基于丝素蛋白材料构建骨组织修复支架的三维多孔结构体系的研究进展

doi:10.12211/2096-8280.2022-026

合成生物学 ›› 2022, Vol. 3 ›› Issue (4): 795-809.DOI: 10.12211/2096-8280.2022-026

基于丝素蛋白材料构建骨组织修复支架的三维多孔结构体系的研究进展

邵云菲¹, 王卉¹, 朱怡然¹, 王树春¹, 姜雨淋¹, 胡建臣¹, 王晶², 张克勤¹

^1.苏州大学纺织与服装工程学院，现代丝绸国家工程实验室（苏州），纺织行业丝绸功能材料与技术重点实验室，江苏苏州 215123
^2.西安交通大学机械工程学院，陕西西安 710049

收稿日期:2022-04-28 修回日期:2022-07-12 出版日期:2022-08-31 发布日期:2022-09-08
通讯作者: 王卉,张克勤
作者简介:邵云菲（1995—），女，博士研究生。研究方向为丝素蛋白基骨组织工程支架制备及生物学应用。E-mail：361503687@qq.com
王卉（1980—），女，副教授，硕士生导师。研究方向：向自然学习，利用受生物启发的合成策略和仿生原理设计构建具有仿生微/纳多级结构的生物材料，通过研究材料表/界面拓扑结构与功能的内在联系，探索仿生结构材料诱导组织再生修复的机制，开发理想的组织再生材料。E-mail：whui@suda.edu.cn
张克勤（1972—），男，教授，博士生导师。研究方向：长期从事软物质与生物物理、生物与多功能复合纤维材料研究，同时进行功能纤维（中空纤维，结构色纤维和纳米复合纤维）的成果转化。E-mail：kqzhang@suda.edu.cn
基金资助:
国家重点研发计划(2017YFA0204600);国家自然科学基金面上项目(51873134);江苏省自然科学基金面上项目(BK20211317);江苏省丝绸工程重点实验室开放课题(KJS1833);南通市科技计划(JC2021043)

Research progress on the construction of three-dimensional porous structure of bone tissue repair scaffolds based on silk fibroin materials

Yunfei SHAO¹, Hui WANG¹, Yiran ZHU¹, Shuchun WANG¹, Yulin JIANG¹, Jianchen HU¹, Jing WANG², Keqin ZHANG¹

^1.Laboratory National Engineering Laboratory for Modern Silk （Suzhou），College of Textile and Clothing Engineering，Soochow University，Suzhou 215123，Jiangsu，China
^2.School of Mechanical Engineering，Xi'an Jiaotong University，Xi'an 710049，Shaanxi，China

Received:2022-04-28 Revised:2022-07-12 Online:2022-08-31 Published:2022-09-08
Contact: Hui WANG, Keqin ZHANG

摘要/Abstract

摘要：

随医学技术和认知水平的提高，骨组织缺损的治疗理念逐渐从组织移植向组织再生模式转变。三维（3D）多孔支架在骨组织工程研究中起着关键性的作用，是种子细胞在形成组织之前赖以生存的生物学载体，能为组织再生提供空间场所。本文针对基于丝素蛋白（SF）生物材料构建3D多孔支架的研究进展进行了总结和讨论。首先，概述了自然骨组织的多层次多孔结构特征；其次，总结了SF材料的组成和结构特征，及其卓越的生物相容性、力学性能和生物可降解性能等特性；随后，着重讨论了SF基3D骨组织修复多孔支架典型的制备技术，包括冷冻干燥法、粒子沥滤法、生物3D打印法、复合制造技术对3D支架多孔结构的控制能力，以及多孔结构对细胞生长行为和骨组织再生的影响；最后，对SF构建的骨组织修复支架所面临的挑战和发展前景进行了展望，强调了合成生物技术为解决SF基多孔支架应用于骨组织工程领域所存在的问题提供了有力的工具。

关键词: 丝素蛋白, 骨组织工程, 三维多孔支架, 结构调控

Abstract:

Bone defects caused by trauma, tumors or congenital diseases seriously affect the physical and mental health of human beings. Autologous bone and allogeneic bone transplantation are the gold standard in clinical treatment, but they have certain limitations due to their limited sources, risks of immune response and infection. In recent years, with the improvement of medical technology and cognitive level, the treatment concept of bone tissue defect has gradually changed from tissue transplantation to tissue regeneration mode. Three-dimensional (3D) porous scaffolds play a key role in bone tissue engineering research, serving as biological carriers for seed cells to survive before forming tissues, providing a space for tissue regeneration. The ideal bone tissue scaffold should have good biocompatibility, a porous structure which is conducive to the growth and differentiation of bone cells, suitable mechanical properties, and matching degradation properties. Successful 3D scaffold material design requires understanding the composition and structure of natural bone tissue, selecting appropriate biomaterials, and controllably constructing 3D porous structures at multi-scales through certain fabrication techniques. Natural bone tissue is a composite material with a hierarchical porous structure, which is composed of dense cortical bone in the outer layer and porous cancellous bone in the inner layer. From the perspective of bionics, the regulation of porous scaffolds at multiple scales is an important link in mimicking the hierarchical structure of bone tissue. Silk fibroin (SF), as a natural protein material with good biocompatibility and biodegradability, excellent mechanical properties and easy processing, has become an excellent candidate for the construction of 3D porous scaffolds. This paper summarizes and discusses the research progress of the construction of 3D porous scaffolds based on SF biomaterials. First of all, the characteristics of the multi-layered porous structure of natural bone tissue are summarized; secondly, the composition and structural characteristics of SF materials, as well as their excellent biocompatibility, mechanical properties and biodegradability are described; subsequently, the typical fabrication techniques of SF-based 3D porous scaffolds for bone tissue repair are introduced, including freeze-drying, particle leaching, 3D bioprinting, and composite manufacturing technology, and their ability to control the porous structure of 3D scaffolds, the effects of porous structure on cell growth behavior and bone tissue regeneration are also discussed; finally, the design and fabrication challenges and development prospects of SF-constructed bone tissue repair scaffolds are prosposed, emphasizing that synthetic biology could provide a powerful tool for solving the problems existing in the application of SF-based porous scaffolds in the field of bone tissue engineering.

Key words: silk fibroin, bone tissue engineering, three-dimensional porous scaffold, structure regulation

中图分类号:

Q819

邵云菲, 王卉, 朱怡然, 王树春, 姜雨淋, 胡建臣, 王晶, 张克勤. 基于丝素蛋白材料构建骨组织修复支架的三维多孔结构体系的研究进展[J]. 合成生物学, 2022, 3(4): 795-809.

Yunfei SHAO, Hui WANG, Yiran ZHU, Shuchun WANG, Yulin JIANG, Jianchen HU, Jing WANG, Keqin ZHANG. Research progress on the construction of three-dimensional porous structure of bone tissue repair scaffolds based on silk fibroin materials[J]. Synthetic Biology Journal, 2022, 3(4): 795-809.

图/表 7

图1 天然骨组织的多尺度结构［23］

Fig. 1 Schematic diagrams for the multi-scale structure of native bone tissue[23]

图2 SF的分层结构和化学结构［31］

Fig. 2 Schematic illustration of hierarchical and chemical structure of SF[31]

图3 Ca2+诱导多级多孔结构Ca/SFS支架形成过程［58］（Ca/SFS支架的SEM照片及其表面生长细胞的增殖和成骨分化情况）

Fig. 3 Schematic diagram of the formation process of Ca2+ induced multi-level porous structure Ca/SFS scaffolds, SEM micrographs of Ca/SFS scaffolds and proliferation and osteogenic differentiation of growing cells on surface [58]

图4 反蛋白石法制备SF支架的示意图及支架结构、孔径分布，盐颗粒（黑色柱）和反蛋白石（灰色柱）支架培养6周后测量的钙含量［68，71］

Fig. 4 Schematic diagram of SF scaffold prepared by inverse opal method, scaffold structure and pore size distribution, calcium content measured after 6 weeks in culture for salt-leached (black columns) and inverse opal (gray columns) scaffolds [68,71]

图5 基于3D打印法可控构建SF支架的3D多孔结构

Fig. 5 Controllable construction of 3D porous structures of SF scaffolds based on 3D print

图6 基于复合制造技术可控构建SF支架的3D多孔结构［93］

Fig. 6 Controllable construction of 3D porous structures of SF scaffolds based on composite manufacturing technology [93]

表1 不同制备方法对SF基三维骨组织修复支架的孔结构调控

Tab. 1 Pore structure regulation of SF-based 3D bone tissue repair scaffolds by different preparation methods

制备方法	调控参数	孔隙特征	可控性	优缺点	参考文献
冷冻干燥	SF浓度、二级结构、混合溶液成分、降温速度和温度	随机（各向同性）、线性（各向异性），通常在50～250 μm	简便，不太可控	有利于生物活性分子结合；孔径较小，互连性差	[47-49]
粒子沥滤	致孔剂的形状和数量	孔隙与致孔剂颗粒形貌一致，通常在200～1000 μm	较简单，一定的可控性	孔隙率高；支架厚度受到限制	[44,54-55]
生物3D打印	打印模型设计	多为十字网格形貌，间距调节范围广，可在200 μm～1 mm	快速成型，精确可控	满足不同形状骨缺损修复；仪器昂贵，墨水难制	[73,76]
复合制造技术	各工艺相关参数	宏观-介观-微观多尺度、多层级结构	多尺度，较高的可控性	获得更多层级支架；各类技术结合较难操作	[81-83]

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基于丝素蛋白材料构建骨组织修复支架的三维多孔结构体系的研究进展

Research progress on the construction of three-dimensional porous structure of bone tissue repair scaffolds based on silk fibroin materials

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