CN114452438A - 一种生物活性玻璃复合多孔冷冻凝胶微球及其制备和应用 - Google Patents
一种生物活性玻璃复合多孔冷冻凝胶微球及其制备和应用 Download PDFInfo
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- CN114452438A CN114452438A CN202210074443.XA CN202210074443A CN114452438A CN 114452438 A CN114452438 A CN 114452438A CN 202210074443 A CN202210074443 A CN 202210074443A CN 114452438 A CN114452438 A CN 114452438A
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Abstract
本发明涉及生物医用材料的技术领域，尤其是指一种生物活性玻璃复合多孔冷冻凝胶微球及其制备和应用，其中制备方法包括：S1制备生物活性玻璃悬浊液；S2制备冷冻凝胶溶液；S3将生物活性玻璃悬浊液逐滴滴加到冷冻凝胶溶液中；S4向所得混合溶液中加入交联剂，然后将上述混合液逐滴滴加到液氮或者液态二氧化碳或者低温油相溶液中；S5待液氮或者液态二氧化碳挥发后将生物活性玻璃复合微球转移到零下附近温度放置过夜，冷冻冻干；或者将生物活性玻璃复合微球连同油相溶液转移到零下附近温度放置过夜，清洗，然后冷冻冻干。本发明解决现有技术中生物活性玻璃缺乏合适的载体形式的问题，可以用于多种软硬组织缺损的再生修复。
Description
技术领域
本发明涉及生物医用材料的技术领域，尤其是指一种生物活性玻璃复合多孔冷冻凝胶微球及其制备和应用。
背景技术
生物活性玻璃是一种人工合成的可降解无机非金属材料，具有良好的生物活性和骨诱导性，生物活性玻璃的生物活性特指玻璃的可降解性及其生成磷灰石的能力。
生物活性玻璃可以在体液中降解，释放活性离子(Ca2+、SiO4 4-、PO4 3-等)，促进成骨细胞增殖、分化，上调成骨相关基因(碱性磷酸酶、I型胶原纤维、骨桥蛋白、骨钙蛋白、骨粘连蛋白和Runx2)表达；同时生成类骨样磷灰石(如羟基磷灰石和氟磷灰石等)，与宿主骨形成亲密的键合，诱导骨再生，加速骨组织修复。近些年的研究也发现生物活性玻璃对于软硬组织都有良好的促进再生修复作用，生物活性玻璃通过释放离子刺激促进血管生成相关生长因子(VEGF，bFGF)的表达，并调节局部炎症微环境，诱导巨噬细胞极化表型变化，促进皮肤、神经、心肌等软组织再生修复过程。
虽然生物活性玻璃具有良好的组织再生修复潜力，但是目前在临床转化阶段仍然存在许多限制：1.生物活性玻璃粉体在体内快速降解易形成局部碱性环境，不利于细胞增殖和组织修复；2.生物活性玻璃粉体在使用时容易随着体液/血液转运到身体其他部位，存在异位成骨的风险；3.生物活性玻璃粉体本身强度不高具有脆性，因而尚不能用于大段骨缺损的术后重建。中国专利申请CN112299722A公开了一种用于牙科手术填料的生物活性玻璃及其制备方法，包括生物活性玻璃粉末，生物活性玻璃粉末包括以下重量份的组分：35-50份的SiO2、20-30份的CaO、15-30份的Na2O、3-6份的P2O5、5-20份的CaF2、5-10份的B2O3、2-6份的K2O、2-4份的MgO和1-6份的添加剂。虽然该发明制得的生物活性玻璃力学性能有了一定改善，但是其仅仅可以用于牙科手术填料，并不能用于大段骨缺损的术后重建。中国专利申请CN106474535A公开了一种多孔生物活性玻璃敷料的制备方法，具有前驱液的配置、定量滤纸模板吸附前驱液、焚烧成粉末、制成生物活性玻璃敷料的工艺步骤。虽然该发明所得生物活性玻璃微粒尺寸范围广，但是其并不能作为生物活性玻璃的良好载体。
冷冻凝胶(cryogel)是近年来快速发展的一种新型生物材料，广泛应用于干细胞移植、组织工程、药物控释以及肿瘤免疫治疗的研究领域。冷冻凝胶是通过简单的冷冻－干燥方法制备的大孔支架，聚合物溶液首先在溶剂的冰点以下冷冻而形成冰晶，聚合物分子在引发剂的作用下交联，样品解冻后，即形成具有连通大孔结构的冷冻凝胶。与水凝胶相比，冷冻凝胶显示出优异的渗透性能够进行高效的物质交换；良好的弹性和较高的机械稳定性，可以经历90％的压缩形变后快速回弹，能够保护细胞活性用于可注射的微创治疗；微米级的连通大孔结构，有利于细胞迁移和血管长入。目前已有大量的研究证明冷冻凝胶在抗菌敷料，骨以及软骨的再生修复，卒中模型的组织工程修复，肿瘤细胞免疫疫苗开发中具有良好的效果和应用前景。这种预成型材料体系可以有效避免可注射凝胶的前驱体泄漏到周围组织或被体液稀释的问题，类似地，也为生物活性玻璃粉体提供了良好的载体。然而，目前现有技术存在生物活性玻璃缺乏合适的载体形式的问题。
发明内容
本发明的目的在于克服现有技术的缺点与不足，提出了一种快速制备多孔生物活性玻璃复合多孔冷冻凝胶微球的方法，解决现有技术中生物活性玻璃缺乏合适的载体形式的问题，可以用于多种软硬组织缺损的再生修复。
本发明的技术方案是：
一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法，包括以下步骤：
S1将生物活性玻璃分散到去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2将天然或合成高分子材料充分溶解到其对应溶液中，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中的冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入交联剂，然后将上述混合液逐滴滴加到液氮或者液态二氧化碳或者低温油相溶液中，滴入瞬间形成生物活性玻璃复合微球；
S5待液氮或者液态二氧化碳挥发后将生物活性玻璃复合微球转移到零下附近温度放置过夜，冷冻冻干，得到生物活性玻璃复合多孔冷冻凝胶微球；
或者将生物活性玻璃复合微球连同油相溶液转移到零下附近温度放置过夜，使用乙醇和水反复交替清洗，以去除油相溶液残留，然后冷冻冻干，得到生物活性玻璃复合多孔冷冻凝胶微球。
进一步地，所述步骤S1所述生物活性玻璃可以为熔融法、溶胶凝胶法、溶胶凝胶法结合模板制备的微米级及以下粒径的生物活性玻璃粉体，可以为元素修饰后的上述生物活性玻璃。
进一步地，所述步骤S1所述生物活性玻璃与去离子水的质量体积比为0.1-2:10g/mL。
进一步地，所述步骤S2所述天然或合成高分子材料具有活性侧链氨基，包括但不限于明胶、胶原、丝素、壳聚糖、聚天冬氨酸。
进一步地，所述步骤S2所述冷冻凝胶溶液的质量浓度为1～20％。
进一步地，所述步骤S4所述交联剂为戊二醛、EDC/NHS或京尼平等其他水溶性交联剂。
进一步地，所述步骤S4所述低温油相溶液为温度在-20～-80℃，具有超低熔点的有机溶剂。
进一步地，所述有机溶剂包括但不限于石油醚、乙酸乙酯、甲酸乙酯。
进一步地，所述步骤S5所述零下附近温度为-1～-10℃。此时生物活性玻璃复合微球中水保持冰晶状态，经过浓缩后的交联剂能够在低温下完成交联反应，交联时间为12h。
本发明中的油相溶液具有超低熔点(如石油醚、甲酸乙酯、乙酸乙酯等)，可以在极低温度下承接生物活性玻璃-高分子的混合溶液，温度在-20～-80℃。液氮或者液态二氧化碳，可以在极低温度下承接生物活性玻璃-高分子的混合溶液，且容易挥发。
本发明的另一目的在于提供所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法制得的生物活性玻璃复合多孔冷冻凝胶微球，所述生物活性玻璃复合多孔冷冻凝胶微球具有球形的形貌和三维贯通的多孔结构，粒径为50～2000μm，孔隙率为50～93％，所述生物活性玻璃复合多孔冷冻凝胶微球中生物活性玻璃固含量为1～75％，所述三维贯通的多孔结构中的大孔尺寸为50～200μm。
本发明的再一目的在于提供所述的生物活性玻璃复合多孔冷冻凝胶微球在制备抗菌敷料、止血材料、药物载体、骨质疏松药物、骨关节炎药物、皮肤创面修复材料、骨缺损再生修复材料中的应用。
与现有技术相比，本发明具有以下优势：
(1)本发明设计科学，方法简单，操作简便。本发明利用水油分相结合极速冷冻的方法制备生物活性玻璃复合冷冻凝胶微球，在实现冰晶成核生长制造大孔的同时完成高分子的交联过程，同时赋予微球形貌及大孔结构。
(2)本发明通过极速冷冻过程的温度选择可以制备不同孔径的生物活性玻璃复合冷冻凝胶微球，冷冻凝胶微球内部具有三维贯通的多孔结构，孔径主要分布在50～200μm，有利于营养物质交换，细胞迁移长入，利于血管和骨组织的迁移生长。
(3)采用本发明的方法开发的复合有生物活性玻璃的冷冻凝胶微球，具有良好的球形形貌，粒径为50～2000μm，方便手术过程中的植入。同时生物活性玻璃能够均匀分布在微球内部，提供良好的生物活性，有利于软硬组织的再生修复。
附图说明
图1为本发明的实验原理机制示意图。
图2为本发明实施例1没有复合及复合有生物活性玻璃的丝素冷冻凝胶微球的光学照片。
图3为本发明实施例2-20℃下冷冻制备和实施例3使用液氮急冻的生物活性玻璃复合壳聚糖冷冻凝胶微球的冷冻切片的光学照片。
图4为本发明实施例4使用十二胺作为模板剂结合溶胶凝胶法所得生物活性玻璃的扫描电镜图。
图5为本发明实施例4制得的生物活性玻璃复合明胶多孔冷冻凝胶微球的扫描电镜图及放大图。
图6为本发明实施例2没有复合及复合有生物活性玻璃的多孔壳聚糖冷冻凝胶微球的吸水率比较图。
具体实施方式
以下通过具体实施方式的描述对本发明作进一步说明，但这并非是对本发明的限制，本领域技术人员根据本发明的基本思想，可以做出各种修改或改进，但是只要不脱离本发明的基本思想，均在本发明的范围之内。
本发明中所用原料如无特殊说明，均为市售。如壳聚糖可购自北京百灵威科技有限公司。脱胶蚕丝为芬丝利脱胶蚕丝，可购自苏州丝美特生物技术有限公司。
本发明的实验原理机制示意图如图1所示。
实施例1、一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法
所述快速制备生物活性玻璃复合多孔冷冻凝胶微球的方法，包括以下步骤：
S1称取0.2g使用氨水催化溶胶凝胶法制备的生物活性玻璃分散到20mL去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2使用溴化锂溶解脱胶蚕丝的方法制备5％wt的再生丝素溶液，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中所得20mL冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入100μL 50％戊二醛溶液并搅拌均匀，然后将上述混合液使用胶头滴管逐滴滴加到-40℃的乙酸乙酯中，滴入瞬间形成生物活性玻璃复合微球；
S5将生物活性玻璃复合微球连同乙酸乙酯一起转移到-1℃冰箱中过夜，使用乙醇和水反复交替清洗，以去除油相溶液残留，然后冷冻冻干，得到生物活性玻璃复合多孔丝素冷冻凝胶微球。
另外，参照上述方法，制备没有复合生物活性玻璃的多孔丝素冷冻凝胶微球。
没有复合及复合有生物活性玻璃的多孔丝素冷冻凝胶微球的光学照片见图2。从图2(a)可以看出没有复合生物活性玻璃的多孔丝素冷冻凝胶微球呈现透明，从图2(b)可以看出复合有生物活性玻璃的多孔丝素冷冻凝胶微球不透明。
使用依据阿基米德排水法的原理，利用密度天平测量没有复合生物活性玻璃的多孔丝素冷冻凝胶微球的孔隙率为80％，复合有生物活性玻璃的多孔丝素冷冻凝胶微球的孔隙率为70％。具体步骤如下：(1)将丝素冷冻凝胶微球冷冻干燥后称重，记为W；(2)将冻干水凝胶置于无水乙醇中，然后抽真空1h，直至材料被无水乙醇填满，取出支架材料，用饱和的酒精湿纱布轻轻沾去表面多余的无水乙醇，然后称重，记为W1；(3)将样品置于密度天平中(其中密度天平所装溶液为无水乙醇)，对支架材料进行称重，记为W2。冻干水凝胶孔隙率计算公式为：ω＝(W1-W)/(W1-W2)×100％。
实施例2、一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法
所述快速制备生物活性玻璃复合多孔冷冻凝胶微球的方法，包括以下步骤：
S1称取0.4g盐酸催化溶胶凝胶法制备的生物活性玻璃分散到20mL去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2称取0.8g壳聚糖(300kDa，脱乙酰度90％)完全溶解在20mL 1％wt醋酸溶液中，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中的冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入200μL 50％戊二醛溶液并搅拌均匀，然后将上述混合液使用注射器逐滴滴加到-20℃甲酸乙酯中，滴入瞬间形成生物活性玻璃复合微球；
S5将生物活性玻璃复合微球连同甲酸乙酯一起转移到-10℃冰箱中过夜，使用乙醇和水反复交替清洗，以去除油相溶液残留，然后冷冻冻干，得到生物活性玻璃复合壳聚糖冷冻凝胶微球。利用密度天平测量生物活性玻璃复合多孔壳聚糖冷冻凝胶微球的孔隙率为85％。
另外，参照上述方法，制备没有复合生物活性玻璃的多孔壳聚糖冷冻凝胶微球。利用密度天平测量没有复合生物活性玻璃的多孔壳聚糖冷冻凝胶微球的孔隙率为80％。
采用扫描电子显微镜对制得的生物活性玻璃复合壳聚糖冷冻凝胶微球的形貌进行表征，见图3(a)。从图3(a)可以看出生物活性玻璃复合多孔壳聚糖冷冻凝胶微球内部具有大孔结构。
实施例3、一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法
所述快速制备生物活性玻璃复合多孔冷冻凝胶微球的方法，包括以下步骤：
S1称取0.4g熔融法制备的生物活性玻璃分散到20mL去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2称取0.8g壳聚糖(100kDa，脱乙酰度90％)完全溶解在20mL 1％wt醋酸溶液中，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中的冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入200μL 50％戊二醛溶液并搅拌均匀，然后将上述混合液使用微量进液器逐滴滴加到液氮中，滴入瞬间形成生物活性玻璃复合微球；
S5待液氮挥发后将生物活性玻璃复合微球转移到-4℃冰箱中过夜，冷冻冻干，得到生物活性玻璃复合多孔壳聚糖冷冻凝胶微球。利用密度天平测量生物玻璃复合壳聚糖冷冻凝胶微球的孔隙率为80％。
本实施例得到的生物活性玻璃复合多孔壳聚糖冷冻凝胶微球的冷冻切片的光学照片见图3(b)。从图3(b)可以看出生物活性玻璃复合壳聚糖冷冻凝胶微球内部为致密的微孔。
实施例4、一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法
所述快速制备生物活性玻璃复合多孔冷冻凝胶微球的方法，包括以下步骤：
S1称取4g使用十二胺作为模板剂结合溶胶凝胶法制备的生物活性玻璃分散到20mL去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2称取4g明胶完全溶解在20mL去离子水中，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中的冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入50μL 25％戊二醛溶液并搅拌均匀，然后将上述混合液使用胶头滴管逐滴滴加到-80℃的石油醚中，滴入瞬间形成生物活性玻璃复合微球；
S5将生物活性玻璃复合微球连同石油醚一起转移到-1℃冰箱中过夜，使用乙醇和水反复交替清洗，以去除油相溶液残留，然后冷冻冻干，得到生物活性玻璃复合明胶冷冻凝胶微球。利用密度天平测量生物活性玻璃复合多孔明胶冷冻凝胶微球的孔隙率为80％。
采用扫描电子显微镜对使用十二胺作为模板剂结合溶胶凝胶法所得生物活性玻璃的形貌进行表征，见图4。从图4可以看出本发明所用生物活性玻璃的微观形貌是纳米球形。对制得的生物活性玻璃复合多孔明胶冷冻凝胶微球的形貌进行表征，见图5，其中图5a为生物活性玻璃复合明胶多孔冷冻凝胶微球的扫描电镜图，图5b为生物活性玻璃复合明胶多孔冷冻凝胶微球的扫描电镜放大图。从图5a可以看出生物活性玻璃颗粒均匀地分布在凝胶基质上。从图5b可以看出采用本发明方法所得生物活性玻璃复合多孔明胶冷冻凝胶微球内部具有多孔结构。
实施例5、一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法
所述快速制备生物活性玻璃复合多孔冷冻凝胶微球的方法，包括以下步骤：
S1称取2.4g硝酸催化溶胶凝胶法制备的生物活性玻璃分散到20mL去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2称取0.8g壳聚糖(200kDa，脱乙酰度90％)完全溶解在20mL 1％wt醋酸溶液中，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中的冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入100μL 50％戊二醛溶液并搅拌均匀，然后将上述混合液使用微量进液器逐滴滴加到液氮中，滴入瞬间形成生物活性玻璃复合微球；
S5待液氮挥发后将生物活性玻璃复合微球转移到-4℃冰箱中过夜，冷冻冻干，得到生物活性玻璃复合多孔壳聚糖冷冻凝胶微球。利用密度天平测量生物活性玻璃复合多孔壳聚糖冷冻凝胶微球的孔隙率为70％。
试验例一、吸水性能测试
参照实施例2的方法制备没有复合生物活性玻璃的多孔壳聚糖凝胶微球(CS)。称取一定量没有复合及复合有生物活性玻璃微球的多孔壳聚糖冷冻凝胶微球(CS@BG)于玻璃皿上，滴加适量的PBS吸水1min后使用润湿的无尘布轻轻吸取未被吸收的PBS，至竖立玻璃皿时没有水滴从微球聚集体流下视为吸水完全。称量此时没有复合及复合有生物活性玻璃的壳聚糖冷冻凝胶微球质量，吸水前后微球质量之比即为微球的吸水倍数，如表1、表2、图6所示。
表1：CS微球的吸水性能测试结果
| 组别 | CS吸水前(mg) | CS吸水后(mg) | 吸水倍数 |
| 1 | 14.5 | 553.4 | 38.17 |
| 2 | 12.1 | 426.3 | 35.23 |
| 3 | 12.3 | 436.7 | 35.50 |
| 4 | 13.1 | 464.3 | 35.44 |
表2：CS@BG微球的吸水率测试结果
| 组别 | CS@BG吸水前(mg) | CS@BG吸水后(mg) | 吸水倍数 |
| 1 | 11.9 | 264.5 | 22.23 |
| 2 | 12.1 | 262.2 | 21.67 |
| 3 | 15.4 | 304.0 | 19.74 |
| 4 | 14.1 | 281.3 | 19.95 |
由表1可知，壳聚糖微球具有快速吸水的能力和超高的吸水率。由表2、图6可知，采用本发明的方法将壳聚糖与生物活性玻璃复合制得的生物活性玻璃复合多孔冷冻凝胶微球仍然具有快速吸水能力，可以在短时间内吸收自身体重20倍的PBS，具有止血、充作富血小板血浆载体等临床功能的潜力。
Claims (10)
1.一种生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，包括以下步骤：
S1将生物活性玻璃分散到去离子水中，超声使软团聚的生物活性玻璃解离并分散均匀，得到生物活性玻璃悬浊液；
S2将天然或合成高分子材料充分溶解到其对应溶液中，得到冷冻凝胶溶液；
S3在持续搅拌条件下，将步骤S1所得生物活性玻璃悬浊液逐滴滴加到步骤S2中的冷冻凝胶溶液中，得混合溶液；
S4向步骤S3所得混合溶液中加入交联剂，然后将上述混合液逐滴滴加到液氮或者液态二氧化碳或者低温油相溶液中，滴入瞬间形成生物活性玻璃复合微球；
S5待液氮或者液态二氧化碳挥发后将生物活性玻璃复合微球转移到零下附近温度放置过夜，冷冻冻干，得到生物活性玻璃复合多孔冷冻凝胶微球；
或者将生物活性玻璃复合微球连同油相溶液转移到零下附近温度放置过夜，使用乙醇和水反复交替清洗，以去除油相溶液残留，然后冷冻冻干，得到生物活性玻璃复合多孔冷冻凝胶微球。
2.如权利要求1所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，所述步骤S1所述生物活性玻璃与去离子水的质量体积比为0.1-2g/10mL。
3.如权利要求1所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，所述步骤S2所述天然或合成高分子材料包括但不限于明胶、胶原、丝素、壳聚糖、聚天冬氨酸。
4.如权利要求1所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，所述步骤S2所述冷冻凝胶溶液的质量浓度为1～20％。
5.如权利要求1所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，所述步骤S4所述低温油相溶液为温度在-20～-80℃，具有超低熔点的有机溶剂。
6.如权利要求1所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，所述有机溶剂包括但不限于石油醚、乙酸乙酯、甲酸乙酯。
7.如权利要求1所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法，其特征在于，所述步骤S5所述零下附近温度为-1～-10℃。
8.根据权利要求1-7任一项所述的生物活性玻璃复合多孔冷冻凝胶微球的制备方法制得的生物活性玻璃复合多孔冷冻凝胶微球，其特征在于，所述生物活性玻璃复合多孔冷冻凝胶微球具有球形的形貌和三维贯通的多孔结构，粒径为50～2000μm，孔隙率为50～93％，所述生物活性玻璃复合多孔冷冻凝胶微球中生物活性玻璃固含量为1～75％。
9.根据权利要求8所述的生物活性玻璃复合多孔冷冻凝胶微球，其特征在于，所述三维贯通的多孔结构中的大孔尺寸为50～200μm。
10.根据权利要求8所述的生物活性玻璃复合多孔冷冻凝胶微球在制备抗菌敷料、止血材料、药物载体，作为制备治疗骨质疏松、骨关节炎的填充材料，以及制备皮肤创面修复材料、骨缺损再生修复材料中的应用。
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