CN113633821A - 一种温敏型可注射型胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶材料及其制备方法 - Google Patents
一种温敏型可注射型胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶材料及其制备方法 Download PDFInfo
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Abstract
本发明涉及温敏型可注射型胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶的制备方法,其制备过程包括:胶原溶液、壳聚糖溶液共混,加入经溶胶‑凝胶法制得的掺锌生物玻璃纳米颗粒,调节PH值至中性,将所得的胶原/壳聚糖/掺锌生物玻璃纳米颗粒共混溶液放置于37℃下5分钟可形成水凝胶。本发明所制备的温敏型可注射胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶在医学领域有很大的应用前景,其温敏可注射特性具有微创,方便塑型的优点,可作为医用骨组织再生修复材料用于腔隙性、手术难操作、不规则的骨缺损组织。
Description
技术领域
本发明涉及一种应用于骨组织再生修复的温敏型可注射复合水凝胶材料及其制备方法,尤其涉及一种温敏型可注射型胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶材料及其制备方法,所述温敏可注射复合水凝胶可用于组织工程,细胞培养等方面。
背景技术
水凝胶(Hydrogel)具有优良的生物学特性能模拟天然细胞外基质(ECM),具有高水含量,生物降解性,高孔隙率和生物相容性等生物结构,在水中的溶解度低于百分之一,但具有溶胀性,亲水小分子可以在水凝胶中扩散;水凝胶的组成,结构,机械性能和生化性能可方便地调整以适合各种生物医学应用。
按照水凝胶对外界刺激的响应性,水凝胶可分为两类:一类是环境响应型水凝胶(智能水凝胶根据响应条件的不同可以分为温度敏感型、pH敏感型、光敏感型、电敏感型、磁敏感型等);另一类是环境不响应型水凝胶(普通水凝胶)。其中,作为环境响应型的典型代表——温敏水凝胶,成为近年来的研究热点,温敏可注射水凝胶能够在室温下保持液体,并在37℃体温下形成固态凝胶,因其具有微创、低注射成本等优点,在药物输送、组织修复和重建手术等方面具有广阔的应用前景,甚至可以填充微小和不规则的损坏的空洞。但是,仅仅依靠单纯的水凝胶还是远远不够,这类水凝胶存在力学强度不足、网格结构不稳定、体内维持时间短、具有较差的细胞定向和粘附性,并且缺乏成骨细胞作用所需的蛋白质,因此它们不能直接与宿主骨结合。与此同时,还必须具有生物相容性、生物稳定性和无毒的引发系统。在多种天然聚合物中,胶原、壳聚糖及其衍生物已被大量用于制备具有良好性能的复合水凝胶。
壳聚糖(Chitosan,CS)又称脱乙酰甲壳素,是一种天然的高分子聚合物,是海洋无脊椎动物外壳上的甲壳素脱乙酰基后的产物,来源广泛,主要的结构单元为葡糖胺,是唯一天然存在的阳离子多糖,CS主要通过几丁质酶或溶菌酶来完成降解,降解的单体产物为氨基葡萄糖,其不仅对人体无毒副作用,而且在体内不积累、不会引起抗原反应,因此CS具有良好生物相容性、低细胞毒性和生物体内可降解性等优,另外,CS价格低廉、数量丰富,易于改性、在生物环境中易于被识别和代谢。由于其固有的抗菌活性、伤口愈合特性和低免疫原性,它被大量用于生物材料;此外,CS可以根据需求,被加工成各种结构,例如颗粒、膜、水凝胶和其他复杂的用于骨修复的结构,在骨损伤治疗中发挥了非常好的作用,同时还可作为组织工程支架材料应用于神经、软或硬组织等领域。
但是,CS是弱碱性,不溶于水,只溶于pH低于6.5的酸性溶液中。2000年Chenite发现在CS酸性溶液加入一定量的β-甘油磷酸钠,可以使弱酸性溶液中和至中性,并具备了温敏特性。即在温度较低的室温下呈液态,在达到37℃后呈现凝胶状态,壳聚糖、β-甘油磷酸钠和水之间的相互作用导致溶胶/凝胶转变。
可注射性就是基于温敏水凝胶溶液/凝胶转变这一特性。将壳聚糖或与其他复合材料结合,在室温下,直接通过注射器注射到机体缺损部位。在37℃下,材料能在缺损部位很快形成具有一定机械强度、任意形状的凝胶支架状态,细胞在支架中生长并最终形成组织。由于具有微创性、侵入小以及低费用等特点,可注射性支架具有重要的临床应用价值和良好的发展前景。可注射性水凝胶支架主要通过溶胶/凝胶转变在体内成型,具有良好的细胞相容性和易成型等特点。
胶原蛋白(Collagen,COL)是脊椎动物身体中含量最多的结构蛋白,主要分布于软骨、部分具有生物活性的硬骨等机械支撑组织和血管、肌肉、皮肤等运输和保护组织中。作为常与生物活性玻璃和羟基磷灰石复合的胶原是细胞外基质(ECM)的一种主要组成成分,胶原对细胞有着优异的粘附和诱导生长的作用,COL常被作为生物材料表面改性剂来提高材料表面对细胞的粘附。COL主要是通过金属蛋白酶特别是胶原酶和丝氨酸蛋白酶的作用而降解,具有良好的生物降解性,同时还具有低免疫原性和良好的生物相容性等特点。另外,胶原还可以促进细胞的迁移和分化、刺激细胞的增殖且不产生排斥反应,因此被广泛用于生物医学和组织工程等领域。
生物活性玻璃(Bioactive glasse,BG)最早是由Larry Hench发现的,是骨再生材料发展过程中最重要的里程碑之一,研究发现这些生物玻璃不仅具有良好的生物相容性和降解性,且参与了新生骨骼和牙齿的构建,其与骨和软组织都有良好的生物结合特性,能够在植入部位的生理环境中迅速发生一系列表面反应,并最终导致羟基磷灰石层的形成。生物活性玻璃纳米颗粒是一类重要的生物活性填料,它不仅可以提高仿生复合组织工程支架材料的生物活性,还可以显著增强其力学强度。相比于普通的生物活性玻璃,生物活性纳米颗粒具有普通生物活性玻璃所无法比拟的更大的比表面积且更容易降解,同时具有均一的纳米级介孔结构和良好的生物相容性和热稳定性,使得这种生物玻璃受到越来越广泛的关注,已应用在骨组织工程要药物释放载体方面。纳米介孔生物活性玻璃一般使用溶胶—凝胶法来制备。近年来,溶胶-凝胶技术已成为制备新材料的重要方法。不同于传统的熔融法,溶胶-凝胶法制备的生物活性玻璃是由大量的粒径为几十纳米的微球组成,颗粒分散性差,测得的颗粒尺寸多为微米级。而具有纳米级颗粒尺寸并具有良好分散性的新型纳米生物活性玻璃对于制备高生物活性骨修复体、骨组织工程支架及药物载体具有重要的理论和实际意义。
传统的成骨再生主要将目标靶向于成骨细胞,但是研究表明,免疫微环境的调控和骨再生有密切的联系。巨噬细胞作为免疫系统重要的作用细胞,在外界刺激下,可以向M1型和M2型分化,M1型有促炎作用,释放促炎因子,不利于骨再生;M2型有抑制炎症作用,释放抑炎症因子,有利于组织愈合。另外,生物材料产生的免疫微环境可以通过其表面微观结构,润湿性,粒径,孔隙率和释放的离子来调节。当前已经有研究在生物活性玻璃中添加氟元素促进成骨细胞分化,添加锶元素可以提高细胞活力,促进血管张入;添加银元素有抑菌杀菌作用。锌是构成某些关键酶和转录因子的必需微量元素,适量的锌可以增强抗炎细胞因子的表达并维持抗炎环境。并有研究证实锌离子在骨免疫调节过程中是一种很有前途的添加剂。
CN108744057A公开了一种可注射复合凝胶及其制备方法,包括:壳聚糖溶液、明胶溶液和β-甘油磷酸钠溶液混合步骤;添加生长因子和种子细胞步骤;使制备的凝胶材料具有多种组织修复性能。制得的可注射复合凝胶材料不但具有一定的因子缓释效果还能复合各种细胞,为组织修复提供细胞支持,从而使得该可注射复合凝胶材料能更好地适应损伤部位、减少炎症反应、促进细胞的迁移聚集、种子细胞的分化以及促进新血管的生成和坏死组织的修复。
CN106188361A公开了一种可注射型骨填充用生物活性玻璃复合材料的制备方法以正硅酸四乙酯、磷酸三乙酯、NaNO3、Ca(NO3)2.4H2O、Mg(NO3)2原料作前躯体,聚乙烯醇及聚二甲基硅氧烷作为造孔剂,在催化剂作用下通过溶胶/凝胶法制得生物活性玻璃凝胶,发明了可注射型骨填充用生物活性玻璃复合材料的制备方法,解决了骨填充材料强度低、使用时与缺损组织间存在空隙的问题,有足够强度并且可与骨头紧密贴合,生物相容性好。
CN105664250A公开了一种可注射可降解温敏性水凝胶及其制备方法,其包括:聚N-异丙基丙烯酰胺;以及海藻酸钠、壳聚糖、胶原、透明质酸、甲基纤维素或者聚乳酸-羟基乙酸共聚物。本发明将温敏性材料与具有可降解特性的材料有机结合,在这些材料的组合之下,形成可降解的温敏性水凝胶材料,解决水凝胶材料在体内无法降解的问题
CN111068116A公开了一种注射用软骨修复温敏凝胶,其包括如下组分:壳聚糖、胶原蛋白、β-甘油磷酸钠和成骨细胞因子;包括制备温敏凝胶以壳聚糖与β-甘油磷酸盐共混步骤;加入胶原蛋白和细胞生长因子步骤;应用于软骨缺损修复中,不但具有了可注射性、生物相容性和生物可降解性等功能,同时还为成骨细胞提供了有力的生长空间和诱导定向分化功能。
CN101502673公开了一种可注射壳聚糖/甘油磷酸钠/胶原水凝胶的制备方法,发明制备的壳聚糖/甘油磷酸钠/胶原水凝胶方法简单,原料成本低廉。
PCT专利WO/2014/005471公开了一种京尼平交联的温敏型可注射壳聚糖凝胶产品。在保证水凝胶强度的前提下,解决了交联剂毒性的问题。
但上述材料都没有和抗炎作用结合,虽然部分发明材料也具有温敏可注射性,有的还添加了相关细胞因子,但是太过局限,仅仅靶向于成骨细胞,来促进缺损修复,未将抗炎免疫环境与缺损修复骨再生方面结合。
发明内容
为了解决上述现有技术存在的问题,本发明提供了温敏型可注射型胶原/壳聚糖/介孔生物玻璃复合纳米颗粒水凝胶材料。
因此,本发明的第一个方面是提供一种制备温敏型可注射型胶原/壳聚糖/介孔生物玻璃复合纳米颗粒水凝胶材料的方法,所述方法包括如下步骤:
步骤1,提供胶原溶液、壳聚糖溶液、介孔生物玻璃凝胶;
步骤2,将胶原溶液和壳聚糖溶液混合,然后加入掺锌生物玻璃,得到胶原/壳聚糖/介孔生物玻璃共混溶液;
步骤3,胶原/壳聚糖/掺锌生物玻璃纳米颗粒共混溶液在4℃条件下加入甘油磷酸脂调节PH值至7.0-7.4,然后放置于37℃下5分钟后呈凝胶状态。
其中,所述胶原一般来源于动物,如动物骨或结缔组织,可以是来源于禽类、畜类、水生动物,如牛、猪、驴、羊、骡、马等。其中鱼胶原比传统陆生动物来源的胶原还具有低免疫原性,来源广泛,安全性好等优点。因此,本发明所述胶原优选为鱼胶原。
所述胶原溶液中,溶剂可以是任意能够溶解胶原的有机和/或无机溶剂,如水、羧酸、酯、醇、酮、醛等,具体例子选自:水、甘油、醋酸、卤代有机醇,更优选为选自:氟代有机醇、氟代酮,最优选为乙酸。
所述胶原溶液中,胶原浓度优选为5-15mg/ml,最优选为3.5mg/ml。
其中,所述壳聚糖溶液中,壳聚糖浓度优选为5-15g/100ml,最优选为2g/100ml。
所述壳聚糖数据分子量为1万至40万,更优选为30万至40万
所述壳聚糖溶液中,溶剂可以是任意能够溶解壳聚糖的溶剂,如水、醇、有机羧酸、酯、酮、醛等,并优选为乙酸。
其中,所述掺锌介孔生物玻璃纳米颗粒采用溶胶-凝胶法制备,制备方法为:将聚合物和酸溶解于溶剂中,加入正硅酸酯、钙盐、磷酸酯,60-100℃陈化,得到掺锌介孔生物玻璃纳米颗粒。
所述掺锌介孔生物玻璃纳米颗粒中,介孔生物玻璃纳米颗粒材料的浓度优选为0.5-10g/100ml,更优选为0.5-3g/100ml。
所述甘油磷酸脂溶液中,加入后调节PH至7.0-7.4
本发明上述的方法中,介孔生物玻璃凝胶中,胶原、壳聚糖和掺锌介孔生物玻璃纳米颗粒的重量比优选为(20-1)∶(20-1)∶(0.5-5);更优选为1∶1∶0.5-2
本发明的第二个方面是提供一种胶原/壳聚糖/掺锌介孔生物玻璃纳米颗粒水凝胶材料,其中,所述胶原/壳聚糖/掺锌介孔生物玻璃纳米颗粒水凝胶材料包括胶原、壳聚糖和掺锌介孔生物玻璃纳米颗粒。
所述胶原/壳聚糖/掺锌介孔生物玻璃纳米颗粒材料优选为由本发明第一个方面所述方法制备。
本发明的优点在于:
(1)胶原对细胞有着优异的粘附和诱导生长的作用,具有良好的生物降解性,同时还具有低免疫原性和良好的生物相容性等特点。另外,胶原还可以促进细胞的迁移和分化、刺激细胞的增殖且不产生排斥反应。
(2)壳聚糖不仅对人体无毒副作用,而且在体内不积累、不会引起抗原反应,具有良好生物相容性、低细胞毒性和生物体内可降解性等优,此外,CS可以根据需求,被加工成各种结构,例如颗粒、膜、水凝胶和其他复杂的用于骨修复的结构,在骨再生中可以发挥非常好的作用。
(3)掺锌介孔生物玻璃纳米颗粒不仅可以提高仿生复合组织工程支架材料的生物活性,还可以显著增强其力学强度。具有更大的比表面积且更容易降解,同时具有均一的纳米级介孔结构和良好的生物相容性和热稳定性,对于制备高生物活性骨修复体、骨组织工程支架及药物载体具有重要的理论和实际意义。
(4)本发明生物活性纳米颗粒中,负载的锌元素,可以增强抗炎细胞因子的表达并维持抗炎环境,相对于有学者单纯的温敏可注射胶原/壳聚糖/生物活性玻璃更具优势,添加锌为成骨再生提供合适的免疫微环境。
(5)本发明将壳聚糖与甘油磷酸脂混合配比成中性溶液,并与胶原,掺锌生物玻璃纳米颗粒共混,制成混合溶液,得到温敏型可注射型复合水凝胶。具有较好的生物相容性,降解性,低免疫原性以及较好的机械性能;同时兼具微创,安全,塑性方便,凝胶迅速等优势;在良好的促成骨的同时,还提升了复合材料的抗炎作用。
总之,所述温敏型可注射型复合水凝胶原料来源广泛,体内相容性好,细胞亲和力高,具有良好的成骨再生能力,又具有抗炎作用;尤其适用于腔隙型骨缺损的情况,是一种理想的成骨再生充填材料,可用作复杂骨缺损再生修复等。
附图说明
图1是实施例1制得的温敏型可注射型Col/CS/0.5%Zn-MBGN的扫描电镜图;
图2是实施例2制得的温敏型可注射型Col/CS/1%Zn-MBGN的扫描电镜图;
图3是实施例3制得的温敏型可注射型Col/CS/2%Zn-MBGN的扫描电镜图;
图4是实施例1制得的凝胶的溶胀性和降解性实验结果。
具体实施方式
下面结合具体实例,进一步阐述本发明,需理解这些实例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实例一:
用电子分析天平称取350mg鱼胶原溶于50ml 0.02M乙酸溶液中得到浓度为7mg/ml的鱼胶原溶液;用电子分析天平称取4g壳聚糖溶于200ml 0.1M乙酸溶中,得到浓度为2%的壳聚糖溶液。将8ml 2%壳聚糖溶液加入2ml的7mg/ml鱼胶原溶液中,常温下磁力搅拌待完全溶解。Zn-MBGN通过溶胶凝胶法制备。简言之,2.24g十六烷基三甲基溴化铵(CTAB)溶解在104ml去离子水中,加入32ml乙酸乙酯搅拌。添加28%氢氧化铵并保持PH在10.5。15min后在溶液中加入正硅酸乙酯(TEOS)23.04ml,搅拌30min后加入4.34g Ca(N3O2).4H2O。30min后添加1.09g Zn(N3O2).6H2 O。搅拌4h,离心,烘干,沉淀物在700℃下钙化2h得到Zn-MBGN。在壳聚糖/鱼胶原溶液中加入用2ml去离子水溶解的60mg Zn-MBGN,,得到质量比为1/1/0.5%的鱼胶原/壳聚糖/掺锌介孔生物玻璃纳米颗粒共混溶液,加入56wt%甘油磷酸脂,调节PH至7.0-7.4,在37℃静置五分钟后溶液变成凝胶。实施例1所得凝胶溶胀性和降解性实验结果如图4所示。
实例二:
用电子分析天平称取350mg鱼胶原溶于50ml 0.02M乙酸溶液中得到浓度为7mg/ml的鱼胶原溶液;用电子分析天平称取4g壳聚糖溶于200ml 0.1M乙酸溶中,得到浓度为2%的壳聚糖溶液。
将8ml 2%壳聚糖溶液加入2ml的7mg/ml鱼胶原溶液中,常温下磁力搅拌完全溶解后,再加入用2ml ddH2O溶解的120mg Zn-MBGN,得到质量比为1/1/1%的鱼胶原/壳聚糖/掺锌介孔生物玻璃纳米颗粒共混溶液,加入56wt%甘油磷酸脂,调节PH至7.0-7.4,在37℃静置五分钟后溶液变成凝胶。
实例三:
用电子分析天平称取350mg鱼胶原溶于50ml 0.02M乙酸溶液中得到浓度为7mg/ml的鱼胶原溶液;用电子分析天平称取4g壳聚糖溶于200ml 0.1M乙酸溶中,得到浓度为2%的壳聚糖溶液。
将8ml 2%壳聚糖溶液加入2ml的7mg/ml鱼胶原溶液中,常温下磁力搅拌待完全溶解后,再加入用2ml ddH2O溶解的240mg Zn-MBGN,,得到质量比为1/1/2%的鱼胶原/壳聚糖/掺锌介孔生物玻璃纳米颗粒共混溶液,加入56wt%甘油磷酸脂,调节PH至7.0-7.4,在37℃静置五分钟后溶液变成凝胶。
通过溶胀性和降解性实验我们可以发现,该水凝胶材料具有较好的稳定性,短时间内快速溶胀表明材料具有良好的吸水性能,有利于组织修复,缓慢持续的降解则有利于材料在一定时间内发挥效能。
以上对本发明的具体实施例进行了详细描述,但其只是作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (10)
1.一种制备温敏型可注射型胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶材料的方法,其特征在于,所述方法包括如下步骤:
步骤1,提供胶原溶液、壳聚糖溶液、掺锌生物玻璃纳米颗粒;
步骤2,将胶原溶液和壳聚糖溶液按照一定比例混合,然后加入掺锌生物玻璃纳米颗粒,得到胶原/壳聚糖/掺锌生物玻璃纳米颗粒共混溶液;
步骤3,将得到的胶原/壳聚糖/掺锌生物玻璃纳米颗粒共混溶液加入甘油磷酸脂调节PH,然后放置后呈凝胶状态。
2.根据权利要求1所述的方法,其特征在于,所述胶原为鱼胶原,溶剂为乙酸溶液。
3.根据权利要求1所述的方法,其特征在于,所述壳聚糖溶液中,溶剂为乙酸溶液。
4.根据权利要求1所述的方法,其特征在于,所述掺锌生物玻璃纳米颗粒采用溶胶-凝胶法制备,制备方法为:将聚合物和酸溶解于溶剂中,加入正硅酸酯、钙盐、磷酸酯,60-100℃陈化,得到掺锌生物玻璃纳米颗粒凝胶。
5.根据权利要求1所述的方法,其特征在于,胶原/壳聚糖/掺锌生物玻璃纳米水凝胶中,胶原、壳聚糖和掺锌生物玻璃纳米颗粒的重量比为(1-10):(1-10):(0.5-5)。
6.根据权利要求1所述的方法,其特征在于,步骤3中调节PH至7.0-7.4。
7.一种胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶,其特征在于,所述胶原/壳聚糖/掺锌生物玻璃纳米颗粒水凝胶包括胶原、壳聚糖和掺锌生物玻璃纳米颗粒材料。
8.根据权利要求7所述的水凝胶材料,其特征在于,所述水凝胶材料需要在4℃条件下加入甘油磷酸脂调节PH至7.0-7.4。
9.根据权利要求8所述的水凝胶材料,其特征在于,所述水凝胶材料调节PH值至中性后需要放在37℃条件下5min。
10.根据权利要求7-9任一项所述的水凝胶材料,其特征在于,其由权利要求1-6任一项所述的方法制备获得。
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