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2222材料工程  2022, Vol. 50 Issue (2): 38-49    DOI: 10.11868/j.issn.1001-4381.2021.000185
  生物医用材料专栏 本期目录 | 过刊浏览 | 高级检索 |
骨软骨组织工程仿生梯度支架研究进展
万李1,2, 王海蟒2, 蔡谞3,4, 胡刻铭2, 岳文1,*(), 张洪玉2,*()
1 中国地质大学(北京) 工程技术学院, 北京 100083
2 清华大学 机械工程系 摩擦学国家重点实验室, 北京 100084
3 清华大学附属北京清华长庚医院 骨科, 北京 102218
4 清华大学临床医学院, 北京 102218
Research progress in biomimetic gradient scaffolds for osteochondral tissue engineering
Li WAN1,2, Haimang WANG2, Xu CAI3,4, Keming HU2, Wen YUE1,*(), Hongyu ZHANG2,*()
1 School of Engineering and Technology, China University of Geosciences(Beijing), Beijing 100083, China
2 State Key Laboratory of Tribology, Department of Mechanical Engineering, Tsinghua University, Beijing 100084, China
3 Orthopaedic Department, Beijing Tsinghua Changgung Hospital, Beijing 102218, China
4 School of Clinical Medicine, Tsinghua University, Beijing 102218, China
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摘要 

骨软骨缺损是导致关节发病和残疾的重要原因,骨软骨组织工程是修复骨软骨缺损的方法之一。骨软骨组织工程方法涉及仿生梯度支架的制造,该支架需模仿天然骨软骨组织的生理特性(例如从软骨表面到软骨下骨之间的梯度过渡)。在许多研究中骨软骨仿生梯度支架表现为离散梯度或连续梯度,用于模仿骨软骨组织的特性,例如生物化学组成、结构和力学性能。连续型骨软骨梯度支架的优点是其每层之间没有明显的界面,因此更相似地模拟天然骨软骨组织。到目前为止,骨软骨仿生梯度支架在骨软骨缺损修复研究中已经取得了良好的实验结果,但是骨软骨仿生梯度支架与天然骨软骨组织之间仍然存在差异,其临床应用还需要进一步研究。本文首先从骨软骨缺损的背景、微尺度结构与力学性能、骨软骨仿生梯度支架制造相关的材料与方法等方面概述了离散和连续梯度支架的研究进展。其次,由于3D打印骨软骨仿生梯度支架的方法能够精确控制支架孔的几何形状和力学性能,因此进一步介绍了计算仿真模型在骨软骨组织工程中的应用,例如采用仿真模型优化支架结构和力学性能以预测组织再生。最后,提出了骨软骨缺损修复相关的挑战以及骨软骨组织再生未来研究的展望。例如,连续型骨软骨仿生梯度支架需要更相似地模拟天然骨软骨组织单元的结构,即力学性能和生化性能的过渡更加自然地平滑。同时,虽然大多数骨软骨仿生梯度支架在体内外实验中均取得了良好的效果,但临床研究和应用仍然需要进行进一步深入研究。

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万李
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岳文
张洪玉
关键词 骨软骨组织工程仿生梯度支架生物材料3D打印    
Abstract

Osteochondral defects are the main cause of joint morbidity and disability in elderly patients, and osteochondral tissue engineering is one of the methods to repair osteochondral defects. The method of osteochondral tissue engineering involves the manufacture of osteochondral biomimetic gradient scaffolds that should mimic the physiological properties of natural osteochondral tissue (e.g., the gradient transition between cartilage surface and subchondral bone). The osteochondral biomimetic gradient scaffolds exhibit discrete gradients or continuous gradients to establish the characteristics of osteochondral tissue in many studies, such as biochemical composition, structure and mechanical properties. An advantage of the continuous osteochondral biomimetic gradient scaffold is that there is no obvious interface between each layer, therefore it more closely mimics the natural osteochondral tissue. Although promising results have been achieved so far on the regeneration of the osteochondral biomimetic gradient scaffold, there are still differences between the osteochondral biomimetic gradient scaffold and natural osteochondral tissue. Due to these differences, the current clinical treatment of osteochondral biomimetic gradient scaffolds to repair osteochondral defects needs further research. Firstly, the research progress on discrete and continuous gradient scaffolds from the background of osteochondral defects, the micro-scale structure and mechanical properties of osteochondral to the materials and methods related to the manufacture of osteochondral biomimetic gradient scaffolds was summarized in this article. Secondly, due to the 3D printing method of the osteochondral biomimetic gradient scaffold having the ability to precisely control the geometry of the scaffold hole and the mechanical properties of the scaffold, the application of computational simulation models in osteochondral tissue engineering was further introduced, for example, optimizing scaffold structure and mechanical properties are considered to predict tissue regeneration. Finally, the challenges related to the repair of osteochondral defects and prospects for the future research of osteochondral tissue regeneration were presented.For example, continuous osteochondral bionic gradient scaffolds need to more similarly simulate the structure of natural osteochondral tissue units, that is, the transition of mechanical properties and biochemical properties is more smooth naturally. At the same time, although most osteochondral biomimetic gradient scaffolds have achieved good results in in vivo and in vitro experiments, clinical research and application still need to be further studied.

Key wordsosteochondral    tissue engineering    biomimetic gradient scaffold    biomaterial    3D printing
收稿日期: 2021-03-02      出版日期: 2022-02-23
中图分类号:  TB34  
  R686  
  R318  
基金资助:国家自然科学基金(52022043);清华大学精准医学研究院资助项目(10001020107)
通讯作者: 岳文,张洪玉     E-mail: cugbyw@163.com;zhanghyu@tsinghua.edu.cn
作者简介: 张洪玉(1982-), 男, 副研究员, 博士, 研究方向为植入式生物医用滑润材料与器械, 联系地址: 北京市海淀区清华大学李兆基科技大楼A528(100084), E-mail: zhanghyu@tsinghua.edu.cn
岳文(1982-), 男, 教授, 博士, 研究方向为材料表面工程, 联系地址: 北京市海淀区学院路中国地质大学(北京)工程技术学院(100083), E-mail: cugbyw@163.com
引用本文:   
万李, 王海蟒, 蔡谞, 胡刻铭, 岳文, 张洪玉. 骨软骨组织工程仿生梯度支架研究进展[J]. 材料工程, 2022, 50(2): 38-49.
Li WAN, Haimang WANG, Xu CAI, Keming HU, Wen YUE, Hongyu ZHANG. Research progress in biomimetic gradient scaffolds for osteochondral tissue engineering. Journal of Materials Engineering, 2022, 50(2): 38-49.
链接本文:  
http://jme.biam.ac.cn/CN/10.11868/j.issn.1001-4381.2021.000185      或      http://jme.biam.ac.cn/CN/Y2022/V50/I2/38
Fig.1  骨软骨组织结构
(a)骨软骨单元:软骨和软骨下骨[6, 24](Tidemark表示矿化和非矿化软骨之间的离散带);骨的宏观(b)、微观(c)和纳米(d)结构[24]
Osteochondral tissue Cell state Composition Organizational structure Mechanical behavior
Cartilage The cartilage cell morphology becomes flat on the cartilage surface area, and gradually round and oval in the deep area Type Ⅱ collagen fibrils are parallel to the joint surface in the cartilage surface area, and gradually perpendicular to the joint surface in the deep area Cartilage is a highly interconnected tissue with a porosity of 60%-85% and a pore size of 2-6 nm The compressive modulus of cartilage increases from 0.2 MPa to 6.44 MPa from the surface to the deep
Calcified cartilage The volume of chondrocytes in calcified cartilage is larger than that in non-calcified cartilage areas Collagen fibrils anchor the cartilage and subchondral bone Calcified cartilage is located in the transition zone between cartilage and subchondral bone. Its pore size and porosity gradually increase The compressive modulus values of cartilage, calcified cartilage, and subchondral bone exhibit anisotropy and change in a depth-dependent manner
Subchondral bone Osteoblasts, osteoclasts, mature bone cells and mesenchymal stem cells Plate-like particles of hydroxyapatite crystals with a length of 20-50 nm, width of 15 nm, and thickness of 2-5 nm are deposited on type Ⅰ collagen fibrils The subchondral bone includes cortical bone and trabecular bone. From top to bottom, the pore size ranges from 0.1 μm to 2000 μm, and the porosity ranges from 5% to 90% The compressive modulus values of cortical bone and trabecular bone are 18-22 GPa and 0.1-0.9 GPa respectively
Table 1  天然骨软骨组织的组成、结构和力学性能[11]
Fig.2  离散型骨软骨仿生支架和连续型骨软骨仿生支架示意图[6]
Scaffold Cartilage material Subchondral bone material Mechanical property Conclusion Ref
Discrete gradient scaffold Type Ⅰ and Ⅱ collagen+ hyaluronic acid Type Ⅰ collagen+ collagen+ hydroxyapatite The compressive modulus of the upper layer is 0.3 kPa; the middle layer is 0.35 kPa; the bottom layer is 0.95 kPa.The porosity is greater than 97% Rabbit model; ICRS Ⅰ score for regenerated cartilage: Grade Ⅱ (close to normal); bone volume/total volume is 0.4, and the control group is 0.35 [61]
Gelatin/hyaluronic acid Gelatin/hydroxyapatite Cartilage compressive strength is 5.86 MPa; subchondral bone is 13.44 MPa Rabbit model; showing hyaline cartilage formation at 6 and 12 weeks [62]
Silk fibroin/chondroitin sulfate+bone marrow mesenchymal stem cells Hydroxyapatite+bone marrow mesenchymal stem cells Elastic modulus: upper layer is 0.01-0.2 MPa; lower layer is 6.7 MPa Mouse model; silk fibroin/cartilage sulfate promotes the chondrogenic differentiation of bone marrow mesenchymal stem cells; hydroxyapatite promotes osteogenic differentiation [19]
Fibrin Wollastonite+8% MgSiO3 (CS-Mg8) The compression modulus ratio of the fibrin scaffold is 5.4 kPa; the CS-Mg8 scaffold is 6.378 MPa Rabbit model; bone marrow mesenchymal stem cells adhere to the scaffold and show good spread [18]
Continuous gradient scaffold Chitosan/Gelatin+ transforming growth factor Hydroxyapatite/gelatin/ chitosan+bone morphogenetic protein Rabbit model; new trabecular bone is formed at the 4th week; it is integrated with the surrounding tissue/hyaline cartilage/indistinguishable at the 12th week [57] [54]
Type Ⅰ/Ⅲ collagen (4% w/v)) Type Ⅰ/Ⅲ Collagen+calcium phosphate Overall compressive strength is 1 MPa In the progress of new cartilage formation, 29.8% of new cartilage is formed in the first 6 weeks, and 40.09% of new cartilage is formed in the first 12 weeks.The final volume of new catilage accounts for 31.28% of the bone defect model [63]
N-N acrylamide and N-N [tris(hydroxymethyl) methyl]acryla-mide+transforming growth factor N-N acrylamide and N-N [tris(hydroxymethyl) methyl]acryla-mide+calcium phosphate Tensile strength is 0.41 MPa, strechability is 86% and high compressive strength is 8.4 MPa Mouse model; after 12 weeks, a uniform and smooth new cartilage layer is observed, the thickness is similar to that of adjacent cartilage; the interface between regenerated cartilage and subchondral bone is well integrated [17] [60]
PLGA+mesenchymal stem cells PLGA/alginate+ mesenchymal stem cells The initial mechanical properties are sufficient to maintain the integrity of the scaffold Mouse model; compared to commercial control scaffolds, more regenerated cartilage is observed after 6 months [3]
Table 2  用于动物体内研究的骨软骨仿生梯度支架的性质和性能[3, 17-19, 54, 57, 60-63]
Fig.3  骨软骨仿生梯度支架的制备过程示意图[64]
(a)通过生物3D打印制备三相骨软骨仿生梯度支架;(b)将载有细胞和生长因子的明胶水凝胶前体溶液依次注入到支架网络后,紫外光交联;(c)骨软骨仿生梯度支架在骨软骨组织诱导和再生中的应用
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