CN117959498A - 脱细胞基质生物墨水、组织工程支架及其制备方法 - Google Patents
脱细胞基质生物墨水、组织工程支架及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种脱细胞基质生物墨水、组织工程支架及其制备方法。脱细胞基质生物墨水，它的原料包括脱细胞基质、高分子材料、甲基丙烯酰明胶和核黄素溶液，所述脱细胞基质、高分子材料、甲基丙烯酰明胶的体积比为0.8～1.2：0.8～1.2：0.5。所述脱细胞基质的制备方法包括以下步骤：(S1)取动物背皮，用生理盐水浸泡清洗以去除动物背皮内侧脂肪层；再用生理盐水反复清洗，随后用高渗盐溶液浸泡清洗多次；(S2)将处理后的动物背皮置于恒温水浴中震荡，随后在SDS溶液中搅拌，重复多次后用去离子水清洗，获得脱细胞真皮基质，冷冻干燥后备用。该生物墨水具有较好的流变性、合适的粘度，能够稳定且连续的制备出组织工程支架。
Description
技术领域
本发明属于医用可降解材料技术领域，涉及一种生物墨水，具体是一种脱细胞基质生物墨水、组织工程支架及其制备方法。
背景技术
脱细胞基质生物墨水是由异种或异体皮经过脱细胞处理后得到的一种细胞外基质生物墨水；因其生物相容性良好，被广泛应用于烧伤、整形、组织工程支架等领域。通过生物墨水制备组织工程支架的研究越来越深入，其中，组织工程支架在软骨损伤及骨修复方面的应用尤为重要。以脱细胞的细胞外基质(ECM)为主要成分的支架，由于其极高的生物相容性被广泛应用。
目前，现有技术中以ECM为主要成分的支架有两种：一种是使用冻干的方法，将ECM构建为立体结构，但该方法所得支架结构粗糙不稳定，孔径分布不均匀，不利于软骨修复；另一种方法是通过3D打印技术构建组织工程支架，申请号为202211520760.6的中国发明专利公开了一种生物墨水的制备方法，S1：将乙醇滴加到丝素蛋白溶液中，搅拌均匀后冷藏，解冻后进行离心干燥得到丝素蛋白微球；S2：将白藜芦醇溶解于乙醇溶液中，再将丝素蛋白微球置于混合溶液中，密封避光搅拌后离心干燥，得到载药微球；S3:将明胶、海藻酸钠和载药微球用梯度加热法混合均匀，再与含ATDC-5细胞的细胞悬液混合得到生物墨水。本发明生物墨水的制备方法所制备的生物墨水具有良好的剪切变稀特性和可塑性，能够保证细胞支架打印过程中支架成型良好，同时减少对细胞的损伤。该申请还公开了一种细胞支架的制备方法，采用上述生物墨水为原料，通过3D打印的方式，打印出细胞支架，这种细胞支架具有药物缓释性好、空隙率高的优点。但该方法同样存在一定缺陷，如机械性能差、结构易塌陷及不同批次产品的一致性难以保证。因此，需要提供一种可提高支架机械性能、结构稳定且能批量生产的生物墨水及其制备方法。
发明内容
本发明的目的在于提供一种脱细胞基质生物墨水，以解决上述背景技术中提出的问题。
为实现上述目的，本发明提供如下技术方案：一种脱细胞基质生物墨水，它的原料包括脱细胞基质、高分子材料、甲基丙烯酰明胶和核黄素溶液，
所述脱细胞基质、高分子材料、甲基丙烯酰明胶的质量比为0.8～1.2：0.8～1.2：0.5；
所述脱细胞基质经酸性胃蛋白酶消化处理形成脱细胞真皮溶液，
所述核黄素溶液中核黄素的质量浓度为1％～5％，其用量为所述脱细胞真皮溶液体积的1％～5％。在本申请中，脱细胞基质、高分子材料、甲基丙烯酰明胶的质量比优选为1.0：1.0：0.5，这样有利于支架成型后力学性能的提升。
优化地，所述高分子材料为选自聚乙二醇、海藻酸盐和丝素蛋白中的一种或多种的混合物。
优化地，所述脱细胞基质的制备方法包括以下步骤：
(S1)取动物背皮，用生理盐水浸泡清洗以去除动物背皮内侧脂肪层；再用生理盐水反复清洗，随后用高渗盐溶液浸泡清洗多次；所述高渗盐溶液为0.8～1.5mol/L的NaCl溶液；
(S2)将处理后的动物背皮置于恒温水浴中震荡，随后在SDS溶液中搅拌，重复多次后用去离子水清洗，获得脱细胞真皮基质，冷冻干燥后备用。
进一步地，步骤(S2)中，将处理后的动物背皮置于30～40℃的恒温水浴中震荡20～30h；在SDS溶液中搅拌2～5h。
本发明的又一目的在于提供一种上述脱细胞基质生物墨水的制备方法，包括以下步骤：
(a)将所述脱细胞基质在液氮中冷却处理，粉碎得真皮基质粉末；
(b)将所述真皮基质粉末在酸性胃蛋白酶中进行消化处理；
(c)使用碱液调节步骤(b)产物的pH值至7～7.6，获得预制生物墨水；
(d)将所述预制生物墨水与所述高分子材料、甲基丙烯酰明胶按比例混合均匀，再加入所述核黄素溶液即可。
优化地，步骤(b)中，将所述真皮基质粉末在质量浓度为0.05～0.5％的酸性胃蛋白酶溶液中消化24～50h，消化时的环境温度为20～30℃。
本发明的再一目的在于提供一种组织工程支架，它由上述任一所述脱细胞基质生物墨水经交联固化制得。
本发明的第四目的在于提供一种上述组织工程支架的制备方法，包括以下步骤：
(1)将所述脱细胞基质生物墨水移入注射器内，将所述注射器针头连接透明管，以0.1ml/min～0.2ml/min的挤出速度将所述脱细胞基质生物墨水挤入交联剂溶液中以固化交联；所述交联剂溶液以50-75rpm的速度旋转，挤出时使用紫外光照射透明管；
(2)交联固化的产物用去离子水清洗多次、冻干，获得组织工程支架。
优化地，所述交联剂为选自乙基[3-(二甲氨基)丙基]碳二亚胺盐酸盐、京尼平和戊二醛中的一种或多种。
进一步地，步骤(1)中，所述注射器的容积为5～15ml，所述透明管为透明软管、长度为4～8cm，固化交联的温度为30～40℃、时间为20～30h。
与现有技术相比，本发明的有益效果是：
本发明脱细胞基质生物墨水通过特定组分的复配，使得墨水具有良好的可挤出性、固化后机械性能高、结构稳定且尺寸可调节的修复材料，适用于组织工程支架领域(尤其是关于软骨缺损修复)，其优点或有益效果如下：
(1)可挤出性：该生物墨水具有较好的流变性、合适的粘度，适用于类似湿法纺丝式的挤出方式，支架挤出时通过紫外光照射光交联、在交联剂溶液中旋转牵伸并交联固化，能够稳定且连续的制备出组织工程支架；
(2)机械性能：该生物墨水由脱细胞真皮基质与机械性能良好的高分子材料相结合，挤出时采用旋转的方式给予了支架一定的取向性，使得制备的组织工程支架的机械性能优异，为支架植入体内更好的作用奠定了基础。
(3)结构稳定性：现有生物墨水3D打印的分辨率相对较低，且是一种自下而上的制造方法，对于刚性不足的材料来说，打印过程中结构易坍塌，稳定性不足；冷冻干燥法是先将生物墨水倒入孔板中预冻再进行冻干，在冻干脱水过程中结构易缺失，且冻干后的支架微观结构无序，取向性差。
采用类似于湿法纺丝的方法，通过喷丝头挤出生物墨水并在交联剂溶液中旋转牵伸、交联固化，相比于3D打印和冷冻干燥法，这种一体式的挤出制备方式所获得的支架取向性更高、结构更稳定，且生产效率更高。
(4)尺寸可控：通过改变喷丝头(即注射器针头)的尺寸可以制备不同粗细规格的支架，控制挤出速度和挤出时间可以得到不同长度规格的支架，且可以根据临床需求裁切成不同规格尺寸的支架。
(5)生物活性：该组织工程支架采用脱细胞真皮基质与生物相容性高的高分子材料相混合的生物墨水制成，生物相容性优异，生物活性高。
附图说明
图1为本发明各例中组织工程支架的抗拉强度性能对比图；
图2为本发明各例中组织工程支架的压缩模量性能对比图。
具体实施方式
下面将结合附图对本发明优选实施方案进行详细说明。
实施例1
本实施例提供一种脱细胞基质生物墨水及其制备方法，具体如下：
(a)脱细胞基的制备：
(S1)取新鲜猪脊背皮(也可以根据需要选择其它动物背皮)，用生理盐水浸泡清洗，用取皮机去除猪皮表皮层内侧脂肪层，用生理盐水反复清洗，再用高渗盐溶液(1mol/LNaCl)浸泡清洗3次；
(S2)将猪皮置于37℃恒温水浴中震荡24h，随后在SDS溶液中搅拌4h，重复3次，去除所有细胞，去离子水清洗后，获得脱细胞真皮基质层，冷冻干燥后备用。
将上述制得的脱细胞基质(即脱细胞真皮基质层)在液氮中冷却处理，随后在万能粉碎机中粉碎，得真皮基质粉末；
(b)将上述产物(即真皮基质粉末，2g)在0.1％(质量浓度)的酸性胃蛋白酶溶液中消化48h得脱细胞真皮溶液，消化时在室温环境(25℃)下进行；
(c)使用碱液(浓度为1mol/L的氢氧化钠溶液)调节酸性消化液的pH值至7.4(约7.4)，获得预制生物墨水，于4℃低温储存；
(d)将上述产物与高分子材料(本实施例中为丝素蛋白，2g)、甲基丙烯酰明胶按1：1：0.5的质量比混合均匀得混合溶液，再加入核黄素水溶液(质量浓度为2％，用量为前述脱细胞真皮溶液体积的2％)，获得复合型生物墨水，在避光、室温(25℃)条件下储存备用。
本实施例提供一种组织工程支架及其制备方法，具体如下：
(1)将储存备用的生物墨水(即前述的复合型生物墨水)移入10ml注射器内，注射器针头连接长度为5cm的透明软管，调节单螺杆挤出机的挤出速度为0.1ml/min将注射器固定在挤出机上，向交联剂溶液(乙基[3-(二甲氨基)丙基]碳二亚胺盐酸盐，质量浓度为3％、溶剂为95％的乙醇溶液)匀速挤出生物墨水，同时使交联剂溶液以50rpm的速度旋转，溶液温度保持37℃恒温，挤出过程中用紫外光照射透明软管，挤出后的支架在溶液中固化交联24h；
(2)将上述产物用去离子水多次清洗，冻干，获得生物墨水组织工程支架。
实施例2
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(d)中，高分子材料为海藻酸钠。
实施例3
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(d)中，高分子材料为聚乙二醇。
实施例4
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(1)中，调节单螺杆挤出机的挤出速度为0.15ml/min。
实施例5
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(1)中，调节单螺杆挤出机的挤出速度为0.20ml/min。
实施例6
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例4中的基本一致，不同的是：步骤(1)中，使交联剂溶液以75rpm的速度旋转。
实施例7
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(1)中，交联剂溶液为京尼平。
实施例8
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(1)中，交联剂溶液为戊二醛。
实施例9
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(d)中，核黄素的用量为前述脱细胞真皮溶液体积的5％。
实施例10
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：步骤(d)中，核黄素的用量为前述脱细胞真皮溶液体积的1％。
对比例1
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：未使交联剂溶液旋转。
对比例2
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例1中的基本一致，不同的是：挤出过程中未用紫外光照射透明软管。
对比例3
本实施例提供一种脱细胞基质生物墨水、生物墨水组织工程支架及它们制备方法，它与实施例5中的基本一致，不同的是：步骤(1)中，使交联剂溶液以100rpm的速度旋转。
将实施例1-10、对比例1-3获得的产品使用Instron进行抗拉强度检测：将样品剪成5cm长度，测量样品直径，夹距2.5cm，拉伸测试得到抗拉强度值，如表1所示。
表1实施例1-11、对比例1-2中产品的抗拉强度表
| 实施例 | 抗拉强度 |
| 对比例1 | 75KPa |
| 实施例1 | 115KPa |
| 对比例2 | 90Kpa(易断，不连续) |
| 实施例2 | 110KPa |
| 实施例3 | 107KPa |
| 实施例4 | 100Kpa |
| 实施例5 | 102KPa |
| 实施例6 | 97KPa |
| 对比例3 | 76Kpa(易断) |
| 实施例7 | 113KPa |
| 实施例8 | 109KPa |
| 实施例9 | 110KPa |
| 实施例10 | 106KPa |
将实施例1-10、对比例1-3获得的产品使用Instron进行压缩模量检测：将样品剪成1cm长度，测量样品直径，将样品固定在上下模具之间，逐渐加压，测得样品的压缩模量值，如表2所示。
表2实施例1-11、对比例1-2中产品的压缩模量表
| 实施例 | 抗拉强度 |
| 对比例1 | 550KPa |
| 实施例1 | 746KPa |
| 对比例2 | 587KPa |
| 实施例2 | 724Kpa |
| 实施例3 | 708KPa |
| 实施例4 | 680KPa |
| 实施例5 | 691KPa |
| 实施例6 | 643KPa |
| 对比例3 | 576KPa |
| 实施例7 | 714KPa |
| 实施例8 | 706KPa |
| 实施例9 | 721KPa |
| 实施例10 | 717KPa |
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (10)
1.一种脱细胞基质生物墨水，其特征在于，它的原料包括脱细胞基质、高分子材料、甲基丙烯酰明胶和核黄素溶液，
所述脱细胞基质、高分子材料、甲基丙烯酰明胶的质量比为0.8～1.2：0.8～1.2：0.5；
所述脱细胞基质经酸性胃蛋白酶消化处理形成脱细胞真皮溶液，
所述核黄素溶液中核黄素的质量浓度为1％～5％，其用量为所述脱细胞真皮溶液体积的1％～5％。
2.根据权利要求1所述的脱细胞基质生物墨水，其特征在于：所述高分子材料为选自聚乙二醇、海藻酸盐和丝素蛋白中的一种或多种的混合物。
3.根据权利要求1所述的脱细胞基质生物墨水，其特征在于，所述脱细胞基质的制备方法包括以下步骤：
(S1)取动物背皮，用生理盐水浸泡清洗以去除动物背皮内侧脂肪层；再用生理盐水反复清洗，随后用高渗盐溶液浸泡清洗多次；所述高渗盐溶液为0.8～1.5mol/L的NaCl溶液；
(S2)将处理后的动物背皮置于恒温水浴中震荡，随后在SDS溶液中搅拌，重复多次后用去离子水清洗，获得脱细胞真皮基质，冷冻干燥后备用。
4.根据权利要求3所述的脱细胞基质生物墨水，其特征在于：步骤(S2)中，将处理后的动物背皮置于30～40℃的恒温水浴中震荡20～30h；在SDS溶液中搅拌2～5h。
5.权利要求1至4任一所述脱细胞基质生物墨水的制备方法，其特征在于，包括以下步骤：
(a)将所述脱细胞基质在液氮中冷却处理，粉碎得真皮基质粉末；
(b)将所述真皮基质粉末在酸性胃蛋白酶中进行消化处理；
(c)使用碱液调节步骤(b)产物的pH值至7～7.6，获得预制生物墨水；
(d)将所述预制生物墨水与所述高分子材料、甲基丙烯酰明胶按比例混合均匀，再加入所述核黄素溶液即可。
6.根据权利要求5所述脱细胞基质生物墨水的制备方法，其特征在于：步骤(b)中，将所述真皮基质粉末在质量浓度为0.05～0.5％的酸性胃蛋白酶溶液中消化24～50h，消化时的环境温度为20～30℃。
7.一种组织工程支架，其特征在于，它由权利要求1至4中任一所述脱细胞基质生物墨水经交联固化制得。
8.权利要求7所述组织工程支架的制备方法，其特征在于，包括以下步骤：
(1)将所述脱细胞基质生物墨水移入注射器内，将所述注射器针头连接透明管，以0.1ml/min～0.2ml/min的挤出速度将所述脱细胞基质生物墨水挤入交联剂溶液中以固化交联；所述交联剂溶液以50-75rpm的速度旋转，挤出时使用紫外光照射透明管；
(2)交联固化的产物用去离子水清洗多次、冻干，获得组织工程支架。
9.权利要求8所述组织工程支架的制备方法，其特征在于：所述交联剂为选自乙基[3-(二甲氨基)丙基]碳二亚胺盐酸盐、京尼平和戊二醛中的一种或多种。
10.权利要求8或9所述组织工程支架的制备方法，其特征在于：步骤(1)中，所述注射器的容积为5～15ml，所述透明管为透明软管、长度为4～8cm，固化交联的温度为30～40℃、时间为20～30h。
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