层厚度为80μm；种子细胞接种密度为25万个/cm2；接种细胞后培养时间为24小时。
实施例5
与实施例1不同的是本实施例的步骤1)中，所得支架基底层整体厚度为 60mm，局部出丝直径为500μm，整体孔隙率为70％；步骤3)中，所用生物活性因子为肝素蛋白，所用接枝方法为静电吸附作用层层自组装法；所得表面功能化层厚度为100μm；所用种子细胞为脂肪间充质干细胞；种子细胞接种密度为50万个/cm2；接种细胞后培养时间为12小时。
实施例6
与实施例1不同的是本实施例的步骤3)中，所用种子细胞为血管平滑肌细胞和血管上皮细胞；种子细胞接种密度为100万个/cm2；接种细胞后培养时间为 1小时。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种海绵体损伤修复组织工程支架，其特征在于，包括支架基底层与表面功能化层，所述支架基底层由生物相容性水凝胶经3D打印工艺制造，主要在组织修复过程中提供力学强度与细胞生长的支持；所述表面功能化层包括生物活性因子与种子细胞，主要提供更好的促血管再生和组织修复效果。
2.根据权利要求1所述的一种海绵体损伤修复组织工程支架，其特征在于：所述支架基底层包括未改性及化学改性后的高分子基体材料，该高分子基体材料包括明胶、透明质酸、葡聚糖、壳聚糖、丝胶蛋白、弹性蛋白中的一种或两种，该高分子基体材料改性的方法包括接枝双键化改性、接枝胺基化改性、接枝醛基化改性中的一种或几种。
3.根据权利要求2所述的一种海绵体损伤修复组织工程支架，其特征在于：所述高分子基体材料的质量百分数为9.5％～29.5％。
4.根据权利要求1所述的一种海绵体损伤修复组织工程支架，其特征在于：所述生物活性因子包括肝素、干细胞外泌体、VEGF蛋白中的一种或几种，所述生物活性因子的质量百分数为0.5％～3％。
5.根据权利要求1所述的一种海绵体损伤修复组织工程支架，其特征在于：所述种子细胞包括骨髓间充质干细胞、脂肪间充质干细胞、肌源性干细胞、血管平滑肌细胞、血管上皮细胞中的一种或几种，所述种子细胞接种密度为1万-100万个/cm2。
6.根据权利要求1所述的一种海绵体损伤修复组织工程支架，其特征在于：所述支架基底层的整体厚度为1-80mm，局部出丝直径为100-500μm，整体孔隙率为30-70％。
7.根据权利要求1所述的一种海绵体损伤修复组织工程支架，其特征在于：所述表面功能化层厚度为1-10μm。
8.一种权利要求1-7任一项所述海绵体损伤修复组织工程支架的制备方法，其特征在于，包括以下步骤：
1)将高分子基体材料溶解在PBS溶液或细胞培养基中，得到3D打印墨水；
2)将步骤1)所得的3D打印墨水装入3D打印机料筒中，按照预设的结构进行打印，打印完成后再经过清洗、脱模得到支架基底层；
3)往步骤1)所得的3D打印墨水中掺入生物活性因子及种子细胞，得到生物活性溶液；
4)步骤2)所得的支架基底层通过接枝方法接枝步骤3)所得的生物活性溶液，得到带有表面功能化层的支架基底层，将该带有表面功能化层的支架基底层在特定条件下进行培养一段时间，即可得到海绵体损伤修复组织工程支架。
9.根据权利要求8所述的一种海绵体损伤修复组织工程支架的制备方法，其特征在于：在步骤4)中，所述接枝方法包括静电吸附作用层层自组装、光引发交联、氢键交联、氨基醛基反应中的一种或两种。
10.根据权利要求8所述的一种海绵体损伤修复组织工程支架的制备方法，其特征在于：在步骤4)中，带有表面功能化层的支架基底层的培养条件为37℃，5％CO2，培养时间1-72小时。
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