CN105920675A - 一种制备生物功能化壳聚糖水凝胶的方法 - Google Patents
一种制备生物功能化壳聚糖水凝胶的方法 Download PDFInfo
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- CN105920675A CN105920675A CN201610230497.5A CN201610230497A CN105920675A CN 105920675 A CN105920675 A CN 105920675A CN 201610230497 A CN201610230497 A CN 201610230497A CN 105920675 A CN105920675 A CN 105920675A
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- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明属于组织工程生物材料领域,具体涉及一种制备生物功能化壳聚糖水凝胶的方法,包括如下步骤:不同质量分数京尼平的配制:用75%酒精1ml,分别溶解0.005g、0.01g和0.02g的京尼平配置成0.5%、1.0%、2.0%的京尼平溶液;壳聚糖溶液的制备:1.5g的壳聚糖溶于100ml的3%的醋酸溶液中制备成1.5%的壳聚糖溶液,并加入含有氨基的生物分子,于瓶中搅拌过夜;将上述两种溶液按照不同的比例混合,室温静置24‑72h后即可得到功能化壳聚糖水凝胶;其中,京尼平和含有氨基的生物分子的摩尔比例保持在10:5至10:1之间,壳聚糖和京尼平的摩尔比例保持在300:1至30:10之间。本发明简单易操作,价格低廉,反应条件温和成熟,无细胞或低细胞毒性,方法具有普遍适用性。
Description
技术领域
本发明属于组织工程生物材料领域,具体涉及一种制备生物功能化壳聚糖水凝胶的方法。
背景技术
壳聚糖化学名称为(1,4)-2-氨基-2-脱氧-β-D-葡萄糖,是一种含氨基的天然均态直链多糖,它是天然第二大高分子甲壳素脱乙酰基的产物。壳聚糖在体内降解最终的产物是CO2和糖蛋白,这两种物质可以直接排出体外或被生物体吸收。此外,壳聚糖所含游离氨基使其反应性和功能化大大加强。由于壳聚糖具有来源广泛、生物相容性好和可降解等优点,使壳聚糖基水凝胶成为目前研究最热门的水凝胶材料之一,在生物医用领域表现出极大的应用价值。
作为生物医用材料,壳聚糖的力学性能往往达不到要求,为了提高此类天然高分子材料的强度,人们常常通过交联反应而达到增强的目的。壳聚糖类水凝胶为物理或化学交联的网络。壳聚糖由于其分子间的氢键作用,其酸性水溶液具有一定粘度,而遇到碱性试剂,壳聚糖会立即形成凝胶,但该凝胶受环境pH影响较大,且凝胶强度不够。通过化学交联的方法,使线性的壳聚糖链通过共价键交联变成网络结构,或是壳聚糖链通过氢键、库仑力等分子间的作用力或高分子链相互缠结等物理作用形成网络结构的超分子体系。这样一方面可以使壳聚糖分子对酸性溶液的稳定性增强,另一方面可使其对环境的刺激产生可逆响应。常用的交联方法有:化学交联剂使其交联;光照或辐射与其他高分子形成半互穿或互穿网络;聚电解质通过静电作用或氢键键合使其交联等。
作为组织工程生物材料是壳聚糖水凝胶的一大重要应用,但是传统交联方法都使用化学合成类交联剂,而这类交联剂具有相对较高的细胞毒性,导致所得生物材料在植入生物体后,会影响正常组织的生长以及破坏大分子药物的完整性,从而影响创口的愈合和功能恢复。京尼平是传统中药杜仲的活性成分之一,含有-OH、-COO-等多个活性官能团,可自发与氨基反应达到交联壳聚糖的效果。与传统交联剂相比,天然生物交联剂京尼平具有低毒性和良好的生物相容性。有研究表明在细胞毒性实验中发现戊二醛交联,明胶微球毒性较大,使细胞形态功能发生变化,甚至有死亡现象。而京尼平制作的微球几乎无细胞毒性,在支架中其浓度低于0.5%时组织无明显炎性反应,各浓度细胞毒级均为I级,细胞生长状态良好。因此,以京尼平交联的壳聚糖水凝胶在生物材料领域具有广泛应用价值。
壳聚糖水凝胶的实际应用时,一般都需要对其进行功能化改性,例如:对外界环境响应、增加选择性、增加细胞贴附性能、刺激细胞生长分化等。但传统功能化的方法仍然存在亟待解决的问题,例如,(1)步骤复杂,这种方法需要将壳聚糖提前进行修饰或者对合成水凝胶进行修饰,任何的化学修饰步骤都有可能引入对生物体不利的因素,Kim等将2-羧乙基丙烯酸酯截止到壳聚糖的伯氨基上,然后与PEO六硫醇混合得到壳聚糖-PEO原位水凝胶;(2)反应条件苛刻,通过紫外光或辐射等方法合成特殊功能化的壳聚糖共混水凝胶,但是对于生物功能化材料来说,该类方法可导致引入的生物功能分子(蛋白、DNA等)变性失活;(3)化学试剂种类多,化学试剂对生物功能分子以及壳聚糖水凝胶的生物应用都会增加细胞毒性等,Kim等用2,2-二甲氧基-2-苯基乙酰苯(DM-PAP)和亚甲基二丙烯酰胺(MBAAm)作为引发剂和交联剂反应制备壳聚糖/聚丙烯酰胺互穿网络(IPN)水凝胶。
发明内容
针对上述壳聚糖水凝胶功能化方法所面临的各种问题,本发明提供一种制备生物功能化壳聚糖水凝胶的方法,采用一步法,通过中药京尼平的桥接作用,制备生物功能化的壳聚糖水凝胶,简单易操作,价格低廉,反应条件温和成熟,无细胞或低细胞毒性,方法具有普遍适用性,所制备水凝胶可以作为生物界面材料和支架材料,用于控制细胞贴附生长和分化,伤口愈合,可用于神经修复、肌肉或皮肤组织修复、骨或软骨等组织的修复等,在临床医学方面具有极大的应用潜力。
为了实现上述发明目的,本发明所采用的一个技术方案为:一种制备生物功能化壳聚糖水凝胶的方法,其特征在于,包括如下步骤:
(1)首先,不同质量分数京尼平的配制:用75%酒精1ml,分别溶解0.005g、0.01g和0.02g的京尼平配置成0.5%、1.0%、2.0%的京尼平溶液;
(2)壳聚糖溶液的制备:1.5g的壳聚糖溶于100ml的3%的醋酸溶液中制备成1.5%的壳聚糖溶液,并加入含有氨基的生物分子,于瓶中搅拌过夜;
(3)将上述两种溶液按照不同的比例混合,室温静置24-72h后即可得到功能化壳聚糖水凝胶;其中,京尼平和含有氨基的生物分子的摩尔比例保持在10:5至10:1之间,壳聚糖和京尼平的摩尔比例保持在300:1至30:10之间。
在步骤(3)之后,还包括步骤(4)功能化壳聚糖水凝胶的性能判定。
在步骤(1)中,75%酒精是指酒精占酒精水溶液的体积比为75%;0.5%、1.0%、2.0%是指京尼平占京尼平溶液的质量体积比(g/ml)。
在步骤(2)中,3%的醋酸溶液是指醋酸占醋酸水溶液的体积比为3%。1.5%的壳聚糖溶液是指壳聚糖占壳聚糖溶液的质量体积比(g/ml)。
在步骤(2)中,含有氨基的生物分子为氨基化荧光分子、N端无修饰的生物活性多肽、生长因子、具有生物功能的氨基化DNA或RNA分子的一种或几种的混合物。
在步骤(2)中,氨基化荧光分子为香豆素类荧光分子、罗丹明类荧光分子、氟硼荧类分子、花菁类荧光分子或异硫氰酸荧光分子;N端无修饰的生物活性多肽为细胞粘附肽、细胞生长肽、抗菌肽、神经活性肽、激素调节肽、抗高血压活性肽、抗氧化活性肽或免疫活性肽;生长因子为成骨细胞生长因子、神经分化因子、成纤维细胞生长因子、表皮细胞生长因子、转化生长因子-β、血小板衍化生长因子或角化细胞生长因子;具有生物功能的氨基化DNA RNA分子为抗肿瘤类核酸分子、肿瘤细胞表面受体类核酸分子。
本发明与现有技术相比,具有以下有益效果:本发明方法简单易行,避免了繁复的修饰步骤,只需一步法即可制备生物功能化的壳聚糖水凝胶;反应条件温和,无需辐射的苛刻条件或加入引发剂等毒性化学物质,只需中性条件即可,是一种完全亲和生物体的方法;成本低、制备速度快、可量产,所得产品功能化水凝胶后处理方法简单,可满足临床等实际应用。该方法制备功能化壳聚糖水凝胶效率高、污染低,适于推广应用。
附图说明
图1为京尼平交联的壳聚糖水凝胶原理示意图;
图2为一步法制备生物功能化壳聚糖水凝胶示意图;
图3为荧光功能化的壳聚糖水凝胶的荧光显微镜照片;
图4为细胞在RGD功能化水凝胶表面的贴附性能示意图。
具体实施方式
下面通过实施例对本发明作进一步地说明。
本发明的目的在于开发一种简便制备生物功能化的壳聚糖水凝胶的新方法,即一步法制备含有特殊生物功能且无毒的京尼平交联的壳聚糖水凝胶。本制备方法简单易操作、反应条件温和成熟、细胞毒性,价格低廉,适于推广和临床应用。
京尼平作为壳聚糖水凝胶的交联剂已有诸多报道。其交联过程示意图如图1:京尼平与壳聚糖的反应是自发的,其与氨基(H2N-R)的自发反应可同时发生在两个活性部位,即烯碳原子受氨基亲核进攻后形成杂环胺化合物,以及酯基与氨基发生亲核取代反应生成酰胺。通过控制反应物的比例,可以制备不同交联度的壳聚糖水凝胶,同时水凝胶中可能存在大量未参与交联反应的京尼平活性反应点。这为本发明提供了简单易行的功能化方法,如图2。
图2显示了在反应同时加入含有氨基的生物功能化分子,可通过一步法直接引入壳聚糖水凝胶,并使其获得特殊的生物功能,例如通过荧光分子、生长因子、生物活性多肽和蛋白以及DNA或RNA核酸分子的引入,得到荧光标记的、调控细胞贴附增值迁移以及定向分化等多种生物功能的壳聚糖水凝胶。
用于本发明的特殊生物功能的分子包括:
(1)氨基化荧光分子,如:香豆素类荧光分子、罗丹明类荧光分子、氟硼荧类分子、花菁类荧光分子、异硫氰酸荧光分子等;
(2)N端无修饰的生物活性多肽,如:细胞粘附肽、细胞生长肽、抗菌肽、神经活性肽、激素调节肽、抗高血压活性肽、抗氧化活性肽、免疫活性肽等;
(3)各种蛋白及生长因子,如:成骨细胞生长因子(BMP-2)、神经分化因子(NGF)、成纤维细胞生长因子(FGF)、表皮细胞生长因子(EGF)、转化生长因子-β(TGF-β)、血小板衍化生长因子(PDGF)、角化细胞生长因子(KGF)、胰岛蛋白(Insulin)、溶菌酶蛋白(Lysozyme)等
(4)所有具有生物功能的氨基化DNA或RNA aptamer:抗肿瘤类核酸分子、肿瘤细胞表面受体类核酸分子。
一种制备生物功能化壳聚糖水凝胶的方法,包括以下具体步骤:
(1)首先,不同质量分数京尼平的配制:用75%酒精1ml,溶解0.005g、0.01g、0.02g的京尼平配置成0.5%、1.0%、2.0%的京尼平溶液;
(2)壳聚糖溶液的制备:1.5g的壳聚糖溶于100ml的3%的醋酸溶液中制备成1.5%的壳聚糖溶液,并加入含有氨基的生物分子,于锥形瓶中搅拌过夜;
(3)将上述两种溶液按照不同的比例混合,室温静置24-72h后即可得到壳聚糖水凝胶。其中,京尼平和氨基生物分子的摩尔比例保持在10:5至10:1之间,壳聚糖和京尼平的摩尔比例保持在300:1至30:10之间。
(4)功能化壳聚糖水凝胶的性能判定:
对不同功能化的壳聚糖水凝胶,我们可通过鉴定其生物功能进行验证。最直接的验证方法是引入荧光分子的水凝胶检测其荧光性能,若显示明显荧光,则本发明方法可行。我们还可以通过引入RGD的水凝胶考察其对细胞的贴附性能,若细胞贴附性能明显改善,则本发明方法可行。
实施例1:一步法制备荧光功能化的壳聚糖水凝胶
制备方法:
首先,用75%酒精1ml,溶解0.02g的京尼平配置成2.0%的京尼平溶液;与此同时,1.5g的壳聚糖溶于100ml的3%的醋酸溶液中制备成1.5%的壳聚糖溶液,并加入1mg含有氨基的FITC荧光分子,于锥形瓶中搅拌过夜,得到壳聚糖和FITC的混合溶液;将上述两种溶液1:1均匀混合,室温静置48h后即可得到荧光分子FITC功能化的壳聚糖水凝胶。
结果分析:
图3显示加入荧光分子的壳聚糖水凝胶在荧光显微镜下显示出明显的荧光,而未加入荧光分子的壳聚糖水凝胶不显示荧光,结果充分说明本发明是一种简单高效的制备功能化壳聚糖水凝胶的新方法。
实施例2:一步法制备细胞粘附肽RGD功能化的壳聚糖水凝胶
制备方法:
首先,用75%酒精1ml,溶解0.01g的京尼平配置成1.0%的京尼平溶液;与此同时,1.5g的壳聚糖溶于100ml的3%的醋酸溶液中制备成1.5%的壳聚糖溶液,并加入1mg含有氨基的细胞粘附肽GGRGDS,于锥形瓶中搅拌过夜,得到壳聚糖和GGRGDS的混合溶液;将上述两种溶液1:1均匀混合,室温静置72h后即可得到具有细胞粘附分子GGRGDS的壳聚糖水凝胶。
结果分析:
:图4为壳聚糖水凝胶种植MC-3T3细胞,经过24h培养后,其表面细胞的贴附形态。观察前先将细胞和细胞核染色。加入GGRGD的壳聚糖水凝胶显示出对细胞更强的贴附性能,其细胞形态为贴附的铺展状,DAPI和鬼笔环肽染色后发现很明显的粘着斑;而未加入GGRGD的水凝胶对细胞贴附性较差,其细胞形态为收缩球形。这一结果充分证明GGRGDS的成功引入可以有效改进细胞在水凝胶表面的贴附性能。再次验证本发明是一种简单高效的制备功能化壳聚糖水凝胶的新方法,同时该方法具有普适性。
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等同形式的替换,这些改进和等同替换得到的技术方案也应属于本发明的保护范围。
Claims (4)
1.一种制备生物功能化壳聚糖水凝胶的方法,其特征在于,包括如下步骤:
(1)首先,不同质量分数京尼平的配制:用75%酒精1ml,分别溶解0.005g、0.01g和0.02g的京尼平配置成0.5%、1.0%、2.0%的京尼平溶液;
(2)壳聚糖溶液的制备:1.5g的壳聚糖溶于100ml的3%的醋酸溶液中制备成1.5%的壳聚糖溶液,并加入含有氨基的生物分子,于瓶中搅拌过夜;
(3)将上述两种溶液按照不同的比例混合,室温静置24-72h后即可得到功能化壳聚糖水凝胶;其中,京尼平和含有氨基的生物分子的摩尔比例保持在10:5至10:1 之间,壳聚糖和京尼平的摩尔比例保持在300:1至30:10之间。
2.根据权利要求1所述的一种制备生物功能化壳聚糖水凝胶的方法,其特征在于,在步骤(3)之后,还包括步骤(4)功能化壳聚糖水凝胶的性能判定。
3.根据权利要求1所述的一种制备生物功能化壳聚糖水凝胶的方法,其特征在于,在步骤(2)中,含有氨基的生物分子为氨基化荧光分子、N端无修饰的生物活性多肽、活性蛋白、生长因子、具有生物功能的氨基化DNA 或RNA分子的一种或几种的混合物。
4.根据权利要求3所述的一种制备生物功能化壳聚糖水凝胶的方法,其特征在于,在步骤(2)中,氨基化荧光分子为香豆素类荧光分子、罗丹明类荧光分子、氟硼荧类分子、花菁类荧光分子或异硫氰酸荧光分子;N端无修饰的生物活性多肽为细胞粘附肽、细胞生长肽、抗菌肽、神经活性肽、激素调节肽、抗高血压活性肽、抗氧化活性肽或免疫活性肽;生长因子为成骨细胞生长因子、神经分化因子、成纤维细胞生长因子、表皮细胞生长因子、转化生长因子-β、血小板衍化生长因子或角化细胞生长因子;具有生物功能的氨基化DNA /RNA分子为抗肿瘤类核酸分子、肿瘤细胞表面受体类核酸分子。
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CN114539608A (zh) * | 2022-03-01 | 2022-05-27 | 浙江大学 | 一种含氨基天然大分子多孔水凝胶的制备方法 |
CN115501259A (zh) * | 2022-09-22 | 2022-12-23 | 东北农业大学 | 一种用于缓解溃疡性结肠炎的组合物和应用 |
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