CN110141687A - 一种引导牙周硬软组织再生梯度材料及其制备方法 - Google Patents

一种引导牙周硬软组织再生梯度材料及其制备方法 Download PDF

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CN110141687A
CN110141687A CN201910465240.1A CN201910465240A CN110141687A CN 110141687 A CN110141687 A CN 110141687A CN 201910465240 A CN201910465240 A CN 201910465240A CN 110141687 A CN110141687 A CN 110141687A
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fgm
functionally gradient
gradient material
soft tissue
tissue regeneration
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CN110141687B (zh
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李吉东
金蜀鄂
李玉宝
左奕
袁琛
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Sichuan University
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Sichuan University
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Priority to PCT/CN2019/095661 priority patent/WO2020237785A1/zh
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Abstract

本发明公开了一种引导牙周硬软组织再生梯度材料及其制备方法，本发明所述梯度材料通过静电纺丝技术与生物3D打印技术结合构建而得，由于静电纺丝纤维膜的微孔结构可防止牙龈成纤维细胞向根面迁移从而起到机械屏障作用，同时利于营养和代谢物质的传输；因3D打印支架层的结构、形状的高度可设计性可根据临床需要实现牙槽骨个性化修复。所述方法制备工艺简单、稳定，集牙周引导组织再生膜与牙槽骨修复支架材料一体化，且具有实现临床定制化治疗的潜能。所述梯度材料具有良好的体内引导硬软组织修复效果，能更好的应用于牙槽骨及牙周组织同步再生、修复。

Description

一种引导牙周硬软组织再生梯度材料及其制备方法
技术领域
本发明属于生物医用材料技术领域，具体涉及一种引导牙周硬软组织再生梯度材料及其制备方法。
背景技术
引导骨再生(Guided Bone Regeneration,GBR)技术是利用屏障膜阻止牙龈上皮向根表面迁移，从而为受损牙槽骨的重建和再生创造足够空间。引导组织再生技术为辅助治疗牙周疾病、促进骨组织再生提供了新策略。传统的不可降解GBR膜需要通过二次手术去除，会增加感染风险及患者痛苦，因而逐渐被淘汰；胶原基可降解膜由于其胶原成分大多来源于哺乳动物组织，因而存在疾病传播的风险，且存在降解过快的问题；生物合成高分子基可降解膜存在生物相容性不佳的问题。同时，临床上使用GBR膜时需在种植体周围结合使用骨粉以增强骨性结合及修复效果，但对于较大的牙槽骨缺损，植入的骨粉容易移位。基于此，本发明构建了一种集引导组织再生膜和骨充填双重作用一体化的梯度复合材料。
理想的组织修复材料既能从成分、结构上模拟天然组织的局部微环境且具有特定的生物学功能。静电纺丝技术作为一种操作简单、经济有效的制备超细纤维的方法，能制备微纳米级的纤维，纤维结构很好的模拟了细胞外基质结构，且所制备的纤维膜具有比表面积大、孔隙率高等特点，因而广泛应用于生物医学材料领域。3D打印作为一种极具发展前景的打印技术，可以产生具有良好互联性的高孔隙结构，可打印具有特定、复杂形状的组织工程支架材料，其工艺简单，制备的材料结构稳定、可控。
目前，常用于静电纺丝或生物3D打印的生物高分子材料包括左旋聚乳酸、聚己内酯、聚乳酸-羟基乙酸、壳聚糖、聚氨酯等。但是单一的高分子纤维往往由于力学性能较低或生物相容性较差而不能满足临床应用的需求。近年来，研究者通过对高分子纤维改性以期望获得性能优良的组织工程支架材料，并取得了一系列突破性进展。
现有技术中有一种壳聚糖与钙磷盐复合的引导组织再生膜的制备方法，该膜结构为致密层和疏松多孔层，具有良好的促成骨活性，但是壳聚糖基的生物材料存在力学性能较差的缺点。现有技术还有一种基于羟基磷灰石接枝聚丙交酯/聚乳酸共聚羟基乙酸电纺纤维膜的制备方法，构建了一种新的可生物降解的引导组织再生膜，复合膜展示出更好的力学性能，但该复合膜体系缺乏生物活性好的天然成分，如胶原蛋白、明胶等。
Brown等人通过静电纺丝制备了I型胶原改性聚乳酸-羟基乙酸的复合纤维膜，但胶原来源于鼠尾。目前临床使用商业化的胶原基引导组织再生膜(Bio-Gide，Bio-Mend等)也存在缺陷：(1)由于其快速降解行为而丧失维持空间的能力；(2)胶原大多来源于哺乳动物器官或组织，如猪皮、牛跟腱等，存在潜在疾病传播的风险以及宗教限制等问题。
Qingqiang Yao等人以PCL为基体接枝氨基酸后通过3D打印制备了支架材料用于软硬骨一体化修复，但是用于牙周硬软组织再生修复材料也应具有一定的机械屏障作用，防止牙龈上皮细胞向根面迁移，因此支架材料应具有较致密的结构层发挥物理屏障作用。
发明内容
本发明的目的在于：基于上述研究现状和缺陷，本发明将传统的静电纺丝技术与新兴的生物3D打印技术相结合制备出能够同时引导牙周硬软组织再生的一体化修复梯度材料。
本发明采用的技术方案如下：
一种引导牙周硬软组织再生梯度材料，包括3D打印支架层和静电纺丝纤维膜层，所述3D打印支架层中羟基磷灰石含量高于静电纺丝纤维膜层，所述3D打印支架层的孔径大于静电纺丝纤维膜层，所述3D打印支架层的孔径大小为100-1000μm，所述静电纺丝纤维膜层的纤维直径大小为300-5000nm，所述静电纺丝纤维膜层的结构为无规分布或取向排列或网格状结构，静电纺丝纤维膜层厚度为0.08-1mm。
孔结构梯度变化，从纤维膜300-10000nm变化到支架的几百微米；成分的梯度变化，纤维膜中磷灰石含量较低，而3D支架中磷灰石含量较高：鱼胶原在纤维膜中含量较高，在多孔支架中较少，甚至可以不加。由此体现出，纤维膜与多孔支架在孔结构方面和成分含量方面的梯度变化。
鱼胶原可促进来源于软组织的细胞黏附、生长；高的磷灰石含量的支架可促进成骨性细胞的成骨分化。
梯度材料可为静电纺丝纤维膜与生物3D打印支架复合而得，具体复合方式可为纤维膜-3D打印支架形成的ABAB结构，该结构在三维方向上重复交替，孔结构及孔隙率呈重复交替式。
梯度材料可为静电纺丝纤维膜包裹在生物3D打印支架表面，形成硬-软梯度结构，促进支架材料与宿主组织的界面结合。
梯度材料可为静电纺丝纤维膜剪切成碎片后填充于3D打印支架孔结构中形成的复合支架材料。
梯度材料上层由孔隙率较小的静电纺丝纤维膜组成，能够有效阻止牙龈上皮细胞和牙龈结缔组织细胞向根面迁移，下层由具有较大孔隙率的3D打印支架组成。梯度材料具有优异的力学性能、可调控的降解速率、低免疫原性以及良好的体内生物活性，且在结构和成分上均可成梯度变化。
上述引导牙周硬软组织再生梯度材料的制备方法，包括以下步骤：
S1.将纳米羟基磷灰石分散于溶剂，超声分散1-2h，再加入鱼胶原和聚乳酸-羟基乙酸，震荡摇匀1.5-3h，再超声0.5-1h，得到纺丝液；其中超声分散方法为两步超声法；
S2.搅拌步骤S1中所得纺丝液使溶剂挥发，得到3D打印墨水；其中溶剂部分挥发，得到所需浓度的3D打印墨水；
S3.将步骤S1所得纺丝液通过静电纺丝法制备得到静电纺丝纤维膜层；
S4.将步骤S3得到的静电纺丝纤维膜层置于生物3D打印机平台上，使用步骤S2所得3D打印墨水通过生物3D打印机在静电纺丝纤维膜层上打印，构建静电纺丝纤维膜层与3D打印支架层复合的梯度材料。
上述制备方法中，也可先用3D打印墨水通过生物3D打印机打印3D打印支架层，然后在3D打印支架层上通过静电纺丝法制备静电纺丝纤维膜层，从而构建静电纺丝纤维膜层与3D打印支架层复合的梯度材料。
聚乳酸-羟基乙酸是经美国FDA批准应用于生物医药领域的生物高分子，鱼胶原作为蛋白分子引入到聚乳酸-羟基乙酸中能与其分子链发生相互作用形成分子网络结构，从而提高材料的力学性能。纳米羟基磷灰石作为人体骨主要的无机成分引入到聚乳酸-羟基乙酸中可赋予材料显著的生物活性和诱导成骨能力。
梯度材料可通过纳米羟基磷灰石负载生物因子或药物，如地塞米松、BMP、TGF、FGF、黄芩苷等，实现因子或药物的持续性释放，并赋予材料多功能性。
进一步地，静电纺丝纤维膜层中纳米羟基磷灰石含量为5-40wt％，鱼胶原的含量为1-30wt％；优选地，静电纺丝纤维膜层中纳米羟基磷灰石含量为10-25wt％，鱼胶原的含量为5-15wt％。
进一步地，3D打印支架层中纳米羟基磷灰石含量为10-70wt％。
进一步地，步骤S1中羟基磷灰石包括短棒状、针状、微球状及介孔羟基磷灰石，羟基磷灰石可由磷酸钙盐或硅酸钙盐替换。
进一步地，步骤S1中聚乳酸-羟基乙酸可由聚己内酯或聚乳酸或聚氨酯或壳聚糖替换。
进一步地，步骤S1中鱼胶原来源于鱼皮或鱼鳞，鱼为鳕鱼或罗非鱼或草鱼或鲢鱼。
进一步地，步骤S1中溶剂为三氟乙醇或六氟异丙醇或二氯甲烷或丙酮或N,N-二甲基甲酰胺或体积比7-9:1-3的三氟乙醇/N,N-二甲基甲酰胺混合溶液或体积比2-4:1的丙酮/N,N-二甲基甲酰胺混合溶液。
进一步地，步骤S3具体过程为：通过使用平板接收器、取向接收器、网格状接收器分别收集无规分布、取向排列、网格状的纤维膜，所述静电纺丝工艺参数设置为电压7-12kV、接收距离12-18cm、推注速度0.3-0.6mL/h；取向接收器辊筒转速为2000-4000r/min，网格接收器的网格孔径大小为400-800μm；其中，优选的工艺参数为电压7-9kV、接收距离15cm、推注速度0.4-0.5mL/h，取向接收器辊筒优选转速为2500-3000r/min，网格接收器的优选网格孔径大小为500-600μm。
进一步地，步骤S4中通过生物3D打印技术制备3D打印支架层，挤出丝的直径为0.1-0.4mm，支架形状为正方体或圆柱状或菱柱或根据临床需要的其他个性化定制形状。
综上所述，由于采用了上述技术方案，本发明的有益效果是：
1、本发明中，梯度材料为静电纺丝纤维膜层与生物3D打印支架层复合构建的功能梯度材料，能实现牙周硬软组织同步修复，梯度材料的成分、孔结构、纤维膜与3D打印挤出丝的排列方式均可呈现梯度变化，相比于单一的纤维膜或者3D打印支架材料，该梯度材料具有更好的应用前景；
2、本发明梯度材料中纤维膜具有相对致密的微孔结构，能够作为机械屏障膜阻止牙龈成纤维细胞向根面迁移，同时引导牙周软组织修复；所述梯度材料中3D打印支架材料能引导牙槽骨再生，从而实现牙周硬软组织一体化修复；
3、本发明使用的鱼胶原为海洋生物来源，其氨基酸组成与哺乳动物相似，具有较高的生物相容性、较低的免疫原性、较高的细胞亲和力和生物降解性，其氨基酸序列与哺乳动物不同，具有不同的免疫表位，能避免疾病传播的风险，且没有宗教文化、伦理问题；
4、本发明通过在聚乳酸-羟基乙酸中引入少量鱼胶原，由于鱼胶原分子与聚乳酸-羟基乙酸分子链通过氢键作用形成分子网络结构，显著提高了材料的力学强度，且鱼胶原的引入改变了聚乳酸-羟基乙酸基体的主要降解行为，出现孔洞式降解，显著加快了梯度材料的降解速率，且通过调控鱼胶原的添加量调控材料的降解速率；
5、本发明通过静电纺丝制备纤维膜，模拟了细胞外基质结构，且操作简单、技术成熟、工艺稳定，通过生物3D打印技术制备支架具有极强的可设计性与重复性，能够根据缺损部位形状大小满足患者定制化需求，实现临床上个性化治疗。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1为纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜的形貌图；
图2为纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜的纤维直径分布图；
图3为纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜在磷酸盐缓冲液中降解8周后的形貌图；
图4为纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜(PFC5H15)在大鼠颅骨双侧缺损模型中植入4周后Micro-CT重建的缺损区骨修复效果图；
图5为网格状纤维膜形貌图；
图6为应力-应变曲线图；
图7为纤维膜与不同孔结构3D打印支架复合构建的梯度材料图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明，即所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。通常在此处附图中描述和示出的本发明实施例的组件可以以各种不同的配置来布置和设计。
因此，以下对在附图中提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示本发明的选定实施例。基于本发明的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
需要说明的是，术语“第一”和“第二”等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下，由语句“包括一个……”限定的要素，并不排除在包括所述要素的过程、方法、物品或者设备中还存在另外的相同要素。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实施例1
本发明较佳实施例提供的一种引导牙周硬软组织再生梯度材料的制备方法，原料包括：生工生物股份有限公司的鱼胶原，阿拉丁公司的六氟异丙醇，山东济南岱罡生物科技有限公司的聚乳酸-羟基乙酸，具体步骤如下：
步骤1：称取0.06g纳米羟基磷灰石分散于2mL六氟异丙醇中，用超声细胞粉碎机超声分散1h；
步骤2：称取0.02g鱼胶原加入步骤1所得分散液，用恒温振荡器震荡摇匀10min；
步骤3：称取0.4g聚乳酸-羟基乙酸加入到步骤2所得混合溶液，在恒温振荡器中于25℃下震荡摇匀2h，得纺丝液；
步骤4：将步骤3所得纺丝液再次用超声细胞粉碎机超声分散30min；
步骤5：将步骤4所得纺丝液通过静电纺丝机制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜，所用针头为平头针23G，采用平板接收器，纺丝参数设置为：电压8kV，推注速度0.5mL/h，接收距离16cm；
步骤6：步骤5中使用网格状接收器，连续收集1h后取下纤维膜，置于真空干燥箱中干燥3天，即得静电纺丝纤维膜层；
步骤7：称取0.6g纳米羟基磷灰石分散于10mL二氯甲烷中，用超声波清洗机超声预分散20min；
步骤8：将步骤7所得分散液液用超声细胞粉碎机超声分散30min；
步骤9：称取0.2g鱼胶原加入步骤8所得分散液，用恒温振荡器震荡摇匀20min,得鱼胶原均匀分散在溶液里的混合悬浊液；
步骤10：称取4g聚乳酸-羟基乙酸加入到步骤9所得混合悬浊液，在恒温振荡器中于25℃下震荡摇匀2h；
步骤11：将步骤10所得混合溶液在通风橱中搅拌，测量其粘度为40±10mPa·s，得3D打印墨水；
步骤12：将步骤6所得静电纺丝纤维膜层置于生物3D打印机平台上，取步骤11所得墨水通过生物3D打印机在复合纤维膜上打印，制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合支架，所用针头为锥形针头，内径0.16-0.41mm，3D打印参数设置为：支架尺寸10×10×5mm3，推出气压5bar，针头温度30℃，接收平台温度20℃，针头速度4mm/s，初始针头平台间距0.208mm，层间距0.208mm，初始针尖平台距离0.208mm，打印线间距0.3-0.8mm。
步骤13：将打印支架置于真空干燥箱中干燥3天，即得。
实施例2
本发明较佳实施例提供的一种引导牙周硬软组织再生梯度材料的制备方法，原料包括：生工生物股份有限公司的鱼胶原，阿拉丁公司的六氟异丙醇，山东济南岱罡生物科技有限公司的聚乳酸-羟基乙酸，具体步骤如下：
步骤1：称取0.06g纳米羟基磷灰石分散于2mL六氟异丙醇中，用超声细胞粉碎机超声分散1h；
步骤2：称取0.02g鱼胶原加入步骤1所得分散液，用恒温振荡器震荡摇匀10min；
步骤3：称取0.4g聚乳酸-羟基乙酸加入到步骤2所得混合溶液，在恒温振荡器中于25℃下震荡摇匀2h，得纺丝液；
步骤4：将步骤3所得纺丝液再次用超声细胞粉碎机超声分散30min；
步骤5：将步骤4所得纺丝液通过静电纺丝机制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜，所用针头为平头针23G，采用平板接收器，纺丝参数设置为：电压8kV，推注速度0.5mL/h，接收距离16cm；
步骤6：步骤5中使用网格状接收器，连续收集1h后取下纤维膜，置于真空干燥箱中干燥3天，即得静电纺丝纤维膜层；
步骤7：称取0.6g纳米羟基磷灰石分散于10mL二氯甲烷中，用超声波清洗机超声预分散20min；
步骤8：将步骤7所得分散液液用超声细胞粉碎机超声分散30min；
步骤9：称取0.2g鱼胶原加入步骤8所得分散液，用恒温振荡器震荡摇匀20min,得鱼胶原均匀分散在溶液里的混合悬浊液；
步骤10：称取4g聚乳酸-羟基乙酸加入到步骤9所得混合悬浊液，在恒温振荡器中于25℃下震荡摇匀2h；
步骤11：将步骤10所得混合溶液在通风橱中搅拌，测量其粘度为40±10mPa·s，得3D打印墨水；
步骤12：将步骤6所得静电纺丝纤维膜层置于生物3D打印机平台上，取步骤11所得墨水通过生物3D打印机在复合纤维膜上打印，打印一层后暂停，将步骤6所得静电纺丝纤维膜层置于3D打印第一层之上，重复以上操作十次，制备静电纺丝纤维膜与生物3D打印支架逐层交替形成的纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合梯度支架材料，所用针头为锥形针头，内径0.16-0.41mm，3D打印参数设置为：支架尺寸10×10×5mm3，推出气压5bar，针头温度30℃，接收平台温度20℃，针头速度4mm/s，初始针头平台间距0.208mm，层间距0.2-0.3mm，初始针尖平台距离0.208mm，打印线间距0.3-0.8mm；
步骤13：将打印支架置于真空干燥箱中干燥3天，即得。
实验例1
实验采用静电纺丝方法制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸的复合纤维膜，具体步骤如下：
步骤1：称取0.06g纳米羟基磷灰石分散于2mL六氟异丙醇中，用超声细胞粉碎机超声分散1h；
步骤2：称取0.02g鱼胶原加入步骤1所得分散液，用恒温振荡器震荡摇匀10min；
步骤3：称取0.4g聚乳酸-羟基乙酸加入到步骤2所得混合溶液，在恒温振荡器中于25℃下震荡摇匀2h，得纺丝液；
步骤4：将步骤3所得纺丝液再次用超声细胞粉碎机超声分散30min；
步骤5：将步骤4所得纺丝液通过静电纺丝机制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜，所用针头为平头针23G，采用平板接收器，纺丝参数设置为：电压8kV，推注速度0.5mL/h，接收距离16cm；
步骤6：连续收集2h后，将纤维膜从接收器上取下，置于真空干燥箱中干燥3天，使溶剂充分挥发；
步骤7：静电纺丝制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸纤维膜；
使用扫描电镜观察纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸纤维膜的形貌，结果如图1所示，纤维光滑、无串珠形成；测量其直径分布，结果如图2所示，纤维平均直径为486±64nm，通过两步超声法实现了纳米羟基磷灰石在纤维中的均匀分布，纤维形貌良好。
通过扫描电镜观察体外降解实验8周后复合纤维膜的形貌，结果如图3所示，表明鱼胶原的引入改变了纤维的主要降解行为，纤维断裂、溶胀、腐蚀的同时，出现了孔洞式降解，显著加快了纤维膜的降解速率。
通过大鼠颅骨双侧缺损模型评价复合纤维膜体内骨修复效果，结果如图4所示，颅骨缺损区明显有新生骨组织形成，表明复合纤维膜在引导组织再生领域极具应用前景。
实验例2
实验采用静电纺丝方法制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸的复合纤维膜，具体步骤如下：
步骤1：称取0.06g纳米羟基磷灰石分散于2mL六氟异丙醇中，用超声细胞粉碎机超声分散1h；
步骤2：称取0.02g鱼胶原加入步骤1所得分散液，用恒温振荡器震荡摇匀10min；
步骤3：称取0.4g聚乳酸-羟基乙酸加入到步骤2所得混合溶液，在恒温振荡器中于25℃下震荡摇匀2h，得纺丝液；
步骤4：将步骤3所得纺丝液再次用超声细胞粉碎机超声分散30min；
步骤5：将步骤4所得纺丝液通过静电纺丝机制备纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜，所用针头为平头针23G，采用平板接收器，纺丝参数设置为：电压8kV，推注速度0.5mL/h，接收距离16cm；
步骤6：步骤5中使用网格状接收器，连续收集1h后取下纤维膜，置于真空干燥箱中干燥3天；
通过扫描电镜观察网格状纤维膜形貌，结果如图5所示，纤维膜形成了均一的网格重复单元，网格尺寸大小为500μm左右。
实验例3
分别制备聚乳酸-羟基乙酸纤维膜(P)、鱼胶原/聚乳酸-羟基乙酸纤维膜(PFC5)以及纳米羟基磷灰石/鱼胶原/聚乳酸-羟基乙酸复合纤维膜(PFC5H15)，进行拉伸强度测试，结果如图6和下表1所示，可知鱼胶原的引入显著提高了纤维膜的拉伸强度。
表1纤维膜的力学性能表
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种引导牙周硬软组织再生梯度材料，其特征在于：包括3D打印支架层和静电纺丝纤维膜层，所述3D打印支架层中羟基磷灰石含量高于静电纺丝纤维膜层，所述3D打印支架层的孔径大于静电纺丝纤维膜层，所述3D打印支架层的孔径大小为100-1000μm，所述静电纺丝纤维膜层的纤维直径大小为300-5000nm，所述静电纺丝纤维膜层的结构为无规分布或取向排列或网格状结构，静电纺丝纤维膜层厚度为0.08-1mm。
2.权利要求1所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于，包括以下步骤：
S1.将纳米羟基磷灰石分散于溶剂，超声分散1-2h，再加入鱼胶原和聚乳酸-羟基乙酸，震荡摇匀1.5-3h，再超声0.5-1h，得到纺丝液；
S2.搅拌步骤S1中所得纺丝液使溶剂挥发，得到3D打印墨水；
S3.将步骤S1所得纺丝液通过静电纺丝法制备得到静电纺丝纤维膜层；
S4.将步骤S3得到的静电纺丝纤维膜层置于生物3D打印机平台上，使用步骤S2所得3D打印墨水通过生物3D打印机在静电纺丝纤维膜层上打印，构建静电纺丝纤维膜层与3D打印支架层复合的梯度材料。
3.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述静电纺丝纤维膜层中纳米羟基磷灰石含量为5-40wt％，鱼胶原的含量为1-30wt％。
4.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述3D打印支架层中纳米羟基磷灰石含量为10-70wt％。
5.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述步骤S1中羟基磷灰石包括短棒状、针状、微球状及介孔羟基磷灰石，所述羟基磷灰石可由磷酸钙盐或硅酸钙盐替换。
6.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述步骤S1中聚乳酸-羟基乙酸可由聚己内酯或聚乳酸或聚氨酯或壳聚糖替换。
7.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述步骤S1中鱼胶原来源于鱼皮或鱼鳞，鱼为鳕鱼或罗非鱼或草鱼或鲢鱼。
8.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述步骤S1中溶剂为三氟乙醇或六氟异丙醇或二氯甲烷或丙酮或N,N-二甲基甲酰胺或体积比7-9:1-3的三氟乙醇/N,N-二甲基甲酰胺混合溶液或体积比2-4:1的丙酮/N,N-二甲基甲酰胺混合溶液。
9.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于，所述步骤S3具体过程为：通过使用平板接收器、取向接收器、网格状接收器分别收集无规分布、取向排列、网格状的纤维膜，所述静电纺丝工艺参数设置为电压7-12kV、接收距离12-18cm、推注速度0.3-0.6mL/h；取向接收器辊筒转速为2000-4000r/min，网格接收器的网格孔径大小为400-800μm。
10.根据权利要求2所述的引导牙周硬软组织再生梯度材料的制备方法，其特征在于：所述步骤S4中通过生物3D打印技术制备3D打印支架层，挤出丝的直径为0.1-0.4mm。
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