CN114763415A - 一种高性能可加工水凝胶及其制备方法和应用 - Google Patents
一种高性能可加工水凝胶及其制备方法和应用 Download PDFInfo
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- CN114763415A CN114763415A CN202110051089.4A CN202110051089A CN114763415A CN 114763415 A CN114763415 A CN 114763415A CN 202110051089 A CN202110051089 A CN 202110051089A CN 114763415 A CN114763415 A CN 114763415A
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Abstract
本发明公开了一种高性能可加工水凝胶及其制备方法和应用，所述水凝胶包括可加工高分子水凝胶基体和基于海藻酸盐与生物陶瓷材料的分散体系在所述基体中形成的互穿网络结构和/或半互穿网络结构，从而使得水凝胶可以包载具有诱导骨修复能力的生物陶瓷材料颗粒，以及其他类型的生物活性物质如药物、生物活性分子或细胞等，以实现水凝胶对上述生物活性物质的装载和输送。并通过合理优化凝胶网络中各组分的配比，以调节其力学性能、诱导、支撑不规则承力成骨细胞分化的能力，并促进矿化。因此，本发明获得的水凝胶在疾病治疗以及组织工程领域具备较高的应用前景。
Description
技术领域
本发明属于高分子化学材料领域，具体涉及一种高性能可加工水凝胶及其制备方法和应用。
背景技术
生物陶瓷材料，例如经典的生物玻璃(
BG)、羟基磷灰石、磷酸钙骨水泥、硫酸钙盐、碳酸钙、二氧化硅等，其成分与天然骨骼相似。临床研究证实：生物陶瓷材料具有骨诱导并与骨骼结合的能力。如(Hench LL，Polak JM.Third-generation biomedicalmaterials[J].Science.2002；295(5557):1014-7；Jones JR.Review of bioactiveglass:From Hench to hybrids[J].Acta Biomaterialia.2013；9:4457-4486；Marelli B，Ghezzi CE，Mohn D，et al.Accelerated mineralization of dense collagen-nanobioactive glass hybrid gels increases scaffold stiffness and regulatesosteoblastic function[J].Biomaterials.2011；32:8915-8926；Okesola BO，Ni S，Derkus B，et al.Growth-factor free multicomponent nanocomposite hydrogels thatstimulate bone formation[J].Advanced Functional Materials.2020；30:1906205)等研究表明，上述材料与体液反应，会在其表面生成一层具有生物相容性的羟基磷灰石以支持骨细胞的粘附。尤其重要的是，体外及体内实验均表明
溶解释放的水溶性硅、钙离子等能促进相关基因表达(Osteoproduction)以促进骨间充质干细胞的成骨分化，同时自身也将逐渐在体内降解，最终被新生的骨组织所取代。如(Hench LL，Polak JM.Third-generation biomedical materials[J].Science.2002；295(5557):1014-7；Stone-WeissN，Pierce EM，Youngman RE，et al.Understanding the structural drivers governingglass-water interactions in borosilicate based model bioactive glasses[J].Acta Biomater.2018；65:436-449；Zhai XY，Ruan CS，Ma YF，et al.3D-bioprintedosteoblast-laden nanocomposite hydrogel constructs with inducedmicroenvironments promote cell viability，differentiation，and dsteogenesisboth in vitro and in vivo[J].Advanced Science.2018，5，1700550)。然而与人体骨组织相比，这类具备生物活性的颗粒的弹性模量过高、脆性大、断裂韧性与机械强度较低，且由于材料的机械性能与骨组织不匹配而易引起骨修复失败，从而使得该类活性颗粒在骨修复中的应用受限。(Stone-Weiss N，Pierce EM，Youngman RE，et al.Understanding thestructural drivers governing glass-water interactions in borosilicate basedmodel bioactive glasses[J].Acta Biomater.2018；65:436-449；HenchLL.Bioceramics:From concept to clinic[J].Journal of the American CeramicSociety.1991；74(7):1487-510)。
水凝胶由于其与细胞外基质的相似性以及模量的可调性，因而在与血液、体液及人体组织相接触时表现出良好的生物相容性。将其应用于人体组织时，既能不影响生命体的代谢过程，又可以使代谢产物通过体液循环排出。因此，在组织工程应用领域受到了极大的关注。如(Gao F，Xu ZY，Liang QF，et al.Osteochondral regeneration with 3D-printed biodegradable high-strength supramolecular polymer reinforced-gelatinhydrogel scaffolds[J].Advanced Science News.2019；6:1900867；Boyer C，FigueiredoL，Pace R，et al.Laponite nanoparticle-associated silated hydroxypropylmethylcellulose as an injectable reinforced interpenetrating network hydrogel forcartilage tissue engineering[J].Acta Biomater.2018；65:112-122)等研究表明，水凝胶是良好的载体，可负载几乎所有类型的治疗物质和生物活性物质，包括亲/疏水性药物、蛋白、多肽、基因或细胞，并具有可控释放的能力。同时水凝胶分子具有的多官能团特性，使之易于功能化，因此可针对不同用途赋予其生物降解性、组织粘附性、韧性、弹性等，从而提高其作为支架和载体的效能。此外，在水凝胶制备过程中，可以通过调控高分子的交联动力学使得体系具备原位凝胶化能力，以使水凝胶或水凝胶复合物具有可加工性。如(Yan Y，LiMN，Yang D，et al.Construction of injectable double-network hydrogels for celldelivery[J].Biomacromolecules.2017；18(7):2128-2138；Zhao YR，Li MN，Liu BC，etal.Ultra-tough injectable cytocompatible hydrogel for 3D cell culture andcartilage repair[J]Journal of Materials Chemistry B.2018；6:1351-1358；Zhao YR，Cui ZY，Liu BC，et al.An Injectable Strong Hydrogel for Bone Reconstruction[J].Advanced Healthcare Materials.2019；1900709)。然而，水凝胶自身缺乏生物活性，其力学性能与骨软骨相比仍然存在很大差距，且与受体之间的吻合度差，从而使其在临床骨科中的应用受限。因此，如何获得具备良好生物活性、柔韧性且具备加工性能的水凝胶材料成为组织工程领域亟待解决的技术难题。
发明内容
为了克服上述技术问题，本发明提供一种高性能可加工水凝胶及其制备方法和应用，该水凝胶是基于海藻酸盐与生物陶瓷材料的分散体系在可加工高分子水凝胶基体中形成互穿网络结构和/或半互穿网络结构，从而使得水凝胶不仅具有诱导骨修复能力，同时可以用于包载不同类型的生物活性物质，如药物、生物活性分子和细胞等，并使其不易快速流失。本发明所获得的高性能可加工水凝胶可适用于对生物活性物质的包载和输送、模拟类骨的机械和生物特性及其矿化能力、研制用于骨及软骨的再生治疗，并有望用于疾病治疗和组织工程领域。
本发明提供一种高性能可加工水凝胶，所述水凝胶包括可加工高分子水凝胶基体和基于海藻酸盐与生物陶瓷材料的分散体系在所述基体中形成的高分子网络结构。
根据本发明的实施方案，所述高分子网络结构为互穿网络结构和/或半互穿网络结构。
根据本发明的实施方案，所述可加工高分子水凝胶基体为包含动态共价键交联、次级相互作用交联、或包含上述两种交联方式所形成的具有高分子网络的高分子水基溶液或溶胶中的至少一种。
根据本发明的实施方案，所述动态共价键可以为亚胺键、硼酸酯键、酰腙键、酯键、缩醛键或二硫键中的至少一种；
根据本发明的实施方案，所述次级相互作用可以为静电相互作用、氢键、疏水相互作用中的至少一种；优选地，所述静电相互作用为离子键。
优选地，所述高分子水凝胶基体中的高分子可以选自透明质酸、壳聚糖、壳聚糖衍生物、葡聚糖、羟乙基纤维素、聚乙烯醇、Pluronic-F127(聚氧乙烯聚氧丙烯醚嵌段共聚物，商品名-泊洛沙姆)、聚乳酸共聚物、聚乙交酯丙交酯共聚物、聚乙内酯共聚物、聚乙二醇、聚乙二醇-聚乳酸共聚物、聚乙二醇-聚乙交酯丙交酯共聚物和聚乙二醇-聚己内酯共聚物中的至少一种；更优选地，所述壳聚糖衍生物为羧甲基壳聚糖、羟乙基壳聚糖中的至少一种。
根据本发明的实施方案，所述生物陶瓷材料的粒径不大于0.1mm；例如为10nm～100μm；优选为500nm～80μm；更优选为1μm～50μm；示例性为10nm、500nm、1μm、10μm、50μm、80μm或100μm。
根据本发明的实施方案，所述生物陶瓷材料占所述可加工水凝胶的质量百分比不少于1％；例如所述质量百分比为1～80％；优选为10～60％；示例性为1％、10％、20％、25％、30％、60％、80％。
根据本发明的实施方案，所述生物陶瓷材料可以选自生物活性玻璃、羟基磷灰石、磷酸钙骨水泥、硫酸钙盐、碳酸钙、二氧化硅等具备生物活性的无机颗粒中的至少一种。
根据本发明的实施方案，所述海藻酸盐的平均相对分子质量为5～700kDa；例如10～600kDa；优选为100～300kDa；示例性地，平均相对分子质量为5kDa、10kDa、20kDa、60kDa、100kDa、150kDa、300kDa、400kDa、500kDa、600kDa、700kDa。
根据本发明的实施方案，所述海藻酸盐占所述可加工水凝胶的质量百分比不少于1％；例如所述质量百分比为1～60％；优选为5～50％；示例性为1％、3％、5％、10％、20％、37％、40％、50％、60％。
根据本发明的实施方案，所述高分子网络占所述可加工水凝胶的质量百分比不少于1％；例如所述质量百分比为1～80％；优选为10～60％；示例性为1％、5％、10％、20％、30％、40％、50％、60％、80％。
本发明还提供上述高性能可加工水凝胶的制备方法，该方法包括：将海藻酸盐、生物陶瓷材料，与高分子水凝胶基体混合，凝胶化得到所述高性能可加工水凝胶。
根据本发明的实施方案，所述海藻酸盐可以以单纯的海藻酸盐形式加入，或者以海藻酸盐溶液形式加入。
根据本发明的实施方案，所述海藻酸盐溶液中海藻酸盐的质量百分比不小于1％；例如为1～60％；优选为3～30％；示例性为5％、10％、20％、30％、50％、60％。
根据本发明的实施方案，所述海藻酸盐包括海藻酸钠、海藻酸钾、海藻酸钙、海藻酸铵中的至少一种。
根据本发明的实施方案，所述生物陶瓷材料可以以其固体颗粒形式加入，或者以其分散液的形式加入；优选地，所述生物陶瓷材料颗粒可以配制成混合液的形式加入。
根据本发明的实施方案，所述生物陶瓷材料颗粒分散液中，生物陶瓷材料颗粒的质量百分比大于0；例如为1～60％；优选为10～50％；示例性为1％、10％、15％、20％、30％、50％、60％。
根据本发明的实施方案，所述分散液、以及所述的高分子水基溶液中的溶剂可以选自水、含水溶液或含水分散液；例如可以选自水、磷酸缓冲液中的一种。
根据本发明的实施方案，所述高分子水凝胶基体占可加工水凝胶总体积比例不少于1％；优选为10～50％；示例性为7％、10％、20％、30％、40％、50％。
根据本发明的实施方案，所述混合不限顺序，例如可以将三者同时混合；也可以将三者中的任意两者混合均匀后，再与另一者混合。
根据本发明的实施方案，所述混合可在搅拌条件下进行。
根据本发明的实施方案，所述混合可以通过手塑成型得到。
根据本发明的实施方案，所述混合可以通过直接混合得到，也可以通过注射得到。
优选地，所述注射时所用的注射装置包括但不仅限于双联混药器、蠕动泵、计量泵、注射器、注射泵，以及其它用于液体、熔体、分散体系注射的医疗器械，或者是它们的组合。
根据本发明的实施方案，所述制备方法具体包括以下步骤：
(1)准备海藻酸盐溶液：将海藻酸盐溶解于分散剂中，得到海藻酸盐溶液；
(2)准备高分子水凝胶基体：准备可通过动态共价键交联、或次级相互作用交联，或通过上述两种交联方式所形成的具有高分子网络结构的高分子水基溶液或溶胶，即高分子水凝胶基体；
(3)准备生物陶瓷材料颗粒，或其分散液；
(4)将上述步骤制得的物质混合，凝胶化得到所述高性能可加工水凝胶。
根据本发明的实施方案，所述步骤(1)、(2)和(3)中的任意一步骤，其先后顺序可以任意调换，可以单独进行，也可以将任意两个步骤或三个步骤组合。
本发明还提供一种组合物，所述组合物包含上述高性能可加工水凝胶和生物活性物质。
根据本方面的实施方案，所述生物活性物质为药物、生物活性分子或细胞中的至少一种。
例如，所述药物可以为青霉素、链霉素或胎牛血清；所述生物活性分子可以为DNA、RNA、生长因子；优选地，所述生长因子为BMP-2、VEGF中的至少一种。
本发明还提供上述组合物的制备方法，所述制备方法包括在上述高性能可加工水凝胶制备过程中加入生物活性物质，混合均匀即可。
根据本方面的实施方案，上述高性能可加工水凝胶制备过程可以为制备方法的任一步骤；例如，向准备海藻酸盐溶液、准备高分子水凝胶基体或准备生物陶瓷材料颗粒分散液中的至少一个步骤中加入生物活性物质和/或在步骤(4)的混合过程中加入生物活性物质。
本发明还提供上述高性能可加工水凝胶的用途，用于药物包封与输送、药物制备、组织工程、伤口敷料、手塑成型材料或作为注射材料。
例如，所述药物包括组织修复用药物；优选地，所述组织修复包括骨组织和软骨组织的修复。
本发明利用海藻酸盐属于天然高分子材料，来源广、产量高、与细胞外基质相似，在高分子水凝胶基体中可形成互穿和/或半互穿网络等优异特性，并将生物陶瓷材料颗粒分散于可加工高分子水凝胶基体中，以赋予高分子水凝胶诱导骨修复的能力。同时上述原料还可以在温和条件下通过原位接枝共混得到水凝胶；并通过调节凝胶网络中各组分溶液的百分比浓度，以实现水凝胶力学性能地有效调控。
本发明的有益效果是：
与现有技术相比，本发明高性能可加工水凝胶中，海藻酸盐与生物陶瓷材料颗粒的分散体系在高分子水凝胶基体中形成互穿网络结构和/或半互穿网络结构，使得水凝胶可以包载具有诱导骨修复能力的生物陶瓷材料颗粒，以及其他类型的生物活性物质如药物、生物活性分子或细胞等，从而实现水凝胶对上述生物活性物质的装载和输送。并通过合理优化凝胶网络中各组分的配比，以调节其力学性能、诱导成骨细胞分化的能力，并促进矿化。因此，本发明获得的水凝胶在疾病治疗以及组织工程领域具备较高的应用前景。
附图说明
图1为实施例1制备的水凝胶的压缩曲线(a)及扫描电镜图(b)。
图2为实施例2中制备的水凝胶手塑成型加工过程的照片(a)及压缩曲线(b)。
图3为实施例3制备的水凝胶的压缩曲线。
图4为实施例4中水凝胶注射演示图(a)及压缩曲线(b)。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
根据本发明制备方法，所述的分散液，以及所述的高分子水基溶液中的溶剂可以选自水、含水溶液或含水分散液，例如水、PBS、葡糖糖DMEM。
实施例1、海藻酸钠羟基磷灰石颗粒杂化聚乙烯醇水凝胶的制备
将聚乙烯醇PBS溶液与粒径10nm的羟基磷灰石颗粒混合，得到生物陶瓷材料颗粒质量百分比为1％的聚乙烯醇PBS混合溶液，将4-羧基苯硼酸钠加入到海藻酸钠(平均相对分子量为150kDa)PBS溶液中混合均匀，得到海藻酸盐质量百分比为60％的PBS混合溶液。将上述两种溶液混合均匀后通过手塑成型得到圆柱形水凝胶样品。所得最终目标水凝胶中海藻酸盐，生物陶瓷材料颗粒，4-羧基苯硼酸，聚乙烯醇在水凝胶中的质量百分比分别是50％，0.5％，3％，7％。
测试本实施例获得的水凝胶样品的压缩曲线，结果如图1中(a)所示。从图中可以看出，材料的压缩模量可以达到5MPa，压缩强度达323MPa。
并将本实施例获得的水凝胶样品冻干后进行扫描电子显微镜表征，结果如图1中(b)所示。从图中结果可以看出，目标水凝胶具有互穿网络结构。
实施例2、海藻酸钾-生物活性玻璃颗粒和二氧化硅颗粒杂化葡聚糖水凝胶的制备
将粒径100μm的生物活性玻璃颗粒与粒径100μm的二氧化硅颗粒按照质量比1：1混合后得到的混合物加入葡聚糖水溶液中，得到生物陶瓷材料颗粒质量百分比为10％的葡聚糖混合水溶液；
将海藻酸钾(平均相对分子质量为5kDa)与环氧氯丙烷混合得到海藻酸盐质量百分比为50％的均匀水溶液；
将上述两种溶液混合后，按照图2中(a)所示的手塑加工过程，通过手塑成型得到不同字母形状的水凝胶样品；其中，所得最终目标水凝胶中海藻酸钾，生物陶瓷材料颗粒，葡聚糖，环氧氯丙烷的质量百分比分别是40％，5％，10％，5％。
测试本实施例获得的水凝胶样品的压缩曲线，结果如图2中(b)所示。从图中可以看出，目标水凝胶材料具备很好的塑性，可以满足对不规则形状的塑造需求，且压缩模量可以达到1MPa，压缩强度可达60MPa。
实施例3、海藻酸钙、海藻酸铵-二氧化硅颗粒和碳酸钙骨水泥颗粒和硫酸盐钙颗粒和碳酸钙颗粒杂化聚乙二醇-聚乳酸共聚物、聚乙交酯/丙交酯共聚物、聚乙内酯共聚物水凝胶的制备
将粒径100nm的二氧化硅颗粒、粒径80nm的碳酸钙骨水泥颗粒、粒径10μm的硫酸盐钙颗粒和粒径20nm的碳酸钙颗粒按照质量比1：2：1：2加入到聚乙二醇-聚乳酸共聚物、聚乙交酯/丙交酯共聚物、聚乙内酯共聚物的混合水溶液中搅拌均匀，得到生物陶瓷材料颗粒质量百分比为15％的混合水溶液。将海藻酸钙、海藻酸铵按照质量比1：2(平均相对分子质量700kDa)配成海藻酸盐质量百分比为30％的水溶液，将上述两种溶液直接混合均匀，通过手塑成型，得到与兔骨同尺寸的样品。所得最终目标水凝胶中海藻酸盐，生物陶瓷材料颗粒，聚乙二醇-聚乳酸共聚物，聚乙交酯/丙交酯共聚物，聚乙内酯共聚物的质量百分比分别是20％，7％，5％，3％，7％。
将本实施例手塑成型得到的样品与同尺寸规格的兔骨(兔骨是经实验室动物科学研究伦理委员会批准后，取6个月大新西兰雄兔股骨)进行压缩对比，其压缩曲线如图3所示。从图3中结果可以看出，目标水凝胶样品的压缩模量与兔骨相似，但其压缩强度、抗压形变性能均优于同尺寸规格的新西兰雄兔股骨样品。
实施例4、注射法制备含DNA、RNA的海藻酸钠-碳酸钙颗粒杂化Pluronic-F127水凝胶
在37℃下将质粒DNA、siRNA溶解于Pluronic-F127的PBS溶液混合，然后加入粒径10nm的碳酸钙颗粒搅拌均匀，得到生物陶瓷材料颗粒质量百分比为20％PBS混合溶液。将海藻酸钠(平均相对分子质量为80kDa)的PBS溶液与羟乙基纤维素混合均匀，得到海藻酸盐质量百分比为20％的PBS混合溶液。在室温下通过计量泵和注射器注射，得到含DNA、RNA的杂化可注射Pluronic-F127水凝胶。所得最终目标水凝胶中海藻酸钠，生物陶瓷材料颗粒，Pluronic-F127，DNA，siRNA质量百分比分别是10％，10％，20％，0.01％，0.02％。
本实施例制得的水凝胶的挤出过程如图4中(a)所示，从图4中(a)可以看出目标水凝胶可以在室温条件下顺利挤出，挤出后材料可以迅速凝胶。
测试本实施例挤出后获得的水凝胶样品的压缩曲线，结果如图4中(b)所示。从图中可以看出，材料的压缩模量可达1MPa，压缩强度可达8MPa。
实施例5、包封细胞的海藻酸钠-羟基磷灰石颗粒和硫酸盐钙颗粒杂化壳聚糖、羧甲基壳聚糖、羟乙基壳聚糖水凝胶的制备
将ATDC5细胞分散于DMEM溶液，并与端苯甲醛修饰的PEO的DMEM溶液混合，然后加入海藻酸钠(平均相对分子质量为130kDa)完全溶解，得到海藻酸盐质量百分比为10％的DMEM混合溶液，向质量比为1：1：5的壳聚糖、羟甲基壳聚糖、羧乙基壳聚糖混合溶液中加入粒径10μm的羟基磷灰石颗粒和10μm的硫酸盐钙颗粒(所述羟基磷灰石颗粒和硫酸盐钙颗粒的质量比为1：5)混合均匀，得到生物陶瓷材料颗粒质量百分比为30％的DMEM混合溶液。通过蠕动泵注入多孔板，在37℃条件下形成凝胶，所得最终目标水凝胶海藻酸钠，生物陶瓷材料颗粒，壳聚糖、羧甲基壳聚糖、羟乙基壳聚糖混合溶液，端醛基修饰PEO的质量百分比分别为7％，20％，2％，5％。向孔板中加入DMEM培养基，另外加入溶液百分比浓度为10％胎牛血清(FBS)、溶液百分比浓度为1％青霉素和溶液百分比浓度为1％链霉素。
其中，端苯甲醛修饰的PEO的制备方法如下：
将2.4g 4-羧基苯甲醛分散于30mL二氯甲烷溶液中，超声振荡溶解，将3.3g二环己基碳二亚胺，0.488g 4-二甲氨基吡啶用10mL二氯甲烷超声溶解后加入上述溶液中，最后加入4g平均相对分子质量为2000Da的聚乙二醇(PEO)的二氯甲烷溶液，并于37℃反应24小时后用200μL乙酸乙酯终止反应。半小时后过滤，将滤出物旋蒸，抽滤，加入异丙醇70℃溶解，冷却后放入-20℃冰箱重结晶，结晶产物过滤，将固体用乙醚和异丙醇各洗涤两次，再于10000rpm/min下离心10min，取上清液，冻干即得到端苯甲醛修饰的PEO。
CCK-8试剂盒测定ATDC5细胞在凝胶中的增殖情况为：细胞在3天内增殖初始细胞量的150％，第7天增殖500％，第14天增殖1030％，期间水凝胶保持形状。由此可以看出，所制备的凝胶具有很好的生物相容性，并能促进ATDC5细胞的增殖。
实施例6、含青霉素和胎牛血清的海藻酸钾/海藻酸铵-二氧化硅颗粒杂化透明质酸水凝胶的制备
用质量百分比浓度为10％的胎牛血清(FBS)的PBS溶液配制海藻酸钾/海藻酸铵按照质量比1：1混合(平均相对分子质量为370kDa)-透明质酸溶液，并将生长因子BMP-2、VEGF与海藻酸盐-透明质酸溶液混合，得到海藻酸盐质量百分比为5％的PBS混合溶液，装入双联混药器A管；同样用含溶液百分比浓度为10％胎牛血清(FBS)的PBS溶液配制含有钙离子的聚乙二醇二丙烯酸酯(PEGDA)溶液，加入直径100nm的二氧化硅颗粒搅拌均匀，得到生物陶瓷颗粒材料质量百分比为50％的PBS混合溶液，并在溶液中混入1000单位青霉素，混合均匀后装入双联混药器B管。
使用双联混药器向缺损部位注射，所得最终目标水凝胶中海藻酸盐，生物陶瓷材料颗粒，透明质酸，聚乙二醇二丙烯酸酯(PEGDA)，BMP-2，VEGF质量百分比分别为5％，40％，7％，5％，0.05％，0.09％。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种高性能可加工水凝胶，其特征在于，所述水凝胶包括可加工高分子水凝胶基体和基于海藻酸盐与生物陶瓷材料的分散体系在所述基体中形成的高分子网络结构；
优选地，所述高分子网络结构为互穿网络结构和/或半互穿网络结构；
优选地，所述可加工高分子水凝胶基体为包含动态共价键交联、次级相互作用交联、或包含上述两种交联方式所形成的具有高分子网络的高分子水基溶液或溶胶中的至少一种；
优选地，所述动态共价键可以为亚胺键、硼酸酯键、酰腙键、酯键、缩醛键或二硫键中的至少一种；
优选地，所述次级相互作用可以为静电相互作用、氢键、疏水相互作用中的至少一种；进一步优选地，所述静电相互作用为离子键。
2.如权利要求1所述的高性能可加工水凝胶，其特征在于，所述高分子水凝胶基体中的高分子可以选自透明质酸、壳聚糖、壳聚糖衍生物、葡聚糖、羟乙基纤维素、聚乙烯醇、Pluronic-F127(聚氧乙烯聚氧丙烯醚嵌段共聚物，商品名-泊洛沙姆)、聚乳酸共聚物、聚乙交酯丙交酯共聚物、聚乙内酯共聚物、聚乙二醇、聚乙二醇-聚乳酸共聚物、聚乙二醇-聚乙交酯丙交酯共聚物和聚乙二醇-聚己内酯共聚物中的至少一种；
优选地，所述壳聚糖衍生物为羧甲基壳聚糖、羟乙基壳聚糖中的至少一种；
优选地，所述生物陶瓷材料的粒径不大于0.1mm；例如为10nm～100μm；优选为500nm～80μm；更优选为1μm～50μm；示例性为10nm、500nm、1μm、10μm、50μm、80μm或100μm；
优选地，所述生物陶瓷材料占所述可加工水凝胶的质量百分比不少于1％；例如所述质量百分比为1～80％；优选为10～60％；示例性为1％、10％、20％、25％、30％、60％、80％；
优选地，所述生物陶瓷材料可以选自生物活性玻璃、羟基磷灰石、磷酸钙骨水泥、硫酸钙盐、碳酸钙、二氧化硅等具备生物活性的无机颗粒中的至少一种；
优选地，所述海藻酸盐的平均相对分子质量为5～700kDa；例如10～600kDa；优选为100～300kDa；示例性地，平均相对分子质量为5kDa、10kDa、20kDa、60kDa、100kDa、150kDa、300kDa、400kDa、500kDa、600kDa、700kDa。
3.如权利要求1或2所述的高性能可加工水凝胶，其特征在于，所述海藻酸盐占所述可加工水凝胶的质量百分比不少于的1％；例如所述质量百分比为1～60％；优选为5～50％；示例性为1％、3％、5％、10％、20％、37％、40％、50％、60％；
优选地，所述高分子网络占所述可加工水凝胶的质量百分比不少于1％；例如所述质量百分比为1～80％；优选为10～60％；示例性为1％、5％、10％、20％、30％、40％、50％、60％、80％。
4.如权利要求1-3任一项所述的高性能可加工水凝胶的制备方法，其特征在于，所述方法包括：将海藻酸盐、生物陶瓷材料，与高分子水凝胶基体混合，凝胶化得到所述高性能可加工水凝胶；
优选地，所述海藻酸盐可以以单纯的海藻酸盐形式加入，或者以海藻酸盐溶液形式加入；
优选地，所述海藻酸盐溶液中海藻酸盐的质量百分比不小于1％；例如为1～60％；优选为3～30％；示例性为1％、3％、5％、10％、20％、30％、50％、60％；
优选地，所述海藻酸盐包括海藻酸钠、海藻酸钾、海藻酸钙、海藻酸铵中的至少一种；
优选地，所述生物陶瓷材料可以以其固体颗粒形式加入，或者以其分散液的形式加入；优选地，所述生物陶瓷材料颗粒可以配制成混合液的形式加入；
优选地，所述生物陶瓷材料颗粒分散液中，生物陶瓷材料颗粒的质量百分比大于0；例如为1～60％；优选为10～50％；示例性为1％、10％、15％、20％、30％、50％、60％；
优选地，所述分散液、以及所述的高分子水基溶液中的溶剂可以选自水、含水溶液或含水分散液；例如可以选自水、磷酸缓冲液中的一种。
5.如权利要求4所述的制备方法，其特征在于，所述高分子水凝胶基体占可加工水凝胶总体积比例不少于1％；优选为10～50％；示例性为7％、10％、20％、30％、40％、50％；
优选地，所述混合不限顺序，例如可以将三者同时混合；也可以将三者中的任意两者混合均匀后，再与另一者混合；
优选地，所述混合可在搅拌条件下进行；
优选地，所述混合可以通过手塑成型得到；
优选地，所述混合可以通过直接混合得到，也可以通过注射得到；
优选地，所述注射时所用的注射装置包括但不仅限于双联混药器、蠕动泵、计量泵、注射器、注射泵，以及其它用于液体、熔体、分散体系注射的医疗器械，或者是它们的组合。
6.如权利要求4所述的制备方法，其特征在于，所述制备方法具体包括以下步骤：
(1)准备海藻酸盐溶液：将海藻酸盐溶解于分散剂中，得到海藻酸盐溶液；
(2)准备高分子水凝胶基体：准备可通过动态共价键交联、或次级相互作用交联，或通过上述两种交联方式所形成的具有高分子网络结构的高分子水基溶液或溶胶，即高分子水凝胶基体；
(3)准备生物陶瓷材料颗粒，或其分散液；
(4)将上述步骤制得的物质混合，凝胶化得到所述高性能可加工水凝胶。
7.如权利要求6所述的制备方法，其特征在于，所述步骤(1)、(2)和(3)中的任意一步骤，其先后顺序可以任意调换，可以单独进行，也可以将任意两个步骤或三个步骤组合。
8.一种组合物，其特征在于，所述组合物包含权利要求1-3任一项所述的高性能可加工水凝胶和/或权利要求4-7任一项所述的制备方法制得的高性能可加工水凝胶和生物活性物质；
优选地，所述生物活性物质为药物、生物活性分子或细胞中的至少一种；
例如，所述药物可以为青霉素、链霉素或胎牛血清；所述生物活性分子可以为DNA、RNA、生长因子；优选地，所述生长因子为BMP-2、VEGF中的至少一种。
9.如权利要求8所述的组合物的制备方法，其特征在于，所述制备方法包括在权利要求4-7任一项所述的制备方法过程中加入生物活性物质，混合均匀即可；
优选地，所述高性能可加工水凝胶制备方法过程可以为制备方法的任一步骤；例如，向准备海藻酸盐溶液、准备高分子水凝胶基体或准备生物陶瓷材料颗粒分散液中的至少一个步骤中加入生物活性物质和/或在步骤(4)的混合过程中加入生物活性物质。
10.权利要求1-3任一项所述的高性能可加工水凝胶和/或权利要求4-7任一项所述的制备方法制得的高性能可加工水凝胶的用途，其特征在于，用于药物包封与输送、药物制备、组织工程、伤口敷料、手塑成型材料或作为注射材料；
例如，所述药物包括组织修复用药物；优选地，所述组织修复包括骨组织和软骨组织的修复。
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| CN107949598A (zh) * | 2015-07-02 | 2018-04-20 | 里尔大学 | 制备基于壳聚糖和负电荷聚电解质的水凝胶的方法以及由该水凝胶得到的蜂窝多孔材料 |
| CN109381749A (zh) * | 2018-10-23 | 2019-02-26 | 杭州捷诺飞生物科技股份有限公司 | 骨组织修复墨水、组合物、支架及制备方法以及试剂盒 |
| CN110237301A (zh) * | 2019-04-19 | 2019-09-17 | 湖北联结生物材料有限公司 | 一种海藻酸钠基可诱导骨修复凝胶及其制备方法和应用 |
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