CN116603115A - 一种辅助esd/emr的可注射全降解无菌水凝胶及其制备方法与应用 - Google Patents
一种辅助esd/emr的可注射全降解无菌水凝胶及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医用高分子材料、生物医药和医疗器械领域，具体涉及一种辅助ESD/EMR的可注射全降解无菌水凝胶及其制备方法与应用，包括阴离子生物黏多糖、阳离子纳米晶体及其稳定剂。本发明通过静电相互作用和氢键相互作用构建物理交联的生物全降解可注射水凝胶，作为一种黏膜下注射液极易通过内窥镜针直接注入消化道黏膜下层组织，注射后形成辅助肿瘤组织隆起便于手术切除，此外，本发明所制备的水凝胶还具有较强的成膜性可以粘附在手术切除部位保护创面、减少创面出血、加速创面愈合。本发明所用原料易得且安全，制备方式温和、绿色环保、生物相容性好且成本较低，制得的水凝胶具有较强的注射性能和黏膜下隆起性质，显著高于商用黏膜下注射液，具备较强的临床应用价值。
Description
技术领域
本发明属于生物医用高分子材料、生物医药和医疗器械领域，具体涉及一种辅助ESD/EMR的可注射全降解无菌水凝胶及其制备方法与应用。
背景技术
胃肠道癌症主要包括食管癌、胃癌、结直肠癌、肝癌和胰腺癌，占全球癌症发病率的26％，占所有与癌症相关的死亡人数的35％。随着胃肠道肿瘤发病率和死亡率的不断上升，对消化道肿瘤的早期发现、筛查以及干预措施对患者的治疗和预后护理至关重要。近年来，内窥镜切除已被广泛接受为无淋巴结转移的早期胃肠道肿瘤的标准微创治疗方法，临床医生通过EMR/ESD将病变组织切除并进行组织病理学分析，从而降低肿瘤复发的可能性，提高整块切除大尺寸病变的切除率。
迄今为止，用于辅助胃肠道肿瘤EMR/ESD等内镜手术的黏膜下注射材料主要由大分子、蛋白质或多糖组成，而多糖基自修复水凝胶因具有类细胞外基质的结构和功能以及优异的生物相容性、生物可降解性、良好的机械性能和自愈合性能；在ESD黏膜下注射材料的研制中具有能够解决临床难点的巨大优势。
在施行EMR/ESD手术进行黏膜下剥离时通常伴随着出血或穿孔等不良事件的发生，为了避免相关并发症，作为人体凝血因子的纤维蛋白原引起了研究人员的注意，研究证实纤维蛋白原可以提供持久的黏膜下抬高，黏膜下注射纤维蛋白原混合液进行EMR/ESD时，其提供的手术视野、所需的注射量、手术时间、并发症和其他手术相关的结果均优于生理盐水。但是，由于纤维蛋白原来源于人血清中的凝固蛋白，因此有可能被肝炎病毒或其他病毒污染造成不必要的传染。
此外，ESD/EMR手术中对消化道黏膜的机械性损伤造成创面裸露，不可避免地会导致术后医源性大溃疡的产生，并且由于无良好的创面保护措施，溃疡创面遭受胃或胆汁分泌物的侵袭使得创面愈合不良，容易引起出血、穿孔和其他胃肠道并发症。目前，虽然质子泵抑制剂和黏膜保护剂作为抗溃疡药物被广泛使用，但仍有大约5-20％的病例发生溃疡愈合延迟8周以上，术后人工溃疡的治疗仍然是临床上的一大痛点，其治疗措施对于恢复患者健康至关重要。
理想的黏膜下注射凝胶应易通过内窥镜针注射，并形成持久的黏膜下隆起高度和隆起时间，具有优异的生物相容性和生物可降解性；同时还应对病变部位进行精准识别，减少创面出血，促进切除后的创面愈合；此外，还应具有较高的临床应用价值。
发明内容
有鉴于此，本发明的目的在于提供一种辅助ESD/EMR的可注射全降解无菌水凝胶，静电相互作用和氢键相互作用构建物理交联，使其具有较强的可注射性能和优异的黏膜下隆起性质，便于通过内窥镜针直接注入消化道黏膜下层组织，注射后形成稳定的黏膜下隆起高度和持久的隆起时间方便ESD/EMR手术切除。此外，本发明所制备的水凝胶还具有较强的成膜性可以粘附在手术切除部位保护创面、减少创面出血、加速创面愈合。
为实现上述目的，本发明采用如下的技术方案：
将阴离子生物黏多糖溶解到生理盐水中溶解得到阴离子生物黏多糖溶液，然后将阳离子纳米晶体分散到阴离子生物黏多糖溶液中后调节pH值，滴加稳定剂及染色剂待滴加完全后反应即可得到可注射全降解无菌水凝胶。
优选的，阴离子生物黏多糖包括但不限于羧甲基壳聚糖、羧甲基壳聚糖衍生物、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素衍生物、海藻酸钠、海藻酸钠衍生物、羧甲基淀粉、羧基甲淀粉钠、羧甲基淀粉衍生物、黄原胶、黄原胶衍生物、卡拉胶、卡拉胶及其衍生物中的任意一种；阴离子生物黏多糖溶解后的质量浓度为0.1-5％。
优选的，阳离子纳米晶体包括但不限于生物活性玻璃、骨水泥、乳酸钙、硅酸钠镁锂、硅酸镁锂、硅酸钠、硅酸钾、硅酸铝钠、硅酸钙、硅酸镁、白磷钙石中的任意一种及以上；阳离子纳米晶体与阴离子生物黏多糖的质量比为30∶1～1∶10；pH值调整为3-9。
优选的，稳定剂包括但不限于聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮、丙烯酸树脂、聚氨酯中的任意一种；稳定剂的质量浓度为0.1-10％，稳定剂的滴加速度为0.1-20mL/min。
优选的，阳离子纳米晶体的分散方式包括但不限于超声分散、机械搅拌分散、高速均质分散；反应温度为25-80℃；反应时间为2-36小时。
优选的，染色剂包括但不限于靛蓝胭脂红、亚甲基蓝、亮蓝、台盼蓝、甲苯胺蓝。
优选的，灭菌方式包括但不限于湿热灭菌、低温等离子体灭菌、辐照灭菌、流程灭菌、膜过滤、无菌生产。
本发明还提供由上述方法制得的可注射全降解无菌水凝胶。
本发明还提供由上述方法制得的可注射全降解无菌水凝胶作为一种辅助ESD/EMR切除的注射液在医疗器械、组织工程材料领域中的应用。
所述应用包括：黏膜下隆起注射液、消化道溃疡修复、消化道止血。
本发明的有益效果在于：
本发明所用原料易得且安全，制备方式温和、绿色环保、生物相容性好且成本较低，制得的水凝胶具有较强的注射性能和黏膜下隆起性质，显著高于商用黏膜下注射液。本发明所制备的水凝胶还具有较强的成膜性可以粘附在手术切除部位保护创面、减少创面出血、加速创面愈合，具备较强的临床应用价值。
附图说明
图1是本发明所述可注射全降解无菌水凝胶的注射性能。
图2是本发明所述可注射全降解无菌水凝胶的注射效果。
图3是本发明所述可注射全降解无菌水凝胶的降解性能。
图4是本发明所述可注射全降解无菌水凝胶的黏膜下隆起能力。
图5是本发明所述可注射全降解无菌水凝胶的黏膜下隆起效率。
图6本发明所述可注射全降解无菌水凝胶的黏膜下隆起后体内切除效率。
图7本发明所述可注射全降解无菌水凝胶的肝脏止血性能。
图8本发明所述可注射全降解无菌水凝胶的血液相容性。
图9本发明所述可注射全降解无菌水凝胶的细胞相容性。
图10本发明所述可注射全降解无菌水凝胶的微观结构。
图11本发明所述可注射全降解无菌水凝胶的大肠黏膜层的成膜性能。
具体实施方式
以下结合实施例和附图对本发明作进一步说明。根据下述实施例，可以更好地理解本发明。然而，实施例所描述的内容仅用于说明本发明，而不是对本发明权利要求的限制。
实施例1
将羧甲基纤维素衍生物溶解到生理盐水中溶解得到1％质量浓度的羧甲基纤维素衍生物溶液，然后通过超声分散将乳酸钙分散到1％质量浓度的羧甲基纤维素衍生物溶液中后调节pH值为6.5，以1.0mL/min的滴加速度滴加2％质量浓度的聚乙烯吡咯烷酮和靛蓝胭脂红的混合液，待滴加完全后反应，25℃反应6小时，然后通过湿热灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。
实施例2
将黄原胶衍生物溶解到生理盐水中溶解得到2％质量浓度的黄原胶衍生物溶液，然后通过超声分散将乳酸钙分散到2％质量浓度的黄原胶衍生物溶液中后调节pH值为5.5，以6.0mL/min的滴加速度滴加2％质量浓度的聚乙烯吡咯烷酮和靛蓝胭脂红的混合液，待滴加完全后反应，40℃反应8小时，然后通过湿热灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。
实施例3
将卡拉胶溶解到生理盐水中溶解得到0.1％质量浓度的卡拉胶溶液，然后通过超声分散将乳酸钙分散到0.1％质量浓度的卡拉胶溶液中后调节pH值为5.5，以6.0mL/min的滴加速度滴加2％质量浓度的聚乙烯醇和靛蓝胭脂红的混合液，待滴加完全后反应，40℃反应8小时，然后通过湿热灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。
实施例4
将卡拉胶溶解到生理盐水中溶解得到0.5％质量浓度的卡拉胶溶液，然后通过超声分散将乳酸钙分散到0.5％质量浓度的卡拉胶溶液中后调节pH值为5.5，以6.0mL/min的滴加速度滴加2％质量浓度的聚乙烯醇和亚甲基蓝的混合液，待滴加完全后反应，40℃反应8小时，然后通过湿热灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。
实施例5
将卡拉胶溶解到生理盐水中溶解得到1％质量浓度的海藻酸钠衍生物，然后通过超声分散将骨水泥分散到1％质量浓度的海藻酸钠衍生物中后调节pH值为5.5，以1.0mL/min的滴加速度滴加5％质量浓度的聚乙烯醇和亚甲基蓝的混合液，待滴加完全后反应，50℃反应8小时，然后通过辐照灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。
实施例6
将卡拉胶溶解到生理盐水中溶解得到1％质量浓度的海藻酸钠衍生物，然后通过超声分散将硅酸铝钠分散到1％质量浓度的海藻酸钠衍生物中后调节pH值为4.5，以1.0mL/min的滴加速度滴加1％质量浓度的聚氨酯和亚甲基蓝的混合液，待滴加完全后反应，30℃反应18小时，然后通过辐照灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。
实施例7
将羧甲基壳聚糖溶解到生理盐水中溶解得到1％质量浓度的羧甲基壳聚糖，然后通过超声分散将硅酸铝钠分散到1％质量浓度的羧甲基壳聚糖中后调节pH值为7.0，以1.0mL/min的滴加速度滴加1％质量浓度的聚乙烯吡咯烷酮和亚甲基蓝的混合液，待滴加完全后反应，30℃反应24小时，然后通过辐照灭菌方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过内窥镜注射器采用万能试验机测试其注射压力变化，发现随着氢键交联和静电吸附程度的变化影响注射压力(图1)，水凝胶展示较好的注射性能(图2)。
实施例8
将海藻酸钠溶解到生理盐水中溶解得到1％质量浓度的海藻酸钠，然后通过超声分散将白磷钙石和硅酸铝钠分散到1％质量浓度的海藻酸钠中后调节pH值为7.0，以1.0mL/min的滴加速度滴加1％质量浓度的聚乙二醇和亚甲基蓝的混合液，待滴加完全后反应，30℃反应24小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过体外降解实验证实水凝胶的降解性能(图3)。
实施例9
将羧甲基淀粉衍生物溶解到生理盐水中溶解得到1％质量浓度的羧甲基淀粉衍生物，然后通过超声分散将白磷钙石和硅酸铝钠分散到1％质量浓度的羧甲基淀粉衍生物中后调节pH值为6.0，以2.0mL/min的滴加速度滴加1％质量浓度的聚乙二醇和亚甲基蓝的混合液，待滴加完全后反应，30℃反应12小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过猪大肠体外黏膜下隆起实验可以证实本发明具有优异的黏膜下隆起能力(图4)和持久的黏膜下抬举性能(图5)。
实施例10
将羧甲基淀粉衍生物溶解到生理盐水中溶解得到1％质量浓度的羧甲基淀粉衍生物，然后通过超声分散将硅酸镁锂、硅酸钠和硅酸铝钠分散到1％质量浓度的羧甲基淀粉衍生物中后调节pH值为5.0，以1.0mL/min的滴加速度滴加1％质量浓度的聚乙二醇和亚甲基蓝的混合液，待滴加完全后反应，30℃反应12小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过内窥镜辅助设备注入猪大肠体内黏膜下隆起实验可以证实本发明具有优异的黏膜下隆起能力和辅助ESD/EMR切除能力(图6)。
实施例11
将羧甲基淀粉衍生物溶解到生理盐水中溶解得到2％质量浓度的羧甲基淀粉衍生物，然后通过超声分散将乳酸钙、硅酸钠镁锂和硅酸镁锂分散到2％质量浓度的羧甲基淀粉衍生物中后调节pH值为5.0，以2.0mL/min的滴加速度滴加2％质量浓度的丙烯酸树脂和亚甲基蓝的混合液，待滴加完全后反应，30℃反应12小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过建立大鼠肝脏出血模型，并将本发明作用于出血部位，证实其具有较强的止血性能，可以减少ESD/EMR手术的创面出血(图7)。通过溶血实验证实本发明具有较强的血液安全性(图8)。
实施例12
将羧甲基纤维素钠溶解到生理盐水中溶解得到2％质量浓度的羧甲基纤维素钠，然后通过超声分散将硅酸钠镁锂和硅酸镁锂分散到2％质量浓度的羧甲基纤维素钠中后调节pH值为5.0，以2.0mL/min的滴加速度滴加2％质量浓度的丙烯酸树脂和亚甲基蓝的混合液，待滴加完全后反应，30℃反应12小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过建立大鼠肝脏出血模型，并将本发明作用于出血部位，证实其具有较强的止血性能，可以减少ESD/EMR手术的创面出血(图7)。通过溶血实验证实本发明具有较强的血液安全性(图8)。
实施例13
将羧甲基纤维素钠溶解到生理盐水中溶解得到2％质量浓度的羧甲基纤维素钠，然后通过超声分散将硅酸钠镁锂和硅酸镁锂分散到2％质量浓度的羧甲基纤维素钠中后调节pH值为5.0，以5.0mL/min的滴加速度滴加2％质量浓度的丙烯酸树脂和亚甲基蓝的混合液，待滴加完全后反应，60℃反应12小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过体外细胞实验证实其具有较强的细胞安全性(图9)。
实施例14
将羧甲基纤维素钠溶解到生理盐水中溶解得到2％质量浓度的羧甲基纤维素钠，然后通过超声分散将硅酸钠镁锂和硅酸镁锂分散到2％质量浓度的羧甲基纤维素钠中后调节pH值为5.0，以7.0mL/min的滴加速度滴加2％质量浓度的聚乙烯醇和亚甲基蓝的混合液，待滴加完全后反应，60℃反应8小时，然后通过膜过滤方式做终端产品处理，即可得到可注射全降解无菌水凝胶。然后通过扫描电镜证实水凝胶具有相互贯通的多孔结构(图10)，并将其涂抹于大肠黏膜的出血部位，显示出优异的成膜性能(图11)。
综上表明，本发明提供了一种可注射全降解无菌水凝胶，并公开其制备方法及作为一种辅助ESD/EMR切除的注射液在医疗器械、组织工程材料领域中的应用。该水凝胶，绿色环保、安全无毒、易注射且不易流动，相比于传统的黏膜下注射液具有3D网络结构，不易流动，显示出较强的黏膜下抬举高度和抬举时间。本发明所制备的水凝胶还具有较强的成膜性可以粘附在手术切除部位保护创面、减少创面出血、加速创面愈合。
Claims (9)
1.一种辅助ESD/EMR的可注射全降解无菌水凝胶及其制备方法与应用，其特征在于，所述的可降解水凝胶的制备方法为：将阴离子生物黏多糖溶解到生理盐水中溶解得到阴离子生物黏多糖溶液，然后将阳离子纳米晶体分散到阴离子生物黏多糖溶液中后调节pH值，滴加稳定剂及染色剂待滴加完全后反应即可得到可注射全降解无菌水凝胶。
2.根据权利要求1所述的制备方法，其特征在于，阴离子生物黏多糖包括但不限于羧甲基壳聚糖、羧甲基壳聚糖衍生物、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素衍生物、海藻酸钠、海藻酸钠衍生物、羧甲基淀粉、羧基甲淀粉钠、羧甲基淀粉衍生物、黄原胶、黄原胶衍生物、卡拉胶、卡拉胶及其衍生物中的任意一种；阴离子生物黏多糖溶解后的质量浓度为0.1-5％。
3.根据权利要求1所述的制备方法，其特征在于，阳离子纳米晶体包括但不限于生物活性玻璃、骨水泥、乳酸钙、硅酸钠镁锂、硅酸镁锂、硅酸钠、硅酸钾、硅酸铝钠、硅酸钙、硅酸镁、白磷钙石中任意一种及以上；阳离子纳米晶体与阴离子生物黏多糖的质量比为30∶1～1∶10；pH值调整为3-9。
4.根据权利要求1所述的制备方法，其特征在于，稳定剂包括但不限于聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮、丙烯酸树脂、聚氨酯中的任意一种；稳定剂的质量浓度为0.1-10％，稳定剂的滴加速度为0.1-20mL/min。
5.根据权利要求1所述的制备方法，其特征在于，阳离子纳米晶体的分散方式包括但不限于超声分散、机械搅拌分散、高速均质分散；反应温度为25-80℃；反应时间为2-36小时。
6.根据权利要求1所述的制备方法，其特征在于，染色剂包括但不限于靛蓝胭脂红、亚甲基蓝、亮蓝、台盼蓝、甲苯胺蓝。
7.根据权利要求1所述的制备方法，其特征在于，灭菌方式包括但不限于湿热灭菌、低温等离子体灭菌、辐照灭菌、流程灭菌、膜过滤、无菌生产。
8.权利要求1-7所述制备方法可制得可注射全降解无菌水凝胶。
9.权利要求1-7所述制备方法制得的可注射全降解无菌水凝胶作为一种辅助ESD/EMR切除的注射液在医疗器械、组织工程材料领域中的应用。
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