CN111662464B - 一种壳聚糖/海藻酸钠双网络水凝胶的制备方法 - Google Patents
一种壳聚糖/海藻酸钠双网络水凝胶的制备方法 Download PDFInfo
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- sodium alginate
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Abstract
本发明公开了一种壳聚糖/海藻酸钠双网络水凝胶的制备方法,将由改性壳聚糖、改性海藻酸钠、光引发剂和水组成的预聚液通过席夫碱反应,得到单网络水凝胶;再将单网络水凝胶于紫外光照射下反应,得到二次光交联的壳聚糖/海藻酸钠双网络水凝胶;其中,所述的改性壳聚糖为接枝胶原蛋白肽的羧甲基壳聚糖;所述的改性海藻酸钠为甲基丙烯酸改性的醛基化海藻酸钠。本发明所述的胶原蛋白肽具有非免疫原性,在不使用有毒交联剂的情况下,可通过酶促反应接枝在壳聚糖上,提高材料的细胞相容性和促细胞增殖能力。
Description
技术领域
本发明属于医用生物材料技术领域,具体涉及一种壳聚糖/海藻酸钠双网络水凝胶的制备方法。
背景技术
皮肤在身体表面,直接同外界环境接触,具有保护、排泄、调节体温和感受外界刺激等作用,是人体最大的器官。然而皮肤大面积暴露在外,日常生活中极易受到各种各样的损伤,如机械创伤、烧伤、慢性溃疡等。皮肤伤口愈合是临床上的一项重大难题,同时伤口恢复过程中由细菌等导致的伤口感染是最常见的并发症,严重者可导致死亡。水凝胶由于其天然多孔结构和高水分含量可以吸收大量的渗出液,可充当阻挡细菌的屏障,也可在皮肤缺损部位维持潮湿的环境、保持良好的氧气和水渗透性,同时实现药物的缓释作用,因此引起了中外学者们的注意。
壳聚糖又称脱乙酰甲壳素,是由自然界广泛存在的几丁质经过脱乙酰作用而得到。自1859年,法国人Ruget首先得到壳聚糖后,这种天然高分子由于其优异的生物相容性、血液相容性、抗菌性、生物降解性等性能被各行各业广泛关注。但由于其水溶性和力学性能较差,限制了其应用,所以对壳聚糖进行改性、修饰显得至关重要。一般改性方法包括对壳聚糖一级结构进行化学修饰,这可能会改变其初始性质,特别是其氨基参与的反应。另外,大部分壳聚糖的改性需使用交联剂,例如戊二醛,而交联剂一般具有毒性,对后续的应用具有很大的负面影响。
发明内容
发明目的:本发明所要解决的技术问题是针对现有技术的不足,提供一种壳聚糖/海藻酸钠双网络水凝胶的制备方法。
为了解决上述技术问题,本发明公开了一种壳聚糖/海藻酸钠双网络水凝胶的制备方法,由接枝胶原蛋白肽的羧甲基壳聚糖和甲基丙烯酸改性的醛基化海藻酸钠通过席夫碱反应和二次光交联反应制得。
具体地,将由改性壳聚糖、改性海藻酸钠、光引发剂和水组成的预聚液通过席夫碱反应,得到单网络水凝胶;再将单网络水凝胶于紫外光照射下反应,得到二次光交联的壳聚糖/海藻酸钠双网络水凝胶;其中,所述的改性壳聚糖为接枝胶原蛋白肽的羧甲基壳聚糖;所述的改性海藻酸钠为甲基丙烯酸改性的醛基化海藻酸钠。
其中,所述的改性壳聚糖的制备方法为将壳聚糖和氯乙酸于在碱性条件下反应,得到羧甲基壳聚糖;再通过谷氨酰胺转移酶催化胶原蛋白肽接枝于羧甲基壳聚糖,即得接枝胶原蛋白肽的羧甲基壳聚糖。
其中,所述的壳聚糖与氯乙酸的摩尔比为1:2-4,优选为1:3;羧甲基壳聚糖、谷氨酰胺转移酶和胶原蛋白肽的质量比为1:0.1:0.5-1.5,优选为1:0.1:1。
进一步优选地,所述的改性壳聚糖的制备方法为将壳聚糖溶于50wt%NaOH水溶液中,冷冻24h,再将其置于异丙醇中解冻并分散,然后将氯乙酸加入到分散后的物料中,室温搅拌5-12h,优选为5h,搅拌后的物料透析三天后冷冻干燥得到羧甲基壳聚糖;将羧甲基壳聚糖、谷氨酰胺转移酶和胶原蛋白肽分别溶解于PBS缓冲液中,于30-60℃反应4-12h,优选为40℃反应4h,然后在沸水中保持10min,冷却后过滤,将滤液透析四天后冷冻干燥得到接枝胶原蛋白肽的羧甲基壳聚糖。
其中,壳聚糖于50wt%的NaOH水溶液中的浓度为0.1g/mL;所述的异丙醇作为分散溶剂,不需要确定的用量,优选为150-200mL/5g壳聚糖;其中,所述的PBS缓冲液为pH=6的0.2mol/L PBS缓冲液;其中,胶原蛋白肽的浓度为1g/30mL PBS缓冲液。
其中,所述的改性海藻酸钠的制备方法为将海藻酸钠与高碘酸钠反应得到醛基化海藻酸钠,再通过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)将其甲基丙烯酸化,即得。
其中,海藻酸钠与高碘酸钠的摩尔比为1:0.4-1,优选为1:0.6;海藻酸钠、EDC和NHS的摩尔比为2:1:2。
进一步优选地,所述的改性海藻酸钠的制备方法为向0.02g/mL的海藻酸钠水溶液中加入高碘酸钠,避光室温反应3-12h,优选为4h,再加入乙二醇终止反应,搅拌15-30min后得到第一反应液,优选为30min,高碘酸钠和乙二醇的摩尔比为1:1;将第一反应液透析三天后冷冻干燥,得到醛基化海藻酸钠(OSA);将醛基化海藻酸钠溶于MES缓冲液,醛基化海藻酸钠的浓度为0.02g/mL,再向其中加入EDC和NHS,室温反应30-45min,得到第二反应液;再向第二反应液中加入甲基丙烯酸二乙氨基乙酯(AEMA),海藻酸钠与AEMA的摩尔比为1:0.3-0.7,优选为1:0.5,室温下避光反应24-48h,优选为24h,得到第三反应液;将第三反应液透析三天后冷冻干燥,即得。
其中,所述的MES缓冲液为pH=5.5-6,50mM/L MES,0.5M NaCl。
上述壳聚糖/海藻酸钠双网络水凝胶的制备方法中,所述的预聚液中,改性壳聚糖的质量百分比浓度为5-10%,改性海藻酸钠的质量百分比浓度为15-25%,光引发剂的质量百分浓度为0.05-0.2%;优选地改性壳聚糖的质量百分比浓度为7.5%,改性海藻酸钠的质量百分比浓度为20%,光引发剂的质量百分浓度为0.05%。
优选地,所述的光引发剂为I2959。
其中,将预聚液于25℃下反应1-5min,优选为3min。
其中,将单网络水凝胶于波长365nm、功率1mW/cm2的紫外光照射下反应15-20min,优选为15min。
有益效果:与现有技术相比,本发明具有如下优势:
1、本发明选用壳聚糖和海藻酸钠为水凝胶原料,两种原料通过简单改性可发生交联作用,且制备简单,原料并已实现商业化。因此,选用这两种原料对此类水凝胶方法的建立、推广和促进其在组织工程和再生医学中的应用具有非常重要的价值。
2、传统的壳聚糖改性需要使用戊二醛等交联剂,细胞毒性大,而本发明所述的胶原蛋白肽具有非免疫原性且有利于成纤维细胞增殖,通过酶促反应接枝在壳聚糖上,提高其细胞相容性,有利于细胞增殖,同时还不会引进有毒的交联剂。因此,本发明所制备的双网络水凝胶细胞毒性小。
3、相较于其他交联方式,席夫碱反应操作简单且绿色无毒,本发明通过醛基化海藻酸钠与壳聚糖发生席夫碱反应,其无任何副产物且不需要加入任何交联剂;且通过甲基丙烯酸改性后,更可利用二次光交联制备双网络水凝胶,提高其力学性能。
附图说明
下面结合附图和具体实施方式对本发明做更进一步的具体说明,本发明的上述和/或其他方面的优点将会变得更加清楚。
图1为改性壳聚糖和改性海藻酸钠的1H NMR光谱。
图2为单网络水凝胶(下)和双网络水凝胶(上)的压缩应力-应变曲线。
图3为单网络水凝胶(左)和双网络水凝胶(右)的SEM照片。
图4为L929细胞经水凝胶浸提液培养后的相对细胞活性(4A)和活死染色(4B);4A中,每组从左至右依次为对照(control)、OSA/CMC、OSA/CMC-COP和OMSA/CMC-COP。
具体实施方式
以下实施例中所用的壳聚糖为上海源叶生物的S11064壳聚糖,其数均分子量约为20w,单体的分子量约为161.2;海藻酸钠为上海源叶生物的S11053海藻酸钠,其数均分子量为24w,单体的分子量约为216.1。
实施例1
(1)将5g壳聚糖缓慢加入预先制备的50mL 50wt%NaOH水溶液中,并置于-20℃冷冻24h。然后,将壳聚糖解冻并分散在150-200mL异丙醇中以形成均匀溶液。向该溶液中加入8.5g的氯乙酸,并在室温下搅拌5h(25℃,1500rpm)。利用去离子水透析(Mw=3500)3天来纯化产物,然后冷冻干燥以获得羧甲基壳聚糖(CMC)。再将1g羧甲基壳聚糖,0.1g谷氨酰胺转移酶和1g胶原肽分别溶解在30mL PBS(0.2mol/L,pH=6.0)溶液中并在烧瓶中混合,在40℃下反应4h(300rpm),在沸水中保持10min。冷却至室温(25℃)后,将产物用去离子水透析(Mw=3500)4天,然后冷冻干燥以获得羧甲基壳聚糖-胶原肽(CMC-COP)。
(2)首先将5g海藻酸钠(SA)均匀地溶于250mL去离子水中,然后向溶液中缓慢加入3.08g高碘酸钠,并在室温(25℃,500rpm)下避光反应4h,再加入0.89mL乙二醇终止反应,室温下(25℃,500rpm)搅拌30min后将产物通过用去离子水透析(Mw=3500)纯化3天,然后冷冻干燥以获得醛基化海藻酸钠(OSA)。再将1g OSA溶于50mL MES缓冲液(pH=5.5-6,50mM/LMES,0.5M NaCl)中,后加入0.27g NHS和0.87g EDC。室温(25℃,500rpm)反应30min后,向反应混合物中加入0.39g AEMA,然后避光室温搅拌24h(25℃,500rpm)。通过用去离子水透析(Mw=3500)四天来纯化产物,然后冷冻干燥以获得甲基丙烯酸改性的醛基化海藻酸钠(OMSA)。
(3)称取5mg CMC、CMC-COP和OSA、OMSA分别溶解在500μL D2O中。在室温(25℃)下,在NMR光谱仪上记录样品的1H NMR光谱。
CMC和CMC-COP的1H NMR光谱如图1(上)所示。CMC在4.36(a)处出现了新的特征峰,是-CH2COOH特征峰,表明壳聚糖成功的被羧甲基化。CMC-COP由于N-CO旋转受阻,属于自旋的新峰出现在5.31(b)。由于引入了COP,CH3和CH2的0.9-1.4(c)处新增许多小的特征峰。这些结果进一步证明了CMC-COP的合成。
OSA和OMSA的1H NMR光谱如图1(下)所示。OSA在5.31和5.61(a)处显示特征峰,都是次甲基质子,证实了OSA的合成。AMSA的1H NMR光谱显示出6.04(c)处显示出特征峰,这是乙酰基亚甲基的特征峰。1.82(b)处出现的特征峰是甲基质子特征峰。都证明了OSA成功的被甲基丙烯酸化。
实施例2
(1)将实施例1中制备的CMC-COP、实施例1中制备的OSA溶于水中,配成的预聚液,CMC-COP的质量百分比为7.5%,OSA的质量百分比为20%,在玻璃样品瓶中室温(25℃)反应3min得到单网络水凝胶OSA/CMC-COP。
(2)将实施例1中制备的CMC-COP、实施例1中制备的OMSA和I2959光引发剂溶于水中,配成的预聚液,CMC-COP的质量百分比为7.5%,OSA的质量百分比为20%,I2959光引发剂的质量百分比为0.1%,在玻璃样品瓶中室温(25℃)反应3min得到单网络水凝胶。再将单网络水凝胶放置在波长365nm、功率1mW/cm2的紫外光照射15min发生光交联得到双网络水凝胶OMSA/CMC-COP。
(3)分别记录单/双网络水凝胶的直径和厚度之后,将水凝胶放置在下板上,并以5mm/min的应变速率由上板压缩,分析所有样品以获得应力-应变曲线。见图2为水凝胶的压缩应力-应变曲线,其可以反映出水凝胶的力学性能;其中,图2(下)为OSA/CMC-COP单网络水凝胶的压缩应力-应变曲线,图2(上)为OMSA/CMC-COP双网络水凝胶的压缩应力-应变曲线。可以看出,OSA/CMC-COP单网络水凝胶的断裂应力为0.12MPa,而OMSA/CMC-COP双网络水凝胶的断裂应力为0.21MPa,接近于单网络水凝胶的两倍,这是因为单纯席夫碱交联较为脆弱,双网络水凝胶的交联密度要高于单网络,力学性能更强,断裂应力更高。
实施例3:将实施例2中制备的OSA/CMC-COP单网络水凝胶和OMSA/CMC-COP双网络水凝胶应用于本实施例。
将准备好的水凝胶放入冷冻干燥机中,在-56℃下冷冻干燥12h,然后取出。在冷冻干燥后CMC-COP/OSA和CMC-COP/OMSA样品上喷涂一层薄薄的金后,用扫描电子显微镜拍摄水凝胶冷冻干燥后的内部结构。图3为通过扫描电镜表征的水凝胶的内部微观形貌,水凝胶为多孔结构,作为伤口敷料优选材料,其孔径有利于储存水分,保持伤口湿润和透气,也为细胞生长提供了良好的环境。图3(左)为冷冻干燥后OSA/CMC-COP单网络水凝胶的内部微观形貌,其孔径较大,尺寸不一。图3(右)右为冷冻干燥后OMSA/CMC-COP双网络水凝胶的内部微观形貌,相较于单网路水凝胶,其孔径较小,孔分布更为密集且均匀,这也是其力学性能更高的原因之一。
实施例4:将实施例2中制备的OSA/CMC-COP单网络水凝胶和OMSA/CMC-COP双网络水凝胶应用于本实施例。
(1)将实施例1中制备的CMC、实施例1中制备的OSA溶于水中,配成的预聚液,CMC的质量百分比为7.5%,OSA的质量百分比为20%,在玻璃样品瓶中室温(25℃)反应3min得到单网络水凝胶OSA/CMC。
(2)将L929细胞接种在96孔板中(2,000个细胞/孔),并置于CO2培养箱中孵育24h。然后,我们将100μL 0.1g/mL水凝胶提取物添加到96孔板中,向对照组加入等量的完全培养基,继续孵育24h。再向每个孔中添加10μL CCK8溶液,并在CO2培养箱中继续孵育40min。使用酶标仪检测450nm处的吸光度。
其中,所述的水凝胶提取物为将OSA/CMC、OSA/CMC-COP和OMSA/CMC-COP三种水凝胶分别浸泡在完全培养基中,37℃浸泡48h,得到浓度为0.1g/mL的三种水凝胶浸提液。
其中,所述的完全培养基为高糖DMEM培养(含10%胎牛血清,1%双抗)。
(3)将L929细胞接种在96孔板中(2,000个细胞/孔),并置于CO2培养箱中孵育24h。然后,我们将100μL 0.1g/mL的水凝胶提取物添加到96孔板中,向对照组加入等量的完全培养基,孵育24h。再按照说明书向每个孔中添加活细胞和死细胞染色检测试剂,并在CO2培养箱中继续孵育30min,使用倒置荧光显微镜在560nm和600nm作为激发波长观察并记录染色情况。
图4A是利用浓度为0.1mg/mL三种水凝胶浸提液培养细胞,其在24、48和72h得到的CCK8检测结果。计算方法为:Relative Cell Viability(control%)=(样品组吸光度-空白组吸光度)/(对照组吸光度-空白组吸光度)×100%。其中,24h的Control组的吸光度作为对照(100%)。图4B是利用浓度为0.1g/mL的三种不同水凝胶浸提液和对照组(不添加细胞浸提液)的细胞死活染色荧光照片。
各水凝胶对L929细胞生长的影响如图4所示。当样品浓度为0.1g/mL时,细胞相对存活率均高于95%,表明该材料浸提液在该浓度时并不具有细胞毒性。说明单双网络的水凝胶对细胞活性影响较小,细胞毒性小。另外,OMSA/CMC-COP组的细胞活性最高,该材料体系有利于成纤维细胞增殖。因此,相较于OSA/CMC-COP水凝胶,经胶原肽修饰的OMSA/CMC-COP水凝胶更有利于L929细胞培养。
本发明提供了一种双网络的壳聚糖/海藻酸钠复合水凝胶的制备思路及方法,具体实现该技术方案的方法和途径很多,以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。
Claims (7)
1.一种壳聚糖/海藻酸钠双网络水凝胶的制备方法,其特征在于,将由改性壳聚糖、改性海藻酸钠、光引发剂和水组成的预聚液于25℃下反应1-5min,得到单网络水凝胶;再将单网络水凝胶于波长365nm、功率1mW/cm2的紫外光照射下反应15-20min,得到二次光交联的壳聚糖/海藻酸钠双网络水凝胶;其中,所述的改性壳聚糖为接枝胶原蛋白肽的羧甲基壳聚糖;所述的改性海藻酸钠为甲基丙烯酸改性的醛基化海藻酸钠;
其中,所述的预聚液中,改性壳聚糖的质量百分比浓度为7.5%,改性海藻酸钠的质量百分比浓度为20%,光引发剂的质量百分浓度为0.05-0.2%。
2.根据权利要求1所述的制备方法,其特征在于,所述的改性壳聚糖的制备方法为将壳聚糖和氯乙酸于在碱性条件下反应,得到羧甲基壳聚糖;再通过谷氨酰胺转移酶催化胶原蛋白肽接枝于羧甲基壳聚糖,即得接枝胶原蛋白肽的羧甲基壳聚糖。
3.根据权利要求2所述的制备方法,其特征在于,壳聚糖与氯乙酸的摩尔比为1:2-4;羧甲基壳聚糖、谷氨酰胺转移酶和胶原蛋白肽的质量比为1:0.1:0.5-1.5。
4.根据权利要求2所述的制备方法,其特征在于,所述的改性壳聚糖的制备方法为将壳聚糖溶于50wt%NaOH水溶液中,壳聚糖的浓度为0.1g/mL,冷冻24h,再将其置于异丙醇中解冻并分散,然后将氯乙酸加入到分散后的物料中,室温搅拌5-12h,搅拌后的物料透析三天后冷冻干燥得到羧甲基壳聚糖;将羧甲基壳聚糖、谷氨酰胺转移酶和胶原蛋白肽分别溶解于PBS缓冲液中,于30-60℃反应4-12h,然后在沸水中保持10min,冷却后过滤,将滤液透析四天后冷冻干燥得到接枝胶原蛋白肽的羧甲基壳聚糖;其中,胶原蛋白肽的浓度为1g/30mLPBS缓冲液。
5.根据权利要求1所述的制备方法,其特征在于,所述的改性海藻酸钠的制备方法为将海藻酸钠与高碘酸钠反应得到醛基化海藻酸钠,再通过1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺将其甲基丙烯酸化,即得。
6.根据权利要求5所述的制备方法,其特征在于,海藻酸钠与高碘酸钠的摩尔比为1:0.4-1;海藻酸钠、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺的摩尔为2:1:2。
7.根据权利要求5所述的制备方法,其特征在于,所述的改性海藻酸钠的制备方法为向0.02g/mL的海藻酸钠水溶液中加入高碘酸钠,避光室温反应3-12h,再加入乙二醇终止反应,搅拌15-30min后得到第一反应液,高碘酸钠和乙二醇的摩尔比为1:1;将第一反应液透析三天后冷冻干燥,得到醛基化海藻酸钠;将醛基化海藻酸钠溶于MES缓冲液,醛基化海藻酸钠的浓度为0.02g/mL,再向其中加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺,室温反应30-45min,得到第二反应液;再向第二反应液中加入甲基丙烯酸二乙氨基乙酯,海藻酸钠与甲基丙烯酸二乙氨基乙酯的摩尔比为1:0.3-0.7,室温下避光反应24-48h,得到第三反应液;将第三反应液透析三天后冷冻干燥,即得。
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