CN116970102A - 一种自收缩水凝胶及其制备方法和应用 - Google Patents
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Abstract
本发明提供一种自收缩水凝胶及其制备方法和应用,其中,改性壳聚糖衍生物具有式I的结构。本发明中对壳聚糖进行改性后,有效提升了壳聚糖的溶解度,使其在PBS或超纯水中即能分散均匀,拓宽了应用前景,改性壳聚糖衍生物在生化功能上更适宜于加速创面修复。本发明中含改性壳聚糖衍生物的自收缩水凝胶对温度保持敏感,随温度升高可以产生形变收缩,应用到创面可对创面边缘组织产生向心作用力,有利于创面愈合。
Description
技术领域
本发明属于生物医用材料技术领域,尤其涉及一种自收缩水凝胶及其制备方法和应用。
背景技术
各种伤口,包括急性术后伤口、外伤、烧伤和由糖尿病或循环障碍引起的慢性伤口,一直是临床关注的焦点,对患者生活质量及社会资源分配等都产生了重大影响。伤口愈合是一个涉及止血、炎症、增殖和组织重塑等阶段的复杂生理过程。很多敷料的功能也是紧紧围绕这几个阶段进行设计开发,如增强吸收组织渗出液、有效抗细菌感染、消除炎症因子等。大量研究表明,机械应力刺激对机体组织的生长和发育必不可少。现有创面敷料的开发多侧重于生化层面的考量,但很少有关注通过敷料向创面组织提供积极应力刺激从而加速愈合的。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明第一个方面提出一种改性壳聚糖衍生物,具备温敏特性和光交联特性。
本发明的第二个方面提出了一种所述改性壳聚糖衍生物的制备方法。
本发明的第三个方面提出了一种包含所述改性壳聚糖衍生物的自收缩水凝胶。
本发明的第四个方面提出了一种所述自收缩水凝胶的制备方法。
本发明的第五个方面提出了一种所述改性壳聚糖衍生物和/或所述自收缩水凝胶的应用。
根据本发明的第一个方面,提出了式I改性壳聚糖衍生物:
其中,DD为脱乙酰度,所述脱乙酰度为30%~99%;优选为50%~95%。
在本发明的一些实施方式中,式I中,的取代度为1.0~2.0,优选为1.1~1.9;优选地,/>的取代度为0.1~0.5,优选为0.1~0.3;进一步优选地,的取代度为0.1~0.5,优选为0.1~0.3。
在本发明的一些优选的实施方式中,所述改性壳聚糖衍生物的分子量为100000~300000。
根据本发明的第二个方面,提出了一种式I的改性壳聚糖衍生物的制备方法,包括以下步骤:
S1:脱乙酰壳聚糖碱化后与1,2-环氧丁烷反应,制得羟丁基壳聚糖;
S2:羟丁基壳聚糖溶解后再加入不饱和酸酐反应,制得双键羟丁基壳聚糖;
S3:双键羟丁基壳聚糖溶解后与精氨酸反应,制得所述的式I改性壳聚糖衍生物。
在本发明的一些实施方式中,S1中,所述脱乙酰壳聚糖与所述1,2-环氧丁烷的质量体积比为1:(10~30)g/mL。
在本发明的一些优选的实施方式中,S2中,所述羟丁基壳聚糖与所述不饱和酸酐的质量比为2:(3~10)。
在本发明的一些更优选的实施方式中,S3中,所述双键羟丁基壳聚糖与所述精氨酸的质量比为2:(5~15)。
在本发明的一些更优选的实施方式中,所述不饱和酸酐包括甲基丙烯酸酐、丙烯酸酐或马来酸酐的至少一种。
在本发明的一些更优选的实施方式中,S3中所述反应还包括使用N-羟基琥珀酰亚胺(NHS)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)作为活化剂。
在本发明的一些更优选的实施方式中,S2中,所述反应的时间为12h~24h。
在本发明的一些更优选的实施方式中,S3中,所述反应的时间为15h~48h。
在本发明的一些更优选的实施方式中,所述制备方法还包括对每个步骤产物进行纯化处理的步骤;优选的,S1中还包括对反应产物调节pH至中性、过滤、醇沉、干燥;进一步优选地,S2中还包括对反应产物调节pH至中性、透析3~5天、冻干;更进一步优选的,S3中还包括对反应产物透析3~5天、冻干。
根据本发明的第三个方面,提出了一种自收缩水凝胶,包括所述的改性壳聚糖衍生物。
在本发明的一些实施方式中,所述改性壳聚糖衍生物的质量浓度为3%~10%。
根据本发明的第四个方面,提出了一种自收缩水凝胶的制备方法,包括以下步骤:向改性壳聚糖衍生物溶液加入水溶性光交联剂,光交联后制得所述自收缩水凝胶。
根据本发明的第五个方面,提出了一种所述改性壳聚糖衍生物和/或所述自收缩水凝胶在制备创面修复材料中的应用。
本发明的有益效果为:
1.本发明中对壳聚糖进行改性后,有效提升了壳聚糖的溶解度,使其在PBS或超纯水中即能分散均匀,拓宽了应用前景,改性壳聚糖衍生物在生化功能上更适宜于加速创面修复。
2.本发明中含改性壳聚糖衍生物的自收缩水凝胶,具备温度敏感和紫外敏感的特性,光交联前呈溶胶状,可无缝与各种不规则伤口贴合紧密,光交联后使得体系的强度和黏附性进一步增强,对创面进行有效封闭的同时,与机体接触后,体温条件下可促发水凝胶收缩形变,对创面边缘组织产生向心牵引作用,主动收缩伤口,从物理层面促进愈合。精氨酸基团的引入,一方面增强了体系对组织的黏附作用,另一方面精氨酸作为机体内源性组分,可加速血管再生,从生化层面促进愈合。
3.本发明中含改性壳聚糖衍生物的自收缩水凝胶对温度保持敏感,随温度升高可以产生形变收缩,应用到创面可对创面边缘组织产生向心作用力,有利于创面愈合。
附图说明
下面结合附图和实施例对本发明做进一步的说明,其中:
图1为本发明实施例1~实施例3改性壳聚糖衍生物材料实物图。
图2为本发明未改性壳聚糖、实施例1~实施例3制得的改性壳聚糖衍生物的溶解情况。
图3为本发明实施例1~实施例3改性壳聚糖衍生物随温度变化的储能模量和损耗模量。
图4为本发明实施例3中不同改性壳聚糖拉伸强度图。
图5为本发明实施例3改性壳聚糖衍生物对创面组织HIF-1α表达量的影响。
图6为本发明实施例4制得的不同自收缩水凝胶的面积收缩率。
图7为本发明实施例4制得的不同自收缩水凝胶在不同温度下的实物图。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
实施例1
本实施例制备了一种改性壳聚糖衍生物,具体过程为:
S1:羟丁基壳聚糖的合成(HBC):称取4g精制的50%脱乙酰度壳聚糖于250mL烧杯中,25℃200rpm/min搅拌下,逐滴加入30mL质量分数为50%的氢氧化钠溶液,分散24h,随后挤出碱液,蒸馏水清洗2次获得碱化壳聚糖;碱化壳聚糖转移至圆底烧瓶,逐滴加入80mL异丙醇和水的混合溶液(v/v 1:1),25℃200rpm/min搅拌24h使充分分散;逐滴加入80mL1,2-环氧丁烷,加热至55-60℃,反应12h;终止反应,加入1% HCl调节pH至中性,溶液完全溶解呈透明状;转移至3000分子量透析袋,透析3~4天,透析液转移至4℃过夜;滤除杂质,-20℃冷冻,冻干;
S2:双键羟丁基壳聚糖(HBC_m)的合成:2g HBC溶于200mL超纯水中,室温下充分溶解后,逐滴加入6.4g甲基丙烯酸酐;控制反应温度60℃,转速约1000rpm/min进行强力搅拌,持续反应12h~24h;碳酸氢钠调节pH为中性;3000分子量透析袋透析3天~4天;冻干。
S3:改性壳聚糖衍生物(HBC_m_Arg)的合成:2g HBC_m溶于200mL超纯水中,室温下充分溶解;加入1.42g NHS和1.92g EDC搅拌10min;加入精氨酸12g,搅拌24h使反应充分;超纯水中透析3天~4天后;冻干后制得改性壳聚糖衍生物。
实施例2
本实施例制备了一种改性壳聚糖衍生物,具体过程为:
S1:羟丁基壳聚糖的合成(HBC):称取4g精制的90%脱乙酰度壳聚糖于250mL烧杯中,25℃200rpm/min搅拌下,逐滴加入30mL质量分数为50%的氢氧化钠溶液,分散24h,随后挤出碱液,蒸馏水清洗2次获得碱化壳聚糖;碱化壳聚糖转移至圆底烧瓶,逐滴加入80mL异丙醇和水的混合溶液(v/v 1:1),25℃200rpm/min搅拌24h使充分分散;逐滴加入80mL1,2-环氧丁烷,加热至55-60℃,反应12h;终止反应,加入1% HCl调节pH至中性,溶液完全溶解呈透明状;转移至3000分子量透析袋,透析3~4天,透析液转移至4℃过夜;滤除杂质,-20℃冷冻,冻干;
S2:双键羟丁基壳聚糖(HBC_m)的合成:2g HBC溶于200mL超纯水中,室温下充分溶解后,逐滴加入6.4g甲基丙烯酸酐;控制反应温度60℃,转速约1000rpm/min进行强力搅拌,持续反应12h~24h;碳酸氢钠调节pH为中性;3000分子量透析袋透析3天~4天;冻干。
S3:改性壳聚糖衍生物(HBC_m_Arg)的合成:2g HBC_m溶于200mL超纯水中,室温下充分溶解;加入1.42g NHS和1.92g EDC搅拌10min;加入精氨酸12g,搅拌24h使反应充分;超纯水中透析3天~4天后;冻干后制得改性壳聚糖衍生物。
实施例3
本实施例制备了一种改性壳聚糖衍生物,具体过程为:
S1:羟丁基壳聚糖的合成(HBC):称取4g精制的95%脱乙酰度壳聚糖于250mL烧杯中,25℃200rpm/min搅拌下,逐滴加入30mL质量分数为50%的氢氧化钠溶液,分散24h,随后挤出碱液,蒸馏水清洗2次获得碱化壳聚糖;碱化壳聚糖转移至圆底烧瓶,逐滴加入80mL异丙醇和水的混合溶液(v/v 1:1),25℃200rpm/min搅拌24h使充分分散;逐滴加入80mL1,2-环氧丁烷,加热至55-60℃,反应12h;终止反应,加入1% HCl调节pH至中性,溶液完全溶解呈透明状;转移至3000分子量透析袋,透析3~4天,透析液转移至4℃过夜;滤除杂质,-20℃冷冻,冻干;
S2:双键羟丁基壳聚糖(HBC_m)的合成:2g HBC溶于200mL超纯水中,室温下充分溶解后,逐滴加入6.4g甲基丙烯酸酐;控制反应温度60℃,转速约1000rpm/min进行强力搅拌,持续反应12h~24h;碳酸氢钠调节pH为中性;3000分子量透析袋透析3天~4天;冻干。
S3:改性壳聚糖衍生物(HBC_m_Arg)的合成:2g HBC_m溶于200mL超纯水中,室温下充分溶解;加入1.42g NHS和1.92g EDC搅拌10min;加入精氨酸12g,搅拌24h使反应充分;超纯水中透析3天~4天后;冻干后制得改性壳聚糖衍生物。
实施例1~实施例3制得的改性壳聚糖衍生物材料实物图如图1所示。
实施例4
本实施例制备了一种自收缩水凝胶,具体过程为:
分别称取实施例1~实施例3中壳聚糖衍生物(HBC_m_Arg)适量,用超纯水配置成5%浓度(置于4℃冰箱内转速约为300rpm/min进行磁力搅拌溶解);加入水溶性光交联剂LAP,配置成LAP浓度为1%~2%;注入硅胶模具,转移至365nm光交联10min~20min即制得实施例1~实施例3对应的自收缩水凝胶。
试验例1
本试验例对未改性壳聚糖、实施例1~实施例3制得的改性壳聚糖衍生物进行溶解度测试,具体过程为:
分别称取脱乙酰度50%、90%、95%壳聚糖和实施例1~实施例3制得的改性壳聚糖衍生物适量,超纯水配置浓度为5%;4℃搅拌24小时;静置15min后观察溶液澄清度及有无沉淀出现。结果如图2所示。
结果显示,未改性壳聚糖在PBS或超纯水中,无论低温还是室温,抑或加热,均不溶,静置后,明显沉淀出现,溶解度约等于零;而实施例1~实施例3制得的改性壳聚糖衍生物在10℃以下,PBS或超纯水中,溶解度可到5%,静置后,仍保持分散均匀的状态,无沉淀出现。
试验例2
本试验例对实施例1~实施例3制得的改性壳聚糖衍生物进行流变行为测试,具体过程为:实施例1~实施例3制得的改性壳聚糖衍生物按质量浓度为5%浓度4℃低温溶解后,加载到流变仪器中在4℃~50℃条件下进行温度扫描并记录储能模量和损耗模量的变化,结果如图3所示。
从图3可看出,实施例1~实施例3中随壳聚糖脱乙酰度的增加,改性壳聚糖衍生物5%浓度条件下的相转变温度呈逐渐降低趋势,脱乙酰度增加,产物的温度敏感性增强,成胶后至于37℃条件下收缩形变效率更高,形变幅度更大。
试验例3
本试验例对实施例3中不同步骤制得的产物进行黏附性测试,具体过程为:
分别准备好浓度均为5%的HBC、HBC_m、HBC_m_Arg水凝胶;涂布到明胶涂布的玻片上,365nm光交联30秒;至于万能材料测试机上以5mm/min速率拉伸对侧玻片;记录应力和应变结果。结果如图4所示。
从图4可看出,95%脱乙酰度的壳聚糖制备的HBC,明胶玻片粘接拉伸强度为15.9Kpa,HBC_m的拉伸强度为25.5Kpa,HBC_m_Arg的拉伸强度为167.7Kpa。HBC_m_Arg水凝胶的拉伸强度明显高于其他实验组,对生物组织应能表现出更好的粘附性,发生形变时应会对组织表现出更强的牵引力。
试验例4
本试验例对实施例3对应的自收缩水凝胶进行生物功能测试,具体过程为:
取实施例3中制得的HBC和HBC_m_Arg制备成水凝胶;贴敷到大鼠全皮层缺损创面上,作用10天;取大鼠愈合部位的皮肤组织进行HIF-1α蛋白表达量测定(以β-actin作为内参)。结果如图5所示。
从图5可看出,HBC_m_Arg要比HBC更能促进HIF-1α的表达,应更能促进血管再生试验例5
本试验例对实施例4制得的不同自收缩水凝胶进行面积收缩率测试,具体过程为:
分别将实施例4中实施例1~实施例3对应的自收缩水凝胶置于透明玻片上;20℃下用记号笔勾勒出水凝胶外援轮廓,并拍照;将上述水凝胶至于37℃条件下孵育5min后拍照;用imagej软件进行水凝胶初始轮廓和实验终点轮廓描边并计算相应面积。结果如图6、图7所示。
从图6、图7可看出,50%、90%、95%脱乙酰度壳聚糖制备的HBC_m_Arg水凝胶随脱乙酰度增加,相应水凝胶的形变百分比更大(50%脱乙酰度组别平均面积收缩9.85%,90%组平均面积收缩16.05%,95%组平均收面积缩22.43%),形变效率更高。HBC_m_Arg水凝胶的温敏形变性能,是可以调控的。
上面对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (10)
1.式I改性壳聚糖衍生物:
其中,DD为脱乙酰度,所述脱乙酰度为30%~99%。
2.根据权利要求1所述的改性壳聚糖衍生物,其特征在于:式I中,的取代度为1.0~2.0;/>的取代度为0.1~0.5;/>的取代度为0.1~0.5。
3.根据权利要求1所述的改性壳聚糖衍生物,其特征在于:所述改性壳聚糖衍生物的分子量为100000~300000。
4.一种式I的改性壳聚糖衍生物的制备方法,其特征在于:包括以下步骤:
S1:脱乙酰壳聚糖碱化后与1,2-环氧丁烷反应,制得羟丁基壳聚糖;
S2:羟丁基壳聚糖溶解后再加入不饱和酸酐反应,制得双键羟丁基壳聚糖;
S3:双键羟丁基壳聚糖溶解后与精氨酸反应,制得如权利要求1~3任一项所述的式I改性壳聚糖衍生物。
5.根据权利要求4所述的改性壳聚糖衍生物的制备方法,其特征在于:S2中,所述羟丁基壳聚糖与所述不饱和酸酐的质量比为2:(3~10)。
6.根据权利要求4所述的改性壳聚糖衍生物的制备方法,其特征在于:S3中,所述双键羟丁基壳聚糖与所述精氨酸的质量比为2:(5~15)。
7.根据权利要求4所述的改性壳聚糖衍生物的制备方法,其特征在于:所述不饱和酸酐包括甲基丙烯酸酐、丙烯酸酐、马来酸酐的至少一种。
8.一种自收缩水凝胶,其特征在于:包括如权利要求1~3任一项所述的改性壳聚糖衍生物。
9.一种自收缩水凝胶的制备方法,其特征在于:包括以下步骤:向改性壳聚糖衍生物溶液加入水溶性光交联剂,光交联后制得如权利要求8所述的自收缩水凝胶。
10.一种如权利要求1~3任一项所述的改性壳聚糖衍生物和/或如权利要求8所述的自收缩水凝胶在制备创面修复材料中的应用。
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