CN105504316B - 一种透明质酸‑甲基纤维素复合凝胶的活性酯交联方法 - Google Patents
一种透明质酸‑甲基纤维素复合凝胶的活性酯交联方法 Download PDFInfo
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Abstract
本发明属于生物医用材料及组织工程技术领域，具体涉及一种透明质酸‑甲基纤维素复合凝胶的活性酯交联方法。聚乙二醇琥珀酰亚胺琥珀酸酐和去乙酰化透明质酸反应得到交联活性酯，所述交联活性酯与甲基纤维素交联，形成透明质酸‑甲基纤维素复合凝胶。本发明所述复合凝胶具有更好的注射性和流变学性能，有利于受损中枢神经的微创修复，减少了对细胞的刺激，具有更好的细胞相容性。
Description
技术领域
本发明属于生物医用材料及组织工程技术领域，具体涉及一种透明质酸-甲基纤维素复合凝胶的活性酯交联方法。
背景技术
透明质酸(Hyaluronic Acid，HA)是一种线性多糖，广泛存在于细胞外基质中，具有优异的非抗原性和细胞相容性等，同时其溶液的高粘弹性使之在临床医学领域应用中具有良好的分离、保护、充填作用，是一种备受青睐的天然高分子材料。当用于体内的受损神经修复时，透明质酸存在水溶性过高、不能维持正常的体内形态以及降解速度过快等不足，因此常与其它天然或人工合成材料结合使用。
通过复合剪切自稀的透明质酸与热逆性的甲基纤维素(Methyl Cellulose，MC)可以形成一种快速凝胶化的可注射凝胶——透明质酸-甲基纤维素复合凝胶(以下简称HAMC)。HAMC在注射前是一种溶胶，在注射后由于体内温度相对于室温温度的升高，凝胶强度增强。HAMC复合物相比于甲基纤维素单独存在时拥有更低的凝胶化温度和较小的触变环，这些影响归因于透明质酸的阴离子羧酸盐基团。除了可以快速凝胶化以外，HAMC是非细胞粘附的，具有可降解性，并在鞘内空间具备生物相容性。
研究结果表明，相对于透明质酸自身，经过了化学修饰后得到的透明质酸衍生物，其化学稳定性将会提高，抗降解性能也将被改善，在动物体内的半衰期有所延长，但其生物相容性以及生物活性不会有大的改变。将聚乙二醇分子进行酯化，再使透明质酸在碱性环境中经乙酰化处理产生氨基，二者于室温下共价反应即可产生透明质酸-聚乙二醇衍生物(HA-PEG)。对该衍生物材料进行流变性能的测试，结果显示，改性后的透明质酸衍生物材料属于非牛顿流体，具有高聚物的粘弹性，符合医用生物材料要求。
发明内容
本发明提供了一种透明质酸-甲基纤维素复合凝胶的活性酯交联方法，具体技术方案如下：
一种透明质酸-甲基纤维素复合凝胶的活性酯交联方法：聚乙二醇琥珀酰亚胺琥珀酸酐和去乙酰化透明质酸反应得到交联活性酯，所述交联活性酯与甲基纤维素交联，形成透明质酸-甲基纤维素复合凝胶。
具体操作为：
(一)制备聚乙二醇琥珀酰亚胺琥珀酸酐(PEG-SS)：
(1)将分子量为6000的聚乙二醇，溶解于二氧六环中，以吡啶作为催化剂，加入琥珀酸酐，加热状态下回流搅拌，反应完毕后冷却，在快速搅拌下滴加无水乙醚至沉淀不再产生，之后置于冰浴中搅拌，过滤后将沉淀充分溶解于二氯甲烷中，再次滴加无水乙醚至沉淀不再产生，冰浴搅拌，将过滤得到的沉淀真空干燥；
(2)将步骤(1)得到的沉淀与N-羟基琥珀亚酰胺溶于含有二环己基碳化二亚胺(DCC)的N,N-二甲基甲酰胺(DMF)中，搅拌12h后，在快速搅拌下滴加无水乙醚至沉淀不再产生，之后置于冰浴中搅拌，过滤后将沉淀充分溶解于二氯甲烷中，再次滴加无水乙醚至沉淀不再产生，冰浴搅拌，过滤，用无水乙醚多次洗涤，将沉淀进行真空干燥，得到所述的聚乙二醇琥珀酰亚胺琥珀酸酐。
优选地，聚乙二醇、琥珀酸酐、吡啶、N-羟基琥珀亚酰胺、二环己基碳化二亚胺的摩尔比依次为1：1：0.695：2.453：2.563；聚乙二醇与各溶剂的质量体积比为聚乙二醇：二氧六环：步骤(1)中所用的二氯甲烷：步骤(2)中所用的二氯甲烷：N,N-二甲基甲酰胺＝0.48g：20mL：30mL：30mL：1mL。
优选地，步骤(1)中，回流搅拌时的温度为100℃，搅拌时间为4h；步骤(1)和步骤(2)中，两次冰浴搅拌的时间均为：首次搅拌30min，第二次搅拌15min。
(二)制备去乙酰化透明质酸：
向透明质酸的水溶液中滴加氢氧化钠溶液，缓慢搅拌，使透明质酸与氢氧化钠溶液充分接触，反应2h，得到去乙酰化透明质酸。
优选地，所述透明质酸水溶液的浓度为9.8×10-3mol/L，氢氧化钠溶液的浓度为1mol/L；氢氧化钠溶液的添加量以调节pH值至12.65±0.05为准。
(三)透明质酸-甲基纤维素复合凝胶的活性酯交联方法：
(1)将预先配制好的第一份人工脑脊液加热至90℃，加入一定量的氯化钠、磷酸钠和甲基纤维素，搅拌均匀后再加入等体积的第二份人工脑脊液，-4℃冰盐浴中搅拌40min，得到甲基纤维素溶液，4℃冷藏过夜；
(2)将聚乙二醇琥珀酰亚胺琥珀酸酐配制成水溶液，加入去乙酰化透明质酸溶液中，搅拌使溶液混合均匀，室温下反应12h，再向溶液中加入质量分数为95％的乙醇至沉淀产生完全，过滤收集沉淀，用乙醇洗涤沉淀3次以上，真空干燥，得到交联活性酯；
(3)称取一定量的交联活性酯加入甲基纤维素溶液中，调节pH至7.4，搅拌2h以上使交联活性酯充分分散且溶解均匀，4℃冷藏过夜，并对其冷冻干燥，得到透明质酸-甲基纤维素复合凝胶。
优选地，氯化钠、磷酸钠、甲基纤维素、去乙酰化透明质酸的质量之比依次为(2～4)：(0～0.05)：7：1。
优选地，步骤(2)中，聚乙二醇琥珀酰亚胺琥珀酸酐水溶液的浓度为1×10-3mol/L，与去乙酰化透明质酸溶液的体积比为1：10。
如上所述方法制备得到的透明质酸-甲基纤维素复合凝胶。
本发明的有益效果为：
(1)本发明中，聚乙二醇在琥珀酸酐和N-羟基琥珀酰亚胺作用下形成聚乙二醇琥珀酰亚胺琥珀酸酐，然后与去乙酰化透明质酸溶液反应得到交联活性酯，交联活性酯与甲基纤维素反应得到终产物——复合凝胶。所述复合凝胶保持了原透明质酸-甲基纤维素凝胶的空间多孔结构、良好的力学性能和生物相容性，且从透明质酸分子的角度出发，通过结构改造降低了其降解速率，延长了体内存留时间，因此复合凝胶中原本用于延缓降解的甲基纤维素成分比例得以减少，使凝胶具有更好的注射性和流变学性能，有利于受损中枢神经的微创修复。
(2)本发明在对透明质酸-甲基纤维素复合凝胶成胶温度的调控中，尝试改变单一的氯化钠添加剂形式，加入少量磷酸钠以减少氯化钠的用量。该方法使复合凝胶保持了体温下成胶能力，并具有更接近人体体液的渗透压环境，减少对细胞的刺激，获得更好的细胞相容性。
附图说明
图1为实施例1中复合凝胶在扫描电镜下的微观形貌图。
图2为实施例1中复合凝胶在37℃下的G’(ω)和G”(ω)曲线图。
图3为实施例1中复合凝胶在3周内的降解情况曲线图。
图4为不同交联方式下添加3.75wt％NaCl的复合凝胶在3周内的降解情况曲线图。
图5为不同交联方式下添加4wt％NaCl的复合凝胶在3周内的降解情况曲线图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步的说明。
实施例1
(一)制备聚乙二醇琥珀酰亚胺琥珀酸酐(PEG-SS)：
(1)将2.4g聚乙二醇(分子量为6000)溶解于100mL二氧六环中，加入0.022g吡啶作为催化剂，再加入0.04g琥珀酸酐，在100℃下回流搅拌4h，反应完毕后冷却，在快速搅拌下滴加无水乙醚至沉淀不再产生，之后置于冰浴中搅拌30min，过滤后将沉淀充分溶解于150mL二氯甲烷中，再次滴加无水乙醚至沉淀不再产生，冰浴搅拌15min，将过滤得到的沉淀真空干燥；
(2)将步骤(1)得到的沉淀与0.1129g N-羟基琥珀亚酰胺溶于含有0.2114g二环己基碳化二亚胺的5mL N,N-二甲基甲酰胺中，搅拌12h后，在快速搅拌下滴加无水乙醚至沉淀不再产生，之后置于冰浴中搅拌30min，过滤后将沉淀充分溶解于150mL二氯甲烷中，再次滴加无水乙醚至沉淀不再产生，冰浴搅拌15min，过滤，用无水乙醚多次洗涤，将沉淀进行真空干燥，得到聚乙二醇琥珀酰亚胺琥珀酸酐。
(二)制备去乙酰化透明质酸：
向9.8×10-3mol/L的透明质酸水溶液中滴加1mol/L的NaOH溶液，利用pH计检测使溶液pH值为12.65±0.05，缓慢搅拌，使透明质酸与氢氧化钠溶液充分接触，反应2h，得到去乙酰化透明质酸。
(三)透明质酸-甲基纤维素复合凝胶的活性酯交联方法：
(1)取预先配制好的第一份人工脑脊液15mL，加热至90℃，加入0.6g氯化钠、0.015g磷酸钠和2.1g甲基纤维素，搅拌均匀后再加入15mL第二份人工脑脊液，-4℃冰盐浴中搅拌40min，得到甲基纤维素溶液，4℃冷藏过夜；
(2)将聚乙二醇琥珀酰亚胺琥珀酸酐配制成浓度为1×10-3mol/L的水溶液，取2mL加入20mL去乙酰化透明质酸溶液中，搅拌使溶液混合均匀，室温下反应12h，再向溶液中加入质量分数为95％的乙醇至沉淀产生完全，过滤收集沉淀，用乙醇洗涤沉淀3次以上，真空干燥，得到交联活性酯；
(3)称取0.3g交联活性酯加入30mL甲基纤维素溶液中，调节pH至7.4，搅拌2h以上使交联活性酯充分分散且溶解均匀，4℃冷藏过夜，并对其冷冻干燥，得到透明质酸-甲基纤维素复合凝胶。
复合凝胶的微观形貌如图1所示，微米尺度下本发明所述的复合凝胶呈现出多孔结构，且孔隙间有连通性，孔径范围在40μm～60μm。
图2给出了未冷冻干燥的复合凝胶在37℃下的流变测试结果。从图中可以看出，随着频率的增大，凝胶的存储模量G’和损失模量G”均逐渐增大，在对数坐标中满足一定的线性关系，此流变学特征与脑组织相似，说明复合凝胶属于假塑性流体，具备可注射性；G’始终大于G”，说明凝胶在37℃时具有类固体性质，体内成胶后具有一定机械强度。升温过程显示复合凝胶的成胶温度为24.3℃，满足体温下成胶的需求。
体外降解实验中，复合凝胶在3周内的降解率变化如图3所示，从第7天起凝胶的降解率基本稳定在60％，说明在降解速度的控制上，采用交联活性酯为甲基纤维素含量的降低(本例中甲基纤维素含量为7wt％)起到了一定的弥补作用(不加交联剂或仅用未活化聚乙二醇时，维持同等降解率水平一般需要9～11wt％的甲基纤维素)。
实施例2
步骤(三)的第(1)步中，氯化钠加入量为1.125g，未加入磷酸钠，其他操作均与实施例1相同。
图4为本实施例中复合凝胶3周内的体外降解率变化情况(PEG-SS曲线)，凝胶在第1周降解较快，之后降解速度放缓并维持在50～60％的范围内。对比未使用交联剂(Pure曲线)和仅用未活化聚乙二醇交联(PEG曲线)的凝胶，从长期来看，通过交联活性酯进行交联，其降解率明显更低，存留情况较好，有利于所负载的活性分子的持续释放。
实施例3
步骤(三)的第(1)步中，氯化钠加入量为1.2g，其他操作均与实施例2相同。
图5为本实施例中复合凝胶3周内的体外降解率变化情况(PEG-SS曲线)，第3周凝胶的最终降解率仍低于60％，存留情况优于未使用交联剂(Pure曲线)和仅用未活化聚乙二醇交联(PEG曲线)的凝胶。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (10)
1.一种透明质酸-甲基纤维素复合凝胶的活性酯交联方法，其特征在于，聚乙二醇琥珀酰亚胺琥珀酸酐和去乙酰化透明质酸反应得到交联活性酯，所述交联活性酯与甲基纤维素交联，形成透明质酸-甲基纤维素复合凝胶。
2.根据权利要求1所述的方法，其特征在于，具体操作为：
(1)将预先配制好的第一份人工脑脊液加热至90℃，加入一定量的氯化钠、磷酸钠和甲基纤维素，搅拌均匀后再加入等体积的第二份人工脑脊液，-4℃冰盐浴中搅拌40min，得到甲基纤维素溶液，4℃冷藏过夜；
(2)将聚乙二醇琥珀酰亚胺琥珀酸酐配制成水溶液，加入去乙酰化透明质酸溶液中，搅拌使溶液混合均匀，室温下反应12h，再向溶液中加入质量分数为95％的乙醇至沉淀产生完全，过滤收集沉淀，用乙醇洗涤沉淀3次以上，真空干燥，得到交联活性酯；
(3)称取一定量的交联活性酯加入甲基纤维素溶液中，调节pH至7.4，搅拌2h以上使交联活性酯充分分散且溶解均匀，4℃冷藏过夜，并对其冷冻干燥，得到透明质酸-甲基纤维素复合凝胶。
3.根据权利要求2所述的方法，其特征在于，氯化钠、磷酸钠、甲基纤维素、去乙酰化透明质酸的质量之比依次为(2～4)：(0～0.05)：7：1。
4.根据权利要求2所述的方法，其特征在于，步骤(2)中，聚乙二醇琥珀酰亚胺琥珀酸酐水溶液的浓度为1×10-3mol/L，与去乙酰化透明质酸溶液的体积比为1：10。
5.根据权利要求1所述的方法，其特征在于，所述聚乙二醇琥珀酰亚胺琥珀酸酐的制备方法为：
(1)将分子量为6000的聚乙二醇，溶解于二氧六环中，以吡啶作为催化剂，加入琥珀酸酐，加热状态下回流搅拌，反应完毕后冷却，在快速搅拌下滴加无水乙醚至沉淀不再产生，之后置于冰浴中搅拌，过滤后将沉淀充分溶解于二氯甲烷中，再次滴加无水乙醚至沉淀不再产生，冰浴搅拌，将过滤得到的沉淀真空干燥；
(2)将步骤(1)得到的沉淀与N-羟基琥珀亚酰胺溶于含有二环己基碳化二亚胺的N,N-二甲基甲酰胺中，搅拌12h后，在快速搅拌下滴加无水乙醚至沉淀不再产生，之后置于冰浴中搅拌，过滤后将沉淀充分溶解于二氯甲烷中，再次滴加无水乙醚至沉淀不再产生，冰浴搅拌，过滤，用无水乙醚多次洗涤，将沉淀进行真空干燥，得到所述的聚乙二醇琥珀酰亚胺琥珀酸酐。
6.根据权利要求5所述的方法，其特征在于，聚乙二醇、琥珀酸酐、吡啶、N-羟基琥珀亚酰胺、二环己基碳化二亚胺的摩尔比依次为1：1：0.695：2.453：2.563；聚乙二醇与各溶剂的质量体积比为聚乙二醇：二氧六环：步骤(1)中所用的二氯甲烷：步骤(2)中所用的二氯甲烷：N,N-二甲基甲酰胺＝0.48g：20mL：30mL：30mL：1mL。
7.根据权利要求5所述的方法，其特征在于，步骤(1)中，回流搅拌时的温度为100℃，搅拌时间为4h；步骤(1)和步骤(2)中，两次冰浴搅拌的时间均为：首次搅拌30min，第二次搅拌15min。
8.根据权利要求1所述的方法，其特征在于，所述去乙酰化透明质酸的制备方法为：向透明质酸的水溶液中滴加氢氧化钠溶液，缓慢搅拌，使透明质酸与氢氧化钠溶液充分接触，反应2h，得到去乙酰化透明质酸。
9.根据权利要求8所述的方法，其特征在于，所述透明质酸水溶液的浓度为9.8×10- 3mol/L，氢氧化钠溶液的浓度为1mol/L；氢氧化钠溶液的添加量以调节pH值至12.65±0.05为准。
10.权利要求1-9任一项所述方法制备得到的透明质酸-甲基纤维素复合凝胶。
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| CN105879127A (zh) * | 2016-04-25 | 2016-08-24 | 东莞市联洲知识产权运营管理有限公司 | 一种术后防粘连材料的制备方法 |
| CN108892411A (zh) * | 2018-07-11 | 2018-11-27 | 俞小峰 | 一种混凝土防水剂的制备方法 |
| CN109734935A (zh) * | 2018-12-29 | 2019-05-10 | 广西紫荆生物科技有限公司 | 一种生物医用可注射凝胶材料及其制备方法和用途 |
| CN111956866B (zh) * | 2020-08-14 | 2022-09-20 | 南方科技大学 | 一种用于纤维环修复的复合水凝胶及其制备方法和应用 |
| CN114028610B (zh) * | 2021-10-26 | 2022-10-25 | 北京诺康达医药科技股份有限公司 | 一种亲水性注射型皮肤填充组合物及其制备方法与应用 |
| CN115161792B (zh) * | 2022-06-29 | 2024-04-05 | 邦特云纤(青岛)新材料科技有限公司 | 一种耐水洗轻质保暖的气凝胶再生纤维素纤维及其制备方法 |
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| CN101528780A (zh) * | 2006-09-11 | 2009-09-09 | 费迪亚医药股份公司 | 通过“点击化学”交联而获得的透明质酸衍生物 |
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