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
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.
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
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
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2022, Vol. 50 
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