CN111632203A - 一种用于预防手术后组织粘连的多功能超分子水凝胶及制备方法 - Google Patents

一种用于预防手术后组织粘连的多功能超分子水凝胶及制备方法 Download PDF

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CN111632203A
CN111632203A CN202010503431.5A CN202010503431A CN111632203A CN 111632203 A CN111632203 A CN 111632203A CN 202010503431 A CN202010503431 A CN 202010503431A CN 111632203 A CN111632203 A CN 111632203A
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hydrogel
tissue adhesion
multifunctional
polyphenol compound
active oxygen
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张建祥
王言
李兰兰
马永昌
郭嘉伟
窦寅
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Army Medical University
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Abstract

本发明公开了一种用于预防手术后组织粘连的多功能超分子水凝胶及制备方法。所述水凝胶由可注射温敏成凝胶材料、活性氧清除性药物和多酚类化合物三种组分构成。制备时，将上述三种组分按一定顺序在水中均匀混合即可得到用于预防手术后组织粘连的多功能超分子水凝胶。其中，可注射温敏成凝胶材料0.1‑30wt％，活性氧清除性药物0.01‑10wt％，多酚类化合物0.1‑50wt％。该凝胶材料可在椎板切除术中局部应用防治硬膜外纤维化粘连以及其他外科手术后组织粘连。给药方式包括皮下注射、腔内注射、涂抹，以及以上任意方式的组合。本发明制备的水凝胶具有合适的温敏性溶胶‑凝胶相转变温度，具有合适的生物黏附能力，具有理想的粘弹性、柔软性。

Description

一种用于预防手术后组织粘连的多功能超分子水凝胶及制备 方法
技术领域
本发明涉及一种具有温度响应性凝胶化、自愈合、组织粘附性、抗氧化、抗炎症和抗纤维化等多功能的超分子水凝胶，具体是一类通过降低病灶局部氧化应激、炎症水平来实现椎板切除术后硬膜外纤维化粘连及其他外科手术后组织粘连防治的材料及其组成、制备方法。
背景技术
腰椎板切除术是一种最常见的脊柱手术，它可以有效减轻周围组织对脊髓或神经根的压迫。然而，在腰椎板切除术后约有8-40％的患者遭受了腰椎手术失败综合征(FBSS)。FBSS的原因多且复杂,其中硬膜外纤维化造成的脊髓硬膜和神经根与周围肌肉、韧带、纤维环等组织的广泛粘连被认为是引起FBSS的重要原因。近年来，微创脊柱外科发展迅速，微创的手术方法理念和手术设备、工具均有了长足的进步，这些因素显著降低了绝大部分手术的手术规模以及手术造成的组织创伤。然而，术后硬膜外纤维化粘连这一并发症仍然无法避免，这一临床治疗的挑战依旧存在。通过二次手术来解决这种并发症是比较困难和棘手的，因为再次手术中发生神经根损伤和硬膜撕裂的可能性很大，手术风险极高。同时，再次手术治疗给患者造成了很大的痛苦和风险，也给社会医疗资源增加了巨大压力。
目前，许多预防硬膜外纤维化和减少硬膜粘连的实验研究相继被报道，主要包括药物治疗、生物材料屏障保护以及药物与生物材料相结合的方法。然而，已开发的抗纤维化粘连生物材料治疗效果较为有限，并且存在一些副作用，只有极少数进入临床试验阶段，但几乎没有受到广泛认可的临床生物材料产品。
从硬膜外纤维化发生的病理机制上来说，硬膜外粘连是由瘢痕组织逐渐发展而来，而成纤维细胞在瘢痕组织的形成中起到了重要作用。手术操作引起的局部炎症和血肿可以影响成纤维细胞从而促使粘连的逐步形成。在椎板切除区域,炎性细胞因子和生长因子被激活后，大量成纤维细胞广泛增殖，并产生大量的胶原纤维以修复椎板区域局部的组织缺损。同时，氧化应激反应促进了炎性细胞浸润能力，上调了这些分子介质，进一步促进了成纤维细胞增殖、细胞外基质合成，最终形成致密的瘢痕组织。此外，氧化应激介导的活性氧簇(ROS)的释放可诱导细胞损伤，促进炎症介质的产生，进而加重了慢性炎症。曾有学者试图采用一种小分子化合物2,2,6,6-四甲基哌啶氮氧化物(Tpl)，通过清除腹腔手术后手术局部的过氧化氢来达到防治腹膜术后粘连形成的目的。然而，过氧化氢只是诸多ROS中的一种，仅清除手术局部的过氧化氢是远远不够的。因此，联合抗纤维化、抗炎和清除活性氧降低氧化应激是预防术后硬膜外纤维化粘连及其他外科手术后组织粘连的有效策略。
发明内容
针对上述问题，本实发明的目的在于解决现有技术中的一部分问题，或至少缓解这些问题。从而本发明的目的是提供一种超分子多功能水凝胶以及其制备方法。
一种用于预防手术后组织粘连的多功能超分子水凝胶，包括可注射温敏成凝胶材料、活性氧清除性药物和多酚类化合物，它们按照以下比重配制：0.1-30wt％可注射温敏成凝胶材料，0.01-10wt％活性氧清除性药物，0.1-50wt％多酚类化合物。
进一步地，所述可注射温敏成凝胶材料选自泊洛沙姆407、泊洛沙姆188或聚(乳酸-羟基乙酸)-聚乙二醇-聚(乳酸-羟基乙酸)三元共聚物。
进一步地，所述活性氧清除性药物选自N-乙酰半胱氨酸、维生素C、谷胱甘肽、4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基(Tempol)、基于苯硼酸频哪醇酯键合环糊精材料的纳米粒、基于Tempol/苯硼酸频哪醇酯共键合环糊精材料的纳米粒或基于鲁米诺键合环糊精材料的纳米粒。
进一步地，所述多酚类化合物具有组织黏附性，选自鞣酸、表没食子儿茶素没食子酸酯、儿茶素、没食子酸或多巴胺。
本发明还提供一种超分子多功能水凝胶的制备方法，包括以下步骤：首先将多酚类化合物加入水中，搅拌使其充分溶解；之后将可注射温敏成凝胶材料加入该溶液，搅拌充分溶解；最后将活性氧清除性药物加入溶液中，震荡摇匀，即可得到超分子多功能水凝胶。
本发明所述多功能超分子水凝胶在制备预防外科手术后组织粘连的药物中的应用。包括但不限于用于制备防治腰椎板切除手术后硬膜外纤维化粘连的药物。
本发明的给药方式包括皮下注射、肌肉注射、腔内注射、涂抹，以及以上任意方式的组合。
本发明的有益效果在于：
(1)所述水凝胶可以注射使用，能够胜任微创手术操作；
(2)所述水凝胶具有合适的温敏性溶胶-凝胶相转变温度，使用时在组织表面完全覆盖，随后凝胶化形成有效物理屏障；
(3)所述水凝胶具有合适的生物黏附能力，避免材料从脊髓组织剥脱，同时黏附性能可通过多酚类化合物的类型和用量方便地调控；
(4)所述水凝胶在保证临床效果前提下，具有合适的体内残留时间，避免长时间残留导致的严重异物反应；
(5)所述水凝胶具有理想的粘弹性、柔软性，不影响脊髓自然活动且避免可能的神经压迫；
(6)所述水凝胶通过有效的抗氧化应激、抗炎和抗纤维化作用防治硬膜外纤维化以及术后组织粘连；
(7)所述水凝胶具有良好的生物相容性和神经功能安全性；
(8)所述水凝胶还可用作具有生物黏附性的药物递送载体材料；
(9)所述水凝胶制备方法简单，制备工艺稳定可控，易于规模化生产；
(10)所述水凝胶制备方法中，先加入多酚类化合物，待其溶解后再加入可注射温敏成凝胶材料和活性氧清除性药物。若改变加入顺序，溶液的溶解速度会减慢或出现溶解不充分的情况。
附图说明
图1是超分子多功能水凝胶(简称PXNT)在温度变化下的溶胶-凝胶相转变照片。
图2是Cy5标记的基于Tempol/苯硼酸频哪醇酯共键合β环糊精材料的纳米粒(图中的点)在含有FITC标记的泊洛沙姆407(图中的背景)的PXNT水凝胶中散在分布图片。
图3是(a)PXNT水凝胶表面形貌的典型扫描电镜图像，可见纳米粒突起；(b、c、d)为不同分辨率下PXNT水凝胶断裂面的扫描电镜图像，d图可见凝胶中嵌入球形纳米粒。
图4是不同鞣酸含量的PXNT凝胶在硬膜和肌肉组织上的黏附性能评估。
图5是PXNT水凝胶的体外水解与释放性能(a、b)、活体残留时间统计结果(c)，PXN为不含鞣酸的水凝胶。
图6是大鼠经PXNT水凝胶治疗及模型组术后8周的硬膜外大体观图片，以及硬膜外纤维化大体观评分统计。
图7是PXNT水凝胶流变学测试结果。
图8是大鼠经PXNT水凝胶治疗及模型组典型术后8周核磁共振扫描图像，及轴位硬膜外纤维化面积和MRI硬膜外纤维化粘连评分统计。
图9是大鼠经PXNT水凝胶治疗及模型组典型8周后HE染色图片，及硬膜外纤维化评分和成纤维细胞浸润评分统计。
图10是家兔经PXNT水凝胶治疗及模型组典型大体观和核磁共振图像，及大体观评分和核磁共振硬膜外纤维化评分统计。
具体实施方式
下面结合具体实施方式对本发明的发明内容作进一步的详细描述。应理解，本发明的实施例只用于说明本发明而非限制本发明，在不脱离本发明技术思想的情况下，根据本领域普通技术知识和惯用手段，做出的各种替换和变更，均应包括在本发明的范围内。下面结合非限定性的实施例对本发明做详细说明。
实例1
在室温下，先将0.2g鞣酸加入6mL超纯水，室温下搅拌溶解，再加入1.8g泊洛沙姆407，充分搅拌溶解，最后加入2mL浓度为5mg/mL的基于Tempol/苯硼酸频哪醇酯共键合β-环糊精材料的纳米粒的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例2
在室温下，先将0.2g多巴胺加入6mL超纯水，室温下搅拌溶解，再加入1.8g泊洛沙姆188，充分搅拌溶解，最后加入2mL浓度为5mg/mL的N-乙酰半胱氨酸的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例3
在室温下，先将0.3g表没食子儿茶素没食子酸酯加入8mL超纯水，室温下搅拌溶解，再加入1.8g泊洛沙姆188，充分搅拌溶解，最后加入2.5mL浓度为4mg/mL的基于苯硼酸频哪醇酯共键合β-环糊精材料的纳米粒的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例4
在室温下，先将0.2g儿茶素加入6mL超纯水，室温下搅拌溶解，再加入1.8g泊洛沙姆407，充分搅拌溶解，最后加入2mL浓度为5mg/mL的基于鲁米诺键合α-环糊精材料的纳米粒的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例5
在室温下，先将0.8g没食子酸加入50mL超纯水，室温下搅拌溶解，再加入0.5g泊洛沙姆407，充分搅拌溶解，最后加入5mL浓度为1mg/mL的4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基(Tempol)的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例6
在室温下，先将5g鞣酸加入100mL超纯水，室温下搅拌溶解，再加入10g泊洛沙姆407，充分搅拌溶解，最后加入1mL浓度为10mg/mL的基于Tempol/苯硼酸频哪醇酯共键合β-环糊精材料的纳米粒的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例7
在室温下，先将20g儿茶素加入60mL超纯水，室温下搅拌溶解，再加入3g泊洛沙姆188，充分搅拌溶解，最后加入20mL浓度为1mg/mL的谷胱甘肽的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
实例8
在室温下，先将10g表没食子儿茶素没食子酸酯加入20mL超纯水，室温下搅拌溶解，再加入1g聚(乳酸-羟基乙酸)-聚乙二醇-聚(乳酸-羟基乙酸)三元共聚物，充分搅拌溶解，最后加入0.6mL浓度为100mg/mL的维生素C的水溶液，并震荡均匀，即得到本发明所述的超分子多功能水凝胶。
采用实施例1所制备的PXNT来进行性能测试，具体结果如下：
不同鞣酸含量的PXNT凝胶在硬膜和肌肉组织上的黏附性能评估，如图4所示。(其中，TA0表示未添加鞣酸、TA0.5表示0.5wt％的鞣酸、TA1表示1wt％的鞣酸、TA2表示2wt％的鞣酸。)超分子多功能水凝胶的黏附性能随鞣酸浓度增加而增强。
PXNT水凝胶的体外水解与释放性能、活体残留时间统计结果，如图5所示。从图中可以得出该凝胶可在体内残留约7天，并在此期间持续释放生物活性纳米粒。从硬膜外纤维化中炎症反应的发生过程来看，手术后3-5天是该过程的第二阶段，期间手术区域大量炎性因子和介质释放，是造成最终慢性炎症的至关重要的一环，因此该凝胶在体内的残留时间为7天，可以覆盖这一阶段，对治疗效果是有利的。
使用实例1的水凝胶，首先对SD大鼠剃毛消毒，经后正中入路切口，再对大鼠进行腰4椎板的切除操作，止血并充分暴露该节段的硬脊膜，随后将材料凝胶喷涂于硬脊膜之上，待其凝胶化转相后，逐层关闭切口，紧密缝合。大鼠经PXNT水凝胶治疗及模型组典型术后8周的硬膜外大体观图片，以及硬膜外纤维化大体观评分统计，如图6所示。其中，PXNT组表现出了较少的瘢痕组织形成及较轻的组织粘连。
PXNT水凝胶典型流变学测试结果，如图7所示。提示该凝胶可在室温逐渐升至37℃过程中实现快速溶胶-凝胶相转变，成凝胶后具有与正常脊髓组织相似的模量，最大可耐受60％应变量，剪切变稀，具有自我修复能力。图7a表示储能模量(G示)和损耗模量(G和)均随温度升高而增大。随温度进一步升高,G′与G″交会，溶胶-凝胶转变温度为26.9℃，提示PXNT已凝胶化转相。G′在37℃时为3000-3500Pa，与正常脊髓模量值(4000Pa)相近。图7b表示凝胶在37℃时可在15秒内完成凝胶转化。图7c表示角频率测试的粘弹性区域内，G示和G′为线性响应，tanδ变化范围为0.48至0.37，表现出典型弹性改变行为。图7d表示当应变率在1％到60％之间变化时，PXNT是稳定的凝胶状态，可承受人体内最大应变(10％)。图7e表示在200％的高应变率下，PXNT表现出类流体行为，当应变率降低为2％时，PXNT迅速恢复最初模量，且此过程可重复。图7f所示粘度随剪切率变化测试证明了PXNT水凝胶的剪切变稀行为。图7g所示阶梯剪切率变化测试表明，在高剪切和低剪切速率下转换，PXNT可快速自我修复为最初粘度。
大鼠经PXNT水凝胶治疗及模型组典型术后8周核磁共振扫描图像，及轴位硬膜外纤维化面积和MRI硬膜外纤维化粘连评分统计，如图8所示。PXNT组表现出了更低纤维化评分及硬膜外瘢痕组织面积。
大鼠经PXNT水凝胶治疗及模型组典型8周后HE染色图片，及硬膜外纤维化评分和成纤维细胞浸润评分统计，如图9所示。PXNT组大鼠硬膜外组织的纤维化程度更低，其中的成纤维细胞含量更少。
家兔经PXNT水凝胶治疗及模型组典型大体观和核磁共振图像，及大体观评分和核磁共振硬膜外纤维化评分统计，如图10所示。PXNT干预后家兔的硬膜外组织相较于模型组更加稀疏且易于剥离，核磁共振图像中的纤维化粘连程度更低。
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Claims (10)

1.一种用于预防手术后组织粘连的多功能超分子水凝胶，其特征在于：包括可注射温敏成凝胶材料、活性氧清除性药物和多酚类化合物，它们按照以下比重配制：0.1-30wt％可注射温敏成凝胶材料，0.01-10wt％活性氧清除性药物，0.1-50wt％多酚类化合物。
2.根据权利要求1所述一种用于预防手术后组织粘连的多功能超分子水凝胶，其特征在于：所述可注射温敏成凝胶材料选自泊洛沙姆407、泊洛沙姆188或聚(乳酸-羟基乙酸)-聚乙二醇-聚(乳酸-羟基乙酸)三元共聚物。
3.根据权利要求1所述一种用于预防手术后组织粘连的多功能超分子水凝胶，其特征在于：所述活性氧清除性药物选自N-乙酰半胱氨酸、维生素C、谷胱甘肽、4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基、基于苯硼酸频哪醇酯键合环糊精材料的纳米粒、基于Tempol/苯硼酸频哪醇酯共键合环糊精材料的纳米粒或基于鲁米诺键合环糊精材料的纳米粒。
4.根据权利要求1所述一种用于预防手术后组织粘连的多功能超分子水凝胶，其特征在于：所述多酚类化合物具有组织黏附性，选自鞣酸、表没食子儿茶素没食子酸酯、儿茶素、没食子酸或多巴胺。
5.根据权利要求1-4任一项所述一种用于预防手术后组织粘连的多功能超分子水凝胶，其特征在于，通过以下方法制备：首先将多酚类化合物加入水中，搅拌使其充分溶解；之后将可注射温敏成凝胶材料加入该溶液，搅拌充分溶解；最后将活性氧清除性药物加入溶液中，震荡摇匀，即可得到超分子多功能水凝胶。
6.一种用于预防手术后组织粘连的多功能超分子水凝胶的制备方法，其特征在于，包括以下步骤：首先将多酚类化合物加入水中，搅拌使其充分溶解；之后将可注射温敏成凝胶材料加入该溶液，搅拌充分溶解；最后将活性氧清除性药物加入溶液中，震荡摇匀，即可得到超分子多功能水凝胶。
7.根据权利要求6所述一种用于预防手术后组织粘连的多功能超分子水凝胶的制备方法，其特征在于：所述多酚类化合物、可注射温敏成凝胶材料与活性氧清除性药物的加入比例为0.1-50wt％：0.1-30wt％：0.01-10wt％。
8.根据权利要求6所述一种用于预防手术后组织粘连的多功能超分子水凝胶的制备方法，其特征在于：所述活性氧清除性药物的浓度为0.01-10wt％。
9.权利要求1-5任一项所述多功能超分子水凝胶在制备预防外科手术后组织粘连的药物中的应用。
10.根据权利要求9所述多功能超分子水凝胶在制备预防外科手术后组织粘连的药物中的应用，其特征在于：给药方式包括皮下注射、肌内注射、腔内注射、涂抹，以及以上任意方式的组合。
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CN112190707A (zh) * 2020-09-16 2021-01-08 河南有为医药科技有限公司 一种抗hpv重组人凝胶及其制备方法
CN113101407A (zh) * 2021-03-22 2021-07-13 西南大学 一种单宁酸基水下粘合剂制备方法及制品
CN113274548A (zh) * 2021-06-23 2021-08-20 右江民族医学院附属医院 脊髓损伤修复用材料和骨脊髓组织工程支架的制备方法
CN114058033A (zh) * 2021-12-20 2022-02-18 河南省科学院同位素研究所有限责任公司 一种温度敏感型水凝胶的制备方法及其制备的温度敏感型水凝胶产品
CN116509794A (zh) * 2023-05-19 2023-08-01 上海市肿瘤研究所 一种口服温敏凝胶制剂及其制备方法与应用
CN114058033B (zh) * 2021-12-20 2024-06-04 河南省科学院同位素研究所有限责任公司 一种温度敏感型水凝胶的制备方法及其制备的温度敏感型水凝胶产品

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CN112190707A (zh) * 2020-09-16 2021-01-08 河南有为医药科技有限公司 一种抗hpv重组人凝胶及其制备方法
CN113101407A (zh) * 2021-03-22 2021-07-13 西南大学 一种单宁酸基水下粘合剂制备方法及制品
CN113101407B (zh) * 2021-03-22 2022-04-15 西南大学 一种单宁酸基水下粘合剂制备方法及制品
CN113274548A (zh) * 2021-06-23 2021-08-20 右江民族医学院附属医院 脊髓损伤修复用材料和骨脊髓组织工程支架的制备方法
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CN114058033B (zh) * 2021-12-20 2024-06-04 河南省科学院同位素研究所有限责任公司 一种温度敏感型水凝胶的制备方法及其制备的温度敏感型水凝胶产品
CN116509794A (zh) * 2023-05-19 2023-08-01 上海市肿瘤研究所 一种口服温敏凝胶制剂及其制备方法与应用
CN116509794B (zh) * 2023-05-19 2024-03-15 上海市肿瘤研究所 一种口服温敏凝胶制剂及其制备方法与应用

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