微纳米结构生物材料在骨组织再生修复中的研究进展

doi:10.15541/jim20220580

无机材料学报 ›› 2023, Vol. 38 ›› Issue (7): 750-762.DOI: 10.15541/jim20220580 CSTR: 32189.14.10.15541/jim20220580

所属专题：【生物材料】骨骼与齿类组织修复(202409)

微纳米结构生物材料在骨组织再生修复中的研究进展

赵睿¹^,²(), 毛飞¹, 钱晖¹(), 杨晓², 朱向东², 张兴栋²

1.江苏大学医学院检验系, 镇江 212013
2.四川大学国家生物医学材料工程技术研究中心, 成都 610064

收稿日期:2022-09-30 修回日期:2022-10-27 出版日期:2023-03-06 网络出版日期:2023-03-06
通讯作者: 钱晖, 教授. E-mail: 1000007341@ujs.edu.cn
作者简介:赵睿(1995-), 女, 博士, 讲师. E-mail: 1000005729@ujs.edu.cn
基金资助:
国家自然科学基金(82202332);江苏省双创博士基金(JSSCBS20221249)

Micro-/Nano-structured Biomaterials for Bone Regeneration: New Progress

ZHAO Rui¹^,²(), MAO Fei¹, QIAN Hui¹(), YANG Xiao², ZHU Xiangdong², ZHANG Xingdong²

1. Department of Inspection, School of Medicine, Jiangsu University, Zhenjiang 212013, China
2. National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China

Received:2022-09-30 Revised:2022-10-27 Published:2023-03-06 Online:2023-03-06
Contact: QIAN Hui, professor. E-mail: 1000007341@ujs.edu.cn
About author:ZHAO Rui (1995-), female, PhD, lecturer. E-mail: 1000005729@ujs.edu.cn
Supported by:
National Natural Science Foundation of China(82202332);Innovation and Entrepreneurship Doctor of Jiangsu Province(JSSCBS20221249)

摘要/Abstract

摘要：

天然骨组织由有机纳米材料胶原纤维和无机纳米材料羟基磷灰石组成, 具有独特的微纳米结构以及传统人工合成材料无法比拟的生物功能和力学性能优势。在组织工程和再生医学的研究中, 模拟天然骨组织层次特征的微纳米结构生物材料是研究热点之一。近年来, 研究人员发现微纳米结构生物材料能有效调节细胞增殖、分化和迁移, 促进细胞成骨分化, 进而促进体内骨组织再生。本文综述了利用天然骨组织层次特征指导材料分层设计的研究进展以及微纳米结构生物材料的细胞相互作用特性和在骨组织工程中的应用, 以期为生物材料的设计提供新思路。

关键词: 微纳米结构, 骨再生, 生物材料

Abstract:

Natural bone has a unique micro-/nano-structure, which is composed of organic nanomaterials (collagen fibers) and inorganic nanomaterials (hydroxyapatite). Thus, compared with traditional synthetic materials, natural bone has incomparable advantages in biological, functional and mechanical properties. In the research of tissue engineering and regenerative medicine, biomaterial scaffold with micro-/nano-structures simulating the characteristics of natural bone tissue are one of the research focuses. In recent years, researchers have found that micro-/nano-structured biomaterials can effectively regulate cell proliferation, differentiation and migration, and have a strong ability to promote cell osteogenic differentiation, so as to promote bone tissue regeneration in vivo. In this article, we focus on reviewing recent research progress of biomaterial design on simulating the hierarchical characteristics of natural bone, analyzing the complicated interaction between micro-/nano-structured biomaterials and cells, and summarizing their applications in bone tissue engineering to provide new ideas for the design of biomaterials.

Key words: micro-/nano-structure, bone regeneration, biomaterial

中图分类号:

TB33

赵睿, 毛飞, 钱晖, 杨晓, 朱向东, 张兴栋. 微纳米结构生物材料在骨组织再生修复中的研究进展[J]. 无机材料学报, 2023, 38(7): 750-762.

ZHAO Rui, MAO Fei, QIAN Hui, YANG Xiao, ZHU Xiangdong, ZHANG Xingdong. Micro-/Nano-structured Biomaterials for Bone Regeneration: New Progress[J]. Journal of Inorganic Materials, 2023, 38(7): 750-762.

图/表 6

图1 天然骨组织的层次结构模式图和人股骨骨干部皮质骨扫描电镜照片[1,11]

Fig. 1 Schematic diagram of bone hierarchical structural organization (up part) and scanning electron microscope images (bottom part) of the cortical bone specimens located at human femoral diaphysis[1,11] In bone tissue, macroscale arrangements involve both compact/ cortical bone at the surface and spongy/trabecular bone in the interior. Compact bone is composed of osteons and Haversian canals, which surrounded by blood vessels. Osteons have a lamellar structure, with individual lamella consisting of fibers arranged in geometrical patterns. The fibers comprise several mineralized collagen fibrils, composed of collagen protein molecules formed from three chains of amino acids and nanocrystals of hydroxyapatite, and linked by an organic phase to form fibril arrays

图2 不同表面形貌的传统磷酸钙(CaP)、晶须化磷酸钙(wCaP)和微纳米结构磷酸钙(nwCaP)生物陶瓷制备流程图和成骨效果[33]

Fig. 2 Schematic diagram of preparation process and bone forming ability of traditional calcium phosphate (CaP), whiskered calcium phosphate (wCaP) and micro-/nano-structured calcium phosphate (nwCaP) bioceramics with different surface morphologies[33]

图3 微纳米结构磷酸钙(nwCaP)生物陶瓷诱导成骨所涉及的分子机制研究[33]

Fig. 3 Illustration of the possible molecular mechanism involved in nwCaP bioceramics induced osteogenic effect[33] (a) Photos of Alizarin Red S and von Kossa stainings; (b) Cluster analysis of genes and quantitative qRT-PCR analysis expressions; (c) Osteogenesis-related gene expression; (d) Representative western blot analysis; OVX: Ovariectomized

图4 免疫荧光染色评估微纳米结构羟基磷灰石生物陶瓷内部的血管生成[16]

Fig. 4 CD31 and EMCN staining of histological sections from the micro-/nano-structured hydroxyapatite bioceramic groups[16] Green fluorescence: CD31; Red fluorescence: EMCN; Blue fluorescence: Nucleus of the cells

图5 连续荧光标记评估动态骨形成[16]

Fig. 5 In vivo sequential fluorescence labeling of new bone formation inside porous nwHA bioceramics[16] (a) Observed patterns of new bone formation (yellow: tetracycline label; green: calcein label); (b) Two types of osteogenesis discovered inside the pore structure of nwHA bioceramics (green indicating CD 31, Red indicating EMCN, and blue indicating nucleus); (c) Comparison of mineral apposition rate (MAR) between different nwHA groups, with statistical analysis of the relationship between osteogenesis type and pore diameter of the bioceramics, and the relationship between osteogenesis type and MAR

表1 微纳米结构生物材料用于成骨研究的文献总结

Table 1 Summary of previous work on bone formation in the micro-/nano-structured biomaterials

Material	Synthesis method	In vitro results	Animal model	In vivo results	Ref.
β-TCP scaffolds with micro/ nano surface topography	DLP printing and in situ growth crystal process	Promote osteogenic differentiation of stem cells	Rat skull defects	Improve the bone regeneration	[17]
Micro/nano-scale titania fiber-like network on the surface of Ti implants	One-step alkaline treatment in NaOH solution	Facilitate osteogenic and angiogenic differentiation of BMSCs and endothelial cells; Suppress M1 macrophages and stimulate M2 phenotype	Rabbit femur defects	Induce ameliorative osseointegration	[21]
MNBG/PLGA bi-layered membranes	Electrospinning	Promote osteogenesis			[24]
Micro-nano rough Ti₆Al₄V	Acid etch process	Improve osteogenic differentiation of MSCs			[26]
HA bioceramics with submicron- to nano- topographies	Sintering	Maintain the conformation of BMP-2, activate the osteogenic differentiation of BMSCs	Canine intramuscular implantation	Process excellent bone-like apatite forming ability and outstanding osteoinductivity	[28]
HA with micro/nano hierarchical structures	Photolithography and hydrothermal techniques	Promote osteogenic differentiation of hBMSCs and angiogenic acticvity of HUVECs			[41]
β-TCP/CaSiO₃composite ceramics with micro/ nano-HAp the surface layer	3D bioplotting and hydrothermal treatment	Upregulate the cellular differentiation of mBMSCs and gene expression of HUVECs	Ectopic subcutaneous implantation at the back of rats	Promote capillary formation and bone augmentation	[45]
PEEK/CF/n-HA ternary biocomposite with micro/ nano-topographical surface	Oxygen plasma and sandblasting	Promote the proliferation and differentiation of MG-63 cells	Dog mandibles	Boost the osseointegration between implant and bone	[73]
Micro/nano structural silicon nitride and PEKK composite	Femtosecond laser ablation	Promote osteogenic differentiation of rBMSCs; Exhibit a greater bacteriostatic activity	Rabbit femur cavity defect	Promote osseointegration and bone repair	[75]
Silicate-based bioceramic with micro-nano surfaces and hollow channels	3D printing and hydrothermal treatment	Facilitate the attachment and proliferation of BMSCs	Rabbit femur defects	Boost the newly bone formation	[80]
PLLA/CS composite scaffold with micro/nano- fiber hierarchical structure	3D printing and thermally induced phase separation technology	Promote cell adhesion and proliferation			[87]

表1 微纳米结构生物材料用于成骨研究的文献总结

Table 1 Summary of previous work on bone formation in the micro-/nano-structured biomaterials

Material	Synthesis method	In vitro results	Animal model	In vivo results	Ref.
β-TCP scaffolds with micro/ nano surface topography	DLP printing and in situ growth crystal process	Promote osteogenic differentiation of stem cells	Rat skull defects	Improve the bone regeneration	[17]
Micro/nano-scale titania fiber-like network on the surface of Ti implants	One-step alkaline treatment in NaOH solution	Facilitate osteogenic and angiogenic differentiation of BMSCs and endothelial cells; Suppress M1 macrophages and stimulate M2 phenotype	Rabbit femur defects	Induce ameliorative osseointegration	[21]
MNBG/PLGA bi-layered membranes	Electrospinning	Promote osteogenesis			[24]
Micro-nano rough Ti₆Al₄V	Acid etch process	Improve osteogenic differentiation of MSCs			[26]
HA bioceramics with submicron- to nano- topographies	Sintering	Maintain the conformation of BMP-2, activate the osteogenic differentiation of BMSCs	Canine intramuscular implantation	Process excellent bone-like apatite forming ability and outstanding osteoinductivity	[28]
HA with micro/nano hierarchical structures	Photolithography and hydrothermal techniques	Promote osteogenic differentiation of hBMSCs and angiogenic acticvity of HUVECs			[41]
β-TCP/CaSiO₃composite ceramics with micro/ nano-HAp the surface layer	3D bioplotting and hydrothermal treatment	Upregulate the cellular differentiation of mBMSCs and gene expression of HUVECs	Ectopic subcutaneous implantation at the back of rats	Promote capillary formation and bone augmentation	[45]
PEEK/CF/n-HA ternary biocomposite with micro/ nano-topographical surface	Oxygen plasma and sandblasting	Promote the proliferation and differentiation of MG-63 cells	Dog mandibles	Boost the osseointegration between implant and bone	[73]
Micro/nano structural silicon nitride and PEKK composite	Femtosecond laser ablation	Promote osteogenic differentiation of rBMSCs; Exhibit a greater bacteriostatic activity	Rabbit femur cavity defect	Promote osseointegration and bone repair	[75]
Silicate-based bioceramic with micro-nano surfaces and hollow channels	3D printing and hydrothermal treatment	Facilitate the attachment and proliferation of BMSCs	Rabbit femur defects	Boost the newly bone formation	[80]
PLLA/CS composite scaffold with micro/nano- fiber hierarchical structure	3D printing and thermally induced phase separation technology	Promote cell adhesion and proliferation			[87]

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微纳米结构生物材料在骨组织再生修复中的研究进展

Micro-/Nano-structured Biomaterials for Bone Regeneration: New Progress

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