CN114773629A - 用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法 - Google Patents
用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法 Download PDFInfo
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Abstract
本发明公开了用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，本发明以透明质酸为原料，利用甲基丙烯酸酐对透明质酸进行酰化改性后引入光交联得到交联网络水凝胶；采用光交联，对天然高分子水凝胶产生活化网络，通过甲基丙烯酸酐的量来控制甲基丙烯酰化HAMA的接枝率，而得到降解速率可控、力学性能增强的可注射凝胶材料，再结合氧化纤维素，使其抗自由基氧化能力更强，更润滑、缓释效率更高、更有利于止血修复，兼具优异的力学性能及生物相容性，此外，可注射光固化水凝胶结合成纤维细胞生长因子和环孢素A，使其具有抗炎和促进组织修复的功能，有助于可注射功能型水凝胶材料的开发利用。
Description
技术领域
本发明属于生物材料制备技术领域，具体涉及用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法。
背景技术
创伤性脑损伤是由强力外力作用下引起的脑组织机械性损伤，通常伴有脑血管破裂导致的颅内出血。若处理不及时，短时间内出现头痛，呕吐，偏身无力或麻木，随后会出现昏迷。严重创伤性脑损伤通常会伴随患者肢体偏瘫等症状的出现，这与创伤发生后早期缺乏有效的抑制颅内出血的治疗手段有关。因此，在创伤性脑损伤后，及时解决颅内出血显得更为重要。
合适的止血材料能明显缩短手术时间，对创伤或术后恢复至关重要。常见的可吸收止血材料有胶原、明胶、氧化纤维素、氰基丙烯酸类组织胶等。止血材料由于其和其他种类材料相比在创伤急救和快速止血具有独特的优势，目前已成为医疗行业关注的热点之一。
然而，由于这类产品组成复杂，缺乏相关的产品标准，无法适应当下复杂的止血环境，包括出血部位，术腔形态大小，不同渗出血情况的填塞要求，不同止血材料的止血机制与机体的相容性，患者的凝血功能和经济条件等。同时，目前用于大脑内神经组织出血的生物医用材料，都是特异性多肽与高分子材料混合，无法达到缓释的作用。
发明内容
为了解决上述技术问题，本发明提供了用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，得到用于止血方便的水凝胶，以解决上述传统止血材料无法适应复杂止血环境以及无法达到缓释的问题。
为了达到解决上述技术问题的技术效果，本发明是通过以下技术方案实现的：用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于，包括以下步骤：
S1将碳酸钠加入去离子水中，稀释碳酸钠水溶液，加入透明质酸，搅拌溶解，得到透明质酸溶液；
S2于透明质酸溶液加入甲基丙烯酸、N，N-二甲基甲酰胺、三乙胺，隔一段时间后加入碳酸钠；
S3常温下反应后，用去离子水在常温下透析、冷冻干燥得到甲基丙烯酰化透明质酸；
S4配制体积比为100ml/L-750ml/L的乙醇-水溶液，并加入NaOH；
S5乙基纤维素作为原料，在乙醇-水溶液中形成溶液进行水解；
S6反应结束后用去离子水多次洗涤，抽滤，再进行真空干燥；
S7称取0.5g-2.5g/LNaBr、0.1-0.3g/LTEMPO溶解于去离子水中，此溶液进行冰浴；
S8真空干燥的乙基纤维素加入正在进行冰浴的溶液中，在不断搅拌下一次性加入NaClO溶液反应；
S9反应完成后进行抽滤，将抽滤得到的物质浸泡在pH＝1-3的HCl溶液中，将固形物真空干燥即可得到氧化乙基纤维素；
S10避光条件下，按照浓度比为2.5～5g/L的比例取苯基-2,4,6-三甲基苯甲酰基膦酸锂与DMEM培养基/去离子水配制溶液，溶解后，加入质量百分比浓度为0.5％-3％甲基丙烯酰化透明质酸，完全溶解并使用过滤器过滤后，加入氧化纤维素、成纤维细胞生长因子和环孢素A；
S11混合液用移液枪滴置于培养皿中，进行蓝光灯照射,得到一种含成纤维细胞生长因子和环孢素A的可注射光固化止血水凝胶；
进一步的，所述S2中加入甲基丙烯酸酐，甲基丙烯酸酐与透明质酸体积质量比为1-5:1，按1～5ml/L的比例加入N，N-二甲基甲酰胺，按0.2～0.6g/L的比例加入三乙胺，每隔12小时加入0.2-1.0mmol/L碳酸钠；
进一步的，所述S3中透析的条件为：在常温下透析3-7天，每6-18小时换一次水，透析袋截留分子量为：8KDa-14KDa；
进一步的，所述S3中甲基丙烯酰化透明质酸反应化学式如下：
进一步的，所述S4中NaOH加入乙醇-水溶液形成质量分数为0.2g/L-8g/L的溶液；
进一步的，所述S5中乙基纤维素作为原料，在100ml/L-750ml/L NaOH/乙醇-水溶液中形成质量分数为0.2g/L-8g/L的溶液；
进一步的，所述S8一次性加入10mL/L-100mL/L体积的NaClO溶液(有效含量为7.5％)，用0.2g/L-8g/L的NaOH溶液调节pH为8-11；
本发明的有益效果是：
1、本发明通过甲基丙烯酸酐的量来控制甲基丙烯酰化HAMA的接枝率，并进行网络活化交联，从而得到降解速率可控、力学性能增强的可注射凝胶材料，再结合和氧化纤维素，使其抗自由基氧化能力更强，润滑、缓释效率更高、更有利于止血修复；
2、本发明制备的HAMA凝胶体系高度仿生细胞外基质的组成和结构，具有更好的稳定性、保水率，且力学性能可控；
3、本发明以透明质酸为原料，利用甲基丙烯酸酐双键对透明质酸进行酰化改性反应引入光交联得到交联网络水凝胶；本发明采用光交联，对天然高分子水凝胶产生活化网络，使其兼具优异的力学性能及生物相容性，有助于可注射功能型水凝胶材料的开发利用；
4、本发明为了达到更好的治疗效果，携带两种生物活性小因子-环孢素A和成纤维细胞生长因子。材料携带的两种生物活性小因子：环孢素A和成纤维细胞生长因子，前者通过对T细胞的作用，降低创伤性脑损伤后的炎症反应；后者作为神经营养因子，发挥着促进神经前体细胞的增殖分化、修复神经损伤等效果，随着材料的缓释作用，在上述几种活性成分的互作下，可长期改善创伤性脑损伤模式动物的预后。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例描述所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1是复合材料光刺激(405纳米波长)成胶图；
图2是创伤性脑损伤手术以及复合材料在损毁处光固化图；
图3是蒙托亚阶梯行为学检测图；
图4是免疫荧光病理学检测图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
实施例1
用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法的实际应用：
(1)将碳酸钠加入去离子水中，把碳酸钠水溶液稀释调节至pH＝9，然后按20g/L的比例加入透明质酸，然后于50℃下搅拌溶解，得到透明质酸溶液，甲基丙烯酸酐与透明质酸体积质量比为3:1，按3ml/L的比例加入的N，N-二甲基甲酰胺，按0.2g/L的比例加入三乙胺，每隔12小时按1.0mmol/L的比例加入碳酸钠，常温反应24小时后，用去离子水在常温下透析5天，每12小时换一次水，透析袋截留分子量为：8KDa-14KDa，透析结束后，冷冻干燥得到甲基丙烯酰化透明质酸；
(2)配制体积比为100ml/L的乙醇-水溶液，NaOH加入上述乙醇-水溶液形成质量分数为0.2g/L的溶液。乙基纤维素作为原料，在100ml/LNaOH/乙醇-水溶液中形成质量分数为0.2g/L的溶液进行水解，50℃反应18小时，反应结束后用去离子水多次洗涤，抽滤，再进行真空干燥。称取0.5g/LNaBr、0.1g/LTEMPO溶解于去离子水中，此溶液进行冰浴，保证溶液温度在-5℃以下；将真空干燥的乙基纤维素加入正在进行冰浴的溶液中，在不断搅拌下一次性加入10mL/L体积的NaClO溶液(有效含量为7.5％)，用0.2g/L的NaOH溶液调节pH为8左右，反应10min；反应完成后进行抽滤，将抽滤得到的物质浸泡在pH＝1的HCl溶液中，0.3小时后，抽滤得到的固形物多次用去离子水清洗。最后，将固形物真空干燥即可得到氧化乙基纤维素；
(3)避光条件下，按照浓度比为2.5g/L的比例取苯基-2,4,6-三甲基苯甲酰基膦酸锂与DMEM培养基/去离子水配制溶液，溶解后，加入质量百分比浓度为0.5％甲基丙烯酰化透明质酸完全溶解，0.22μm过滤器过滤后，加入质量百分比浓度为0.5％氧化纤维素、20μg/L成纤维细胞生长因子和15mg/kg环孢素A；
(4)混合液用移液枪滴置于培养皿中，蓝光灯照射时间为20-40秒，蓝光波长为405-465纳米(如图1所示)，得到一种含成纤维细胞生长因子和环孢素A的可注射光固化止血水凝胶的制备方法。
实施例2
用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法的实际应用：
(1)将碳酸钠加入去离子水中，把碳酸钠水溶液稀释调节至pH＝10，然后按5g/L的比例加入透明质酸，然后于30℃下搅拌溶解，得到透明质酸溶液，甲基丙烯酸酐与透明质酸体积质量比为5:1，按5ml/L的比例加入的N，N-二甲基甲酰胺，按0.6g/L的比例加入三乙胺，每隔12小时按0.8mmol/L的比例加入碳酸钠，常温反应40小时后，用去离子水在常温下透析5天，每12小时换一次水，透析袋截留分子量为：8KDa-14KDa，透析结束后，冷冻干燥得到甲基丙烯酰化透明质酸；
(2)配制体积比为750ml/L的乙醇-水溶液，NaOH加入上述乙醇-水溶液形成质量分数为8g/L的溶液；乙基纤维素作为原料，在750ml/LNaOH/乙醇-水溶液中形成质量分数为8g/L的溶液进行水解，50℃反应36小时，反应结束后用去离子水多次洗涤，抽滤，再进行真空干燥；称取2.5g/LNaBr、0.3g/LTEMPO溶解于去离子水中，此溶液进行冰浴，保证溶液温度在10℃以下；将真空干燥的乙基纤维素加入正在进行冰浴的溶液中，在不断搅拌下一次性加入100mL/L体积的NaClO溶液(有效含量为7.5％)，用8g/L的NaOH溶液调节pH为11左右，反应50min。反应完成后进行抽滤，将抽滤得到的物质浸泡在pH＝3的HCl溶液中，1.0小时后，抽滤得到的固形物多次用去离子水清洗；最后，将固形物真空干燥即可得到氧化乙基纤维素；
(3)避光条件下，按照浓度比为5g/L的比例取苯基-2,4,6-三甲基苯甲酰基膦酸锂与DMEM培养基/去离子水配制溶液，溶解后，加入质量百分比浓度为3％甲基丙烯酰化透明质酸完全溶解，0.45μm过滤器过滤后，加入质量百分比浓度为3％氧化纤维素、20μg/L成纤维细胞生长因子和15mg/kg环孢素A；
(4)混合液用移液枪滴置于培养皿中，蓝光灯照射时间为20-40秒，蓝光波长为405-465纳米，得到一种含成纤维细胞生长因子和环孢素A的可注射光固化止血水凝胶的制备方法。
实施例3
本实施例为运用用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法的实验案例；
实验1
(1)将碳酸钠加入去离子水中，把碳酸钠水溶液稀释调节至pH＝7，然后按10g/L的比例加入透明质酸，然后于55℃下搅拌溶解，得到透明质酸溶液，甲基丙烯酸酐与透明质酸体积质量比为1:1，按1ml/L的比例加入的N，N-二甲基甲酰胺，按0.2g/L的比例加入三乙胺，每隔12小时按0.2mmol/L的比例加入碳酸钠，常温反应18小时后，用去离子水在常温下透析5天，每12小时换一次水，透析袋截留分子量为8KDa-14KDa，透析结束后，冷冻干燥得到甲基丙烯酰化透明质酸；
(2)配制体积比为450ml/L的乙醇-水溶液，NaOH加入上述乙醇-水溶液形成质量分数为4g/L的溶液；乙基纤维素作为原料，在450ml/LNaOH/乙醇-水溶液中形成质量分数为4g/L的溶液进行水解，50℃反应24小时，反应结束后用去离子水多次洗涤，抽滤，再进行真空干燥；称取1.5g/LNaBr、0.2g/LTEMPO溶解于去离子水中，此溶液进行冰浴，保证溶液温度在4℃以下；将真空干燥的乙基纤维素加入正在进行冰浴的溶液中，在不断搅拌下一次性加入50mL/L体积的NaClO溶液(有效含量为7.5％)，用4g/L的NaOH溶液调节pH为9左右，反应30min。反应完成后进行抽滤，将抽滤得到的物质浸泡在pH＝2的HCl溶液中，0.5小时后，抽滤得到的固形物多次用去离子水清洗；最后，将固形物真空干燥即可得到氧化乙基纤维素。
(3)避光条件下，按照浓度比为2.5g/L的比例取苯基-2,4,6-三甲基苯甲酰基膦酸锂与DMEM培养基/去离子水配制溶液，溶解后，加入质量百分比浓度为1.2％甲基丙烯酰化透明质酸完全溶解，0.22μm过滤器过滤后，加入质量百分比浓度为0.5％氧化纤维素、20μg/L成纤维细胞生长因子和15mg/kg环孢素A；
(4)混合液用移液枪滴置于培养皿中，蓝光灯照射时间为20-40秒，蓝光波长为405-465纳米，得到一种含成纤维细胞生长因子和环孢素A的可注射光固化止血水凝胶的制备方法。
实验2
(1)TBI手术前，对实验大鼠进行环境适应、行为学训练和术前数据的收集；
(2)TBI手术，麻醉剂注射使实验大鼠进入深度麻醉状态，剪开动物颅骨表面皮肤和结缔组织，剥离部分颅骨(Bregma前0.7mm，旁开3.9mm)；利用自制损毁工具在大鼠运动皮层挖取直径1.5mm，深4mm的圆柱形脑组织，形成一个固定大小的损毁区域(如图2所示)；
(3)治疗组与对照组分组；生物复合材料治疗组处理方式为，将含有20μg/L成纤维细胞生长因子、15mg/kg环孢素A和质量百分比浓度为0.5％-3％氧化纤维素的复合水凝胶材料，注射入大鼠脑内损毁区域，使用波长405-465纳米蓝光照射，凝固材料；将颅骨复原，缝合伤口，保暖复苏；对照组处理方式为，将去离子水(材料溶剂)，注射入大鼠脑内损毁区域，使用波长405-465纳米蓝光照射。将颅骨复原，缝合伤口，保暖复苏；
(4)在术后第3，5，7，14天，利用蒙托亚阶梯(Montoya Staircase Tasks)实验范式检测大鼠的上肢精细运动能力(如图3所示)；
(5)在术后第60天，收取动物脑组织样本进行病理学观察(如图4所示)；
综上，病理学发现在损伤灶周围，生物复合材料治疗组相对于对照组，促炎胶质细胞数量和损伤灶面积减小，这与行为学的结果是一致的。以上种种结果都表明了我们的材料在再生医学及临床治疗中应用前景良好。
综上所述，1、本发明通过甲基丙烯酸酐的量来控制甲基丙烯酰化HAMA的接枝率，并进行网络活化交联，从而得到降解速率可控、力学性能增强的可注射凝胶材料，再结合氧化纤维素，使其抗自由基氧化能力更强，更润滑、缓释效率更高、更有利于止血修复；
2、本发明制备的HAMA凝胶体系高度仿生细胞外基质的组成和结构，具有更好的稳定性、保水率，且力学性能可控；
3、本发明以透明质酸为原料，利用甲基丙烯酸酐键对透明质酸进行酰化改性反应引入光交联得到交联网络水凝胶；本发明采用光交联，对天然高分子水凝胶产生活化网络，使其兼具优异的力学性能及生物相容性，有助于可注射功能型水凝胶材料的开发利用；
4、本发明为了达到更好的治疗效果，携带两种生物活性小因子-环孢素A和成纤维细胞生长因子。材料携带的两种生物活性小因子：环孢素A和成纤维细胞生长因子，前者通过对T细胞的作用，降低创伤性脑损伤后的炎症反应；后者作为神经营养因子，发挥着促进神经前体细胞的增殖分化、修复神经损伤等效果，随着材料的缓释作用，在上述几种活性成分的互作下，可长期改善创伤性脑损伤模式动物的预后。
在本说明书的描述中，参考术语“一个实施例”、“示例”、“具体示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
以上公开的本发明优选实施例只是用于帮助阐述本发明。优选实施例并没有详尽叙述所有的细节，也不限制该发明仅为所述的具体实施方式。显然，根据本说明书的内容，可作很多的修改和变化。本说明书选取并具体描述这些实施例，是为了更好地解释本发明的原理和实际应用，从而使所属技术领域技术人员能很好地理解和利用本发明。本发明仅受权利要求书及其全部范围和等效物的限制。
Claims (8)
1.用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于，包括以下步骤：
S1将碳酸钠加入去离子水中，稀释碳酸钠水溶液，加入透明质酸，搅拌溶解，得到透明质酸溶液；
S2于透明质酸溶液加入甲基丙烯酸、N，N-二甲基甲酰胺、三乙胺，隔一段时间后加入碳酸钠；
S3常温下反应后，用去离子水在常温下透析、冷冻干燥得到甲基丙烯酰化透明质酸；
S4配制体积比为100ml/L-750ml/L的乙醇-水溶液，并加入NaOH；
S5乙基纤维素作为原料，在乙醇-水溶液中形成溶液进行水解；
S6反应结束后用去离子水多次洗涤，抽滤，再进行真空干燥；
S7称取0.5g-2.5g/L NaBr、0.1-0.3g/L TEMPO溶解于去离子水中，此溶液进行冰浴；
S8真空干燥的乙基纤维素加入正在进行冰浴的溶液中，在不断搅拌下一次性加入NaClO溶液反应；
S9反应完成后进行抽滤，将抽滤得到的物质浸泡在pH＝1-3的HCl溶液中，将固形物真空干燥即可得到氧化乙基纤维素；
S10避光条件下，按照浓度比为2.5～5g/L的比例取苯基-2,4,6-三甲基苯甲酰基膦酸锂与DMEM培养基/去离子水配制溶液，溶解后，加入质量百分比浓度为0.5％-3％甲基丙烯酰化透明质酸，完全溶解并使用过滤器过滤后，加入氧化纤维素、成纤维细胞生长因子和环孢素A；
S11混合液用移液枪滴置于培养皿中，进行蓝光灯照射,得到一种含成纤维细胞生长因子和环孢素A的可注射光固化止血水凝胶。
2.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S2中加入甲基丙烯酸酐，甲基丙烯酸酐与透明质酸体积质量比为1-5:1，按1～5ml/L的比例加入N,N-二甲基甲酰胺，按0.2～0.6g/L的比例加入三乙胺，每间隔12小时加入0.2-1.0mmol/L碳酸钠。
3.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S3中透析的条件为：在常温下透析3-7天，每6-18小时换一次水，透析袋截留分子量为：8KDa-14KDa。
4.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S3中甲基丙烯酰化透明质酸反应化学式如下：
5.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S4中NaOH加入乙醇-水溶液形成质量分数为0.2g/L-8g/L的溶液。
6.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S5中乙基纤维素作为原料，在100ml/L-750ml/LNaOH/乙醇-水溶液中形成质量分数为0.2g/L-8g/L的溶液。
7.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S8一次性加入10mL/L-100mL/L体积的NaClO溶液(有效含量为7.5％)，用0.2g/L-8g/L的NaOH溶液调节pH为8-11。
8.根据权利要求1所述用于创伤性脑损伤的可注射光固化止血水凝胶的制备方法，其特征在于；所述S10中水凝胶复合材料加入氧化纤维素、成纤维细胞生长因子和环孢素A。
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