CN116603094A - 一种具有原位力学自增强特征的可注射生物降解水凝胶及其制备方法 - Google Patents
一种具有原位力学自增强特征的可注射生物降解水凝胶及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种具有原位力学自增强特征的可注射生物降解水凝胶及其制备方法，本发明采用KH560将含羟基的天然物质改性为修饰有环氧基团的含羟基的天然物质，用溶剂溶解两端含有琥珀酰亚胺基团的交联剂与修饰有环氧基团的含羟基的天然物质，记为组分A，用溶剂溶解含氨基的天然大分子记为组分B，将组分A与组分B分别填充入双筒注射器，混合挤出得到可注射水凝胶；本发明水凝胶具备可原位注射快速成胶、自增强、可降解、自愈合、良好的生物相容性、抗菌、止血等性能，适用于外科手术出血封堵、体内外炎症治疗、体内外组织损伤修复等领域。
Description
技术领域
本发明属于生物医用材料及水凝胶技术领域，涉及一种具有原位力学自增强特征的可注射生物降解水凝胶及其制备方法。
背景技术
日常的事故、疾病等因素影响着人类的安全健康，不可避免地会对人体组织造成不同程度的损害。虽然人体组织能够进行一定程度的自我修复，但其修复能力十分有限，而借助一些可注射材料促进组织的愈合是当下的前沿研究领域。可注射硅胶液体材料为美国早期推行应用的可注射材料，但硅胶类材料的生物相容性较差，在植入人体一段时间后会有极大概率产生排异反应，对病患健康造成衍生的安全隐患。
开发出一种能够适应人体和促进伤口修复且能完全降解避免二次手术伤痛的材料对于人体植入组织工程研究有重大意义。可注射水凝胶由于其类似生物组织的特性和良好的生物相容性受到了广泛的关注，其具有较强的可设计性，通过分子结构设计可制备出具有抗菌、消炎和止血等功能的多功能水凝胶。然而，现有可注射水凝胶的力学性能通常过硬或过弱，若凝胶力学强度过弱会难以发挥支撑伤口的作用，而凝胶若过强也会引起病患的不适。因此，如何在植入时使得凝胶能够快速成胶但较弱，保证病患舒适性；随后在一段时间内逐渐力学性能自增强与周围生物环境适配，实现支撑的功能十分关键。
在此发明前，我们设计了一种注射后可快速成胶并缓慢增强的水凝胶敷料(杨晋涛、袁静锋、郑司雨、张冬，一种注射后可快速成胶并缓慢增强的水凝胶敷料的制备方法，CN202110636898.1)。该发明利用氨基与醛基的席夫碱快速成胶反应和氨基与环氧的缓慢成胶反应构建原位自增强凝胶网络，但席夫碱凝胶体系在生物相容性方面有所欠缺，且目前席夫碱化合物大多具有疏水性及稳定性不佳的缺点。鉴于此，本发明整合了氨基与琥珀酰亚胺交联凝胶体系生物相容性较佳且应用范围更广等优势，提出了一种更具创新性的原位增强可注射凝胶网络制备方法。
发明内容
本发明的目的在于提供一种具有原位力学自增强特征的可注射生物降解水凝胶及其制备方法。
本发明的技术方案如下：
一种具有原位力学自增强特征的可注射生物降解水凝胶，主要由以下原料制成：两端含有琥珀酰亚胺基团的交联剂、KH560(γ-缩水甘油醚氧丙基三甲氧基硅烷)、含羟基的天然物质、含氨基的天然大分子；
其中，两端含有琥珀酰亚胺基团的交联剂包括但不限于：双端琥珀酰亚胺酯聚乙二醇(NHS-PEG-NHS)、琥珀酰亚胺-双硫键活性酯-琥珀酰亚胺(NHS-SS-NHS)、N,N'-碳酸二琥珀酰亚胺基中的一种或几种；
含羟基的天然物质包括但不限于：羟基磷灰石(HAP)、蒙脱土(MMT)、纳晶纤维素(CNC)中的一种或几种；
含氨基的天然大分子包括但不限于：壳聚糖(CS)、壳寡糖(COS)、聚赖氨酸(EPL)、明胶中的一种或几种。
一种具有原位力学自增强特征的可注射生物降解水凝胶的制备方法，包括如下步骤：
(1)将含羟基的天然物质加入溶剂溶解，得到含羟基的天然物质溶液；将KH560加入溶剂溶解，并调节pH至1～5，得到KH560溶液；将KH560溶液加入含羟基的天然物质溶液中，在25～40℃下搅拌反应6～12h，之后经后处理，得到修饰有环氧基团的含羟基的天然物质；
优选含羟基的天然物质与KH560的质量比为3～8：2～9；
溶解含羟基的天然物质的溶剂包括但不限于：水、乙醇、乙醇与水的混合溶剂、醋酸、异丙醇、丙酮中的一种或几种；溶剂与含羟基的天然物质的体积质量比为30～100(mL)：3～8(g)；优选在溶解含羟基的天然物质同时进行超声分散，超声时间为10～100min；
溶解KH560的溶剂包括但不限于：水、乙醇、乙醇与水的混合溶剂、醋酸、异丙醇、丙酮中的一种或几种；溶剂与KH560的体积质量比为20～100(mL)：2～9(g)；KH560溶解后pH的调节使用冰醋酸；
优选KH560溶液加入含羟基的天然物质溶液后进行超声分散，超声时间为10～100min；
具体的后处理方法为：反应结束后，对混合体系进行离心，洗涤，干燥，即得修饰有环氧基团的含羟基的天然物质；其中，离心速度设置为3000～9000rpm，离心时间设置为5～10min；洗涤次数为3～6次，洗涤液包括但不限于：乙醇、水、乙醇和水的混合溶剂、醋酸、异丙醇、丙酮中的一种或几种；烘干温度为60～90℃，烘干时间为6～24h；
(2)将两端含有琥珀酰亚胺基团的交联剂、步骤(1)所得修饰有环氧基团的含羟基的天然物质加入溶剂中混合均匀，记作组分A；将含氨基的天然大分子用溶剂溶解，记作组分B；将组分A、组分B混合挤出，即为所述的具有原位力学自增强特征的可注射生物降解水凝胶；
优选两端含有琥珀酰亚胺基团的交联剂、修饰有环氧基团的含羟基的天然物质与含氨基的天然大分子的投料比例为100～800(μL)：10～20(mg)：30～120(mg)；
优选组分A中两端含有琥珀酰亚胺基团的交联剂与修饰有环氧基团的含羟基的天然物质合计浓度为6～20wt％；组分A中的溶剂包括但不限于：水、PBS溶液、乙醇中的一种或几种；
优选组分B中含氨基的天然大分子的浓度为6～20wt％；组分B中的溶剂包括但不限于：水、PBS溶液、乙醇中的一种或几种；
优选将组分A、组分B分别填入双筒注射器中混合挤出，注射成胶的温度为25～40℃。
本发明的有益效果在于：
1、可注射凝胶可在注射后的几秒内快速成胶。
2、原料皆使用天然材料，生物相容性好、生物降解性能优秀。
3、制备的可注射凝胶具有抗菌、止血、自愈合、促进组织修复等性能。
4、制备的可注射凝胶具有双重成胶机制，具体的，凝胶由双筒注射器挤出，一个料筒中含有含氨基的天然大分子，另一个料筒中含有两端含有琥珀酰亚胺基团的交联剂和修饰有环氧基团的含羟基的天然物质。通过双筒混合注射器混合挤出后，含氨基的天然大分子中的氨基会与两端含有琥珀酰亚胺基团的交联剂中的琥珀酰亚胺基团进行快反应形成凝胶网络，起到短时间内快速支撑组织缺损空腔的作用，同时环氧基团修饰的含羟基的天然物质中的环氧基团会与体系中剩余的氨基反应，缓慢地增强凝胶网络，达到凝胶原位自增强的效果。弱网络快速交联之后强网络缓慢进行交联，以给予人体组织损伤部位适应植入物模量的时间。
5、制备的可注射凝胶可广泛应用于外科手术出血封堵、体内外炎症治疗、体内外组织损伤修复。
附图说明
图1实施例1中可注射凝胶的自增强性能。
图2实施例1中可注射凝胶的生物相容性。
图3实施例1中可注射凝胶的抗菌性能。
图4实施例1中可注射凝胶的止血性能。
具体实施方式
下面通过具体实施例进一步描述本发明，但本发明的保护范围并不仅限于此。
实施例1凝胶的制备
用60ml乙醇超声溶解5g的HAP，超声时间为30min。同时用100mL水与乙醇的混合溶液(水：乙醇＝1：3，体积比)充分溶解2g的KH560。用冰醋酸调解KH560溶液的pH至4后加入HAP悬浮液，再次超声30min。将悬浮液于25℃下搅拌8h。对产物进行离心(9000rpm，7min)，乙醇洗涤产物三次后再次离心，处理过后的产物于80℃真空烘箱中烘干待用。
用1ml的浓度为0.99％的PBS溶液(氯化钠：磷酸氢二钠：磷酸二氢钠＝85：13.22：0.6，质量比)溶解400μL的NHS-PEG-NHS与20mg的修饰有环氧基团的羟基磷灰石(mHAP)，记为A组分；用1ml的PBS溶液溶解100mg的CS，记为组分B。将A，B组分分别填入双筒注射器中，注射于作用部位，快速成胶。
实施例2凝胶的制备
用60ml乙醇超声溶解6g的CNC，超声时间为30min。同时用100mL水与乙醇的混合溶液(水：乙醇＝2：3)充分溶解2.5g的KH560。用冰醋酸调解KH560溶液的pH至5后加入CNC悬浮液，再次超声30min。将悬浮液于25℃下搅拌8h。对产物进行离心(9000rpm，7min)，乙醇洗涤产物三次后再次离心，处理过后的产物于80℃真空烘箱中烘干待用。
用1ml的浓度为0.99％的PBS溶液(氯化钠：磷酸氢二钠：磷酸二氢钠＝85：13.22：0.6，质量比)溶解300μL的NHS-SS-NHS与20mg的修饰有环氧基团的CNC(mCNC)，记为A组分；用1ml的PBS溶液溶解100mg的COS，记为组分B。将A，B组分分别填入双筒注射器中，注射于作用部位，快速成胶。
实施例3凝胶的制备
用60ml乙醇超声溶解5g的HAP，超声时间为40min。同时用100mL乙醇溶液充分溶解2g的KH560。用冰醋酸调解KH560溶液的pH至3.5后加入HAP悬浮液，再次超声30min。将悬浮液于25℃下搅拌8h。对产物进行离心(9000rpm，7min)，乙醇洗涤产物三次后再次离心，处理过后的产物于80℃真空烘箱中烘干待用。
用1ml的浓度为0.99％的PBS溶液(氯化钠：磷酸氢二钠：磷酸二氢钠＝85：13.22：0.6，质量比)溶解450μL的NHS-PEG-NHS与20mg的mHAP，记为A组分；用1ml的PBS溶液溶解100mg的明胶，记为组分B。将A，B组分分别填入双筒注射器中，注射于作用部位，快速成胶。
实施例4凝胶的制备
用80ml乙醇超声溶解5g的HAP，超声时间为30min。同时用100mL水与乙醇的混合溶液(水：乙醇＝1：1)充分溶解2g的KH560。用冰醋酸调解KH560溶液的pH至4后加入HAP悬浮液，再次超声30min。将悬浮液于25℃下搅拌8h。对产物进行离心，乙醇洗涤产物三次后再次离心，处理过后的产物于80℃真空烘箱中烘干待用。
用1ml的去离子水溶解450μL的NHS-SS-NHS与20mg的mHAP，记为A组分；用1ml的去离子水溶解100mg的EPL，记为组分B。将A，B组分分别填入双筒注射器中，注射于作用部位，快速成胶。
实施例5可注射凝胶的自增强性能测试
用高低温双立柱试验机对实施例1中的水凝胶进行压缩测试。由于快速的氨基与琥珀酰亚胺反应与缓慢的环氧基团与氨基反应的双重凝胶交联机制，实施例1中水凝胶在注射后的168h内模量不断上升(图1)。
实施例6可注射凝胶的生物相容性测试
将实施例1中水凝胶在PBS溶液中完全溶解。然后将水凝胶样品与含有10％胎牛血清和1％青霉素的RPMI 1640培养基在37℃下共培养。分别将于第1、第2、第3天的浸提液用细胞培养液稀释至50和100mg/mL。同时，将颅骨成骨细胞(COB)加入孔板，并在细胞培养箱中培养24小时。用不同浓度的水凝胶提取物替代细胞悬液，在细胞培养箱中继续培养24h。然后，再次取出培养基，用的MTT溶液代替。随后，检测溶液的吸光度。通过与对照组正常增殖细胞密度进行比较，获得了实验组的细胞活力。同样，将COB加入孔板中，与水凝胶提取物一起培养。使用多聚甲醛溶液，丢弃培养基后，室温固定20min。用PBS冲洗多次后，每孔进行活/死染色。37℃下培养一段时间后用荧光显微镜进行观察。可见(图2)第一天时COB细胞的密度分别为～107.5％(50mg/mL)和～112.4％(100mg/mL)，到了第三天则达到了近124.5％(50mg/mL)和125.5％(100mg/mL)，体现出实施例1中水凝胶具有优良的生物相容性和促进细胞增殖的性能。
实施例7可注射凝胶的抗菌性能测试
用大肠杆菌(革兰氏阴性)和金黄色葡萄球菌(革兰氏阳性)检测实施例1中水凝胶的杀菌性能。首先，将大肠杆菌和金黄色葡萄球菌在琼脂培养基上37℃培养过夜。然后接种单个菌落LB液体培养基，振荡培养过夜。用LB液体培养基将细菌溶液稀释至标准浓度。将预灭菌的水凝胶放置在含有标准细菌溶液的孔板中，并在恒温气体浴中共培养。采用LIVE/DEAD背光生存试剂盒对24h(大肠杆菌)和12h(金黄色葡萄球菌)进行染色观察。用荧光显微镜观察了粘附在水凝胶表面的活/死细菌的形态。结果如图3所示，在培养一定时间过后，两组均有红色死菌可被观察到。由于CS本身具有抗菌性能，实施例1中的水凝胶对大肠杆菌和金黄色葡萄球菌均有一定程度的杀菌能力。
实施例8可注射凝胶的止血性能测试
通过建立SD大鼠肝出血模型，测试实施例1所述水凝胶的体内止血能力。切开大鼠的腹部，暴露肝脏。用手术刀切开大鼠肝脏上的两个相同的伤口，立即将水凝胶注射到其中一个出血部位，对照组不进行治疗。分别用滤纸在一定时间内吸取从伤口流出的血液。滤纸重量的变化记作伤口出血量。从图4可看出在有实施例1所述水凝胶注射的伤口拥有较小的出血量，体现其良好止血性能。
Claims (10)
1.一种具有原位力学自增强特征的可注射生物降解水凝胶，其特征在于，主要由以下原料制成：两端含有琥珀酰亚胺基团的交联剂、KH560、含羟基的天然物质、含氨基的天然大分子；
其中，两端含有琥珀酰亚胺基团的交联剂选自：双端琥珀酰亚胺酯聚乙二醇、琥珀酰亚胺-双硫键活性酯-琥珀酰亚胺、N,N'-碳酸二琥珀酰亚胺基中的一种或几种；
含羟基的天然物质选自：羟基磷灰石、蒙脱土、纳晶纤维素中的一种或几种；
含氨基的天然大分子选自：壳聚糖、壳寡糖、聚赖氨酸、明胶中的一种或几种。
2.如权利要求1所述的具有原位力学自增强特征的可注射生物降解水凝胶的制备方法，其特征在于，包括如下步骤：
(1)将含羟基的天然物质加入溶剂溶解，得到含羟基的天然物质溶液；将KH560加入溶剂溶解，并调节pH至1～5，得到KH560溶液；将KH560溶液加入含羟基的天然物质溶液中，在25～40℃下搅拌反应6～12h，之后经后处理，得到修饰有环氧基团的含羟基的天然物质；
(2)将两端含有琥珀酰亚胺基团的交联剂、步骤(1)所得修饰有环氧基团的含羟基的天然物质加入溶剂中混合均匀，记作组分A；将含氨基的天然大分子用溶剂溶解，记作组分B；将组分A、组分B混合挤出，即为所述的具有原位力学自增强特征的可注射生物降解水凝胶。
3.如权利要求2所述的制备方法，其特征在于，步骤(1)中，含羟基的天然物质与KH560的质量比为3～8：2～9。
4.如权利要求2所述的制备方法，其特征在于，步骤(1)中，溶解含羟基的天然物质的溶剂选自：水、乙醇、乙醇与水的混合溶剂、醋酸、异丙醇、丙酮中的一种或几种；溶剂与含羟基的天然物质的体积质量比为30～100(mL)：3～8(g)。
5.如权利要求2所述的制备方法，其特征在于，步骤(1)中，溶解KH560的溶剂选自：水、乙醇、乙醇与水的混合溶剂、醋酸、异丙醇、丙酮中的一种或几种；溶剂与KH560的体积质量比为20～100(mL)：2～9(g)。
6.如权利要求2所述的制备方法，其特征在于，步骤(1)中，后处理方法为：反应结束后，对混合体系进行离心，洗涤，干燥，即得修饰有环氧基团的含羟基的天然物质；其中，离心速度设置为3000～9000rpm，离心时间设置为5～10min；洗涤次数为3～6次，洗涤液选自：乙醇、水、乙醇和水的混合溶剂、醋酸、异丙醇、丙酮中的一种或几种；烘干温度为60～90℃，烘干时间为6～24h。
7.如权利要求2所述的制备方法，其特征在于，步骤(2)中，两端含有琥珀酰亚胺基团的交联剂、修饰有环氧基团的含羟基的天然物质与含氨基的天然大分子的投料比例为100～800(μL)：10～20(mg)：30～120(mg)。
8.如权利要求2所述的制备方法，其特征在于，步骤(2)中，组分A中两端含有琥珀酰亚胺基团的交联剂与修饰有环氧基团的含羟基的天然物质合计浓度为6～20wt％；组分A中的溶剂选自：水、PBS溶液、乙醇中的一种或几种。
9.如权利要求2所述的制备方法，其特征在于，步骤(2)中，组分B中含氨基的天然大分子的浓度为6～20wt％；组分B中的溶剂选自：水、PBS溶液、乙醇中的一种或几种。
10.如权利要求1所述的具有原位力学自增强特征的可注射生物降解水凝胶在外科手术出血封堵、体内外炎症治疗、体内外组织损伤修复中的应用。
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