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
WILLIAMS J M , ADEWUNMI A , SCHEK R M , et al. Bone tissue engineering using polycaprolactone scaffolds fabricated via selective laser sintering[J]. Biomaterials, 2005, 26 (23): 4817- 4827.
doi: 10.1016/j.biomaterials.2004.11.057
2
CHEN H , SUN T , YAN Y , et al. Cartilage matrix-inspired biomimetic superlubricated nanospheres for treatment of osteoarthritis[J]. Biomaterials, 2020, 242, 119931.
doi: 10.1016/j.biomaterials.2020.119931
3
CRITCHLEY S , SHEEHY E J , CUNNIFFE G , et al. 3D printing of fibre-reinforced cartilaginous templates for the regeneration of osteochondral defects[J]. Acta Biomater, 2020, 113, 130- 143.
doi: 10.1016/j.actbio.2020.05.040
4
WANG C , LAI J , LI K , et al. Cryogenic 3D printing of dual-delivery scaffolds for improved bone regeneration with enhanced vascularization[J]. Bioact Mater, 2021, 6 (1): 137- 145.
doi: 10.1016/j.bioactmat.2020.07.007
5
DENG Y , SUN J , NI X , et al. Multilayers of poly(ethyleneimine)/poly(acrylic acid) coatings on Ti6Al4V acting as lubricated polymer-bearing interface[J]. J Biomed Mater Res B Appl Biomater, 2020, 108 (5): 2141- 2152.
doi: 10.1002/jbm.b.34553
6
TAMADDON M , WANG L , LIU Z Y , et al. Osteochondral tissue repair in osteoarthritic joints: clinical challenges and opportunities in tissue engineering[J]. Bio-Des Manuf, 2018, 1 (2): 101- 114.
doi: 10.1007/s42242-018-0015-0
7
XUE R , CHUNG B , TAMADDON M , et al. Osteochondral tissue coculture: an in vitro and in silico approach[J]. Biotechnol Bioeng, 2019, 116 (11): 3112- 3123.
doi: 10.1002/bit.27127
8
WANG K , XIONG D . Construction of lubricant composite coating on Ti6Al4V alloy using micro-arc oxidation and grafting hydrophilic polymer[J]. Mater Sci Eng: C, 2018, 90, 219- 226.
doi: 10.1016/j.msec.2018.04.057
9
ZHAO X , KARTHIK N , XIONG D , et al. Bio-inspired surface modification of PEEK through the dual cross-linked hydrogel layers[J]. J Mech Behav Biomed Mater, 2020, 112, 104032.
doi: 10.1016/j.jmbbm.2020.104032
10
SKUBIS-SIKORA A , SIKORA B , WITKOWSKA A , et al. Osteogenesis of adipose-derived stem cells from patients with glucose metabolism disorders[J]. Mol Med, 2020, 26, 67.
11
ZHANG B , HUANG J , NARAYAN R J . Gradient scaffolds for osteochondral tissue engineering and regeneration[J]. J Mater Chem B, 2020, 8 (36): 8149- 8170.
doi: 10.1039/D0TB00688B
12
GIANNONI P , LAZZARINI E , CESERACCIU L , et al. Design and characterization of a tissue-engineered bilayer scaffold for osteochondral tissue repair[J]. J Tissue Eng Regen M, 2015, 9 (10): 1182- 1192.
doi: 10.1002/term.1651
13
XU J , FANG Q , LIU Y , et al. In situ ornamenting poly(epsilon-caprolactone) electrospun fibers with different fiber diameters using chondrocyte-derived extracellular matrix for chondrogenesis of mesenchymal stem cells[J]. Colloids Surf B Biointerfaces, 2020, 197, 111374.
14
KIM T G , SHIN H , LIM D W . Biomimetic scaffolds for tissue engineering[J]. Advanced Functional Materials, 2012, 22 (12): 2446- 2468.
doi: 10.1002/adfm.201103083
15
FEDOROVICH N E , SCHUURMAN W , WIJNBERG H M , et al. Biofabrication of osteochondral tissue equivalents by printing topologically defined, cell-laden hydrogel scaffolds[J]. Tissue Eng Part C, 2012, 18 (1): 33- 44.
doi: 10.1089/ten.tec.2011.0060
16
SALMANI M M , HASHEMIAN M , KHANDAN A . Therapeutic effect of magnetic nanoparticles on calcium silicate bioceramic in alternating field for biomedical application[J]. Ceramics International, 2020, 46 (17): 27299- 27307.
doi: 10.1016/j.ceramint.2020.07.215
17
GAO F , XU Z , LIANG Q , et al. Direct 3D printing of high strength biohybrid gradient hydrogel scaffolds for efficient repair of osteochondral defect[J]. Advanced Functional Materials, 2018, 28, 1706644.
doi: 10.1002/adfm.201706644
18
SHEN T , DAI Y , LI X , et al. Regeneration of the osteochondral defect by a wollastonite and macroporous fibrin biphasic scaffold[J]. ACS Biomaterials Science & Engineering, 2017, 4 (6): 1942- 1953.
19
SHANG L , MA B , WANG F , et al. Nanotextured silk fibroin/hydroxyapatite biomimetic bilayer tough structure regulated osteogenic/chondrogenic differentiation of mesenchymal stem cells for osteochondral repair[J]. Cell Prolif, 2020, 53 (11): e12917.
20
CUI Y , WU Q , HE J , et al. Porous nano-minerals substituted apatite/chitin/pectin nanocomposites scaffolds for bone tissue engineering[J]. Arabian Journal of Chemistry, 2020, 13 (10): 7418- 7429.
doi: 10.1016/j.arabjc.2020.08.018
21
QU H W , FU H Y , HAN Z Y , et al. Biomaterials for bone tissue engineering scaffolds: a review[J]. Rsc Adv, 2019, 9 (45): 26252- 26262.
doi: 10.1039/C9RA05214C
22
BOSCHETTI F , PENNATI G , GERVASO F , et al. Biomechanical properties of human articular cartilage under compressive loads[J]. Biorheology, 2004, 41 (3/4): 159- 166.
23
ANSARI S , KHORSHIDI S , KARKHANEH A . Engineering of gradient osteochondral tissue: from nature to lab[J]. Acta Biomater, 2019, 87, 41- 54.
doi: 10.1016/j.actbio.2019.01.071
24
GONG T , XIE J , LIAO J , et al. Nanomaterials and bone regeneration[J]. Bone Res, 2015, 3, 15029.
doi: 10.1038/boneres.2015.29
25
HARDIN J A , COBELLI N , SANTAMBROGIO L . Consequences of metabolic and oxidative modifications of cartilage tissue[J]. Nature Reviews Rheumatology, 2015, 11 (9): 521- 529.
doi: 10.1038/nrrheum.2015.70
26
EYRE D R , WEIS M A , WU J J . Articular cartilage collagen: an irreplaceable framework?[J]. Eur Cell Mater, 2006, 12, 57- 63.
doi: 10.22203/eCM.v012a07
27
KIANI C , CHEN L , WU Y J , et al. Structure and function of aggrecan[J]. Cell Res, 2002, 12 (1): 19- 32.
doi: 10.1038/sj.cr.7290106
28
ODDE D . Getting cells and tissues into shape[J]. Cell, 2011, 144 (3): 325- 326.
doi: 10.1016/j.cell.2011.01.022
29
ROBLING A G , STOUT S D . Morphology of the drifting osteon[J]. Cells Tissues Organs, 1999, 164 (4): 192- 204.
doi: 10.1159/000016659
30
DISCHER D E , MOONEY D J , ZANDSTRA P W . Growth factors, matrices, and forces combine and control stem cells[J]. Science, 2009, 324 (5935): 1673- 1677.
doi: 10.1126/science.1171643
31
CAPLAN A I . Adult mesenchymal stem cells for tissue engineering versus regenerative medicine[J]. J Cell Physiol, 2007, 213 (2): 341- 347.
doi: 10.1002/jcp.21200
32
WILLIAMS G M , CHAN E F , TEMPLE-WONG M M , et al. Shape, loading, and motion in the bioengineering design, fabrication, and testing of personalized synovial joints[J]. J Biomech, 2010, 43 (1): 156- 165.
doi: 10.1016/j.jbiomech.2009.09.021
33
LEE H , LEE J H , HONG S , et al. Transplantation of human corneal limbal epithelial cell sheet harvested on synthesized carboxymethyl cellulose and dopamine in a limbal stem cell deficiency[J]. J Tissue Eng Regen M, 2021, 15, 139- 149.
doi: 10.1002/term.3159
34
FAN H B , ZHANG C L , LI J , et al. Gelatin microspheres containing TGF-beta 3 enhance the chondrogenesis of mesenchymal stem cells in modified pellet culture[J]. Biomacromolecules, 2008, 9 (3): 927- 934.
doi: 10.1021/bm7013203
35
LYONS F G , AL-MUNAJJED A A , KIERAN S M , et al. The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs[J]. Biomaterials, 2010, 31 (35): 9232- 9243.
doi: 10.1016/j.biomaterials.2010.08.056
36
OBERT L , LEPAGE D , GINDRAUX F , et al. Bone morphogenetic proteins in soft-tissue reconstruction[J]. Injury, 2009, 40, 17- 20.
37
NAHANMOGHADAM A , ASEMANI M , GOODARZI V , et al. Design and fabrication of bone tissue scaffolds based on PCL/PHBV containing hydroxyapatite nanoparticles: dual-leaching technique[J]. Journal of Biomedical Materials Research Part A, 2020, 109 (6): 1- 13.
38
SMOLJANOVIC T , BOJANIC I , CIMIC M. , Re: BODEN S D , ZDEBLICK T A , SANDHU H S , et al. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report[J]. Spine, 2010, 35 (20): 376- 381.
39
GU J , JEONG Y-J , NA J Y , et al. Application of semi-permeable membrane for a scaffold in a nature-mimicking vascular system[J]. Journal of Membrane Science, 2020, 611, 118384.
doi: 10.1016/j.memsci.2020.118384
40
PAVLINAKOVA V , FOHLEROVA Z , PAVLINAK D , et al. Effect of halloysite nanotube structure on physical, chemical structual and biological properties of elastic polycaprolactone galation nanofibers for wound healing applications[J]. Mater Sci Eng: C, 2018, 91, 94- 102.
doi: 10.1016/j.msec.2018.05.033
41
VEPARI C , KAPLAN D L . Silk as a biomaterial[J]. Prog Polym Sci, 2007, 32 (8/9): 991- 1007.
42
LIU J , FANG Q , LIN H , et al. Alginate-poloxamer/silk fibroin hydrogels with covalently and physically cross-linked networks for cartilage tissue engineering[J]. Carbohydr Polym, 2020, 247, 116593.
doi: 10.1016/j.carbpol.2020.116593
43
WANG F , LI Z Q , KHAN M , et al. Injectable, rapid gelling and highly flexible hydrogel composites as growth factor and cell carriers[J]. Acta Biomater, 2010, 6 (6): 1978- 1991.
doi: 10.1016/j.actbio.2009.12.011
44
DORSEY S M , MCGARVEY J R , WANG H , et al. MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit ventricular remodeling after myocardial infarction[J]. Biomaterials, 2015, 69, 65- 75.
doi: 10.1016/j.biomaterials.2015.08.011
45
YU J , LEE S , CHOI S , et al. Fabrication of a polycaprolactone/alginate bipartite hybrid scaffold for osteochondral tissue using a three-dimensional bioprinting system[J]. Polymers (Basel), 2020, 12, 2203.
doi: 10.3390/polym12102203
46
ALEXANDER A , AJAZUDDIN , KHAN J , et al. Poly(ethylene glycol)-poly(lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications[J]. J Control Release, 2013, 172 (3): 715- 729.
doi: 10.1016/j.jconrel.2013.10.006
47
SUH J K F , MATTHEW H W T . Application of chitosan-based polysaccharide biomaterials in cartilage tissue engineering: a review[J]. Biomaterials, 2000, 21 (24): 2589- 2598.
doi: 10.1016/S0142-9612(00)00126-5
48
XU Y , PENG J , RICHARDS G , et al. Optimization of electrospray fabrication of stem cell-embedded alginate-gelatin microspheres and their assembly in 3D-printed poly(epsilon-caprolactone) scaffold for cartilage tissue engineering[J]. J Orthop Translat, 2019, 18, 128- 141.
doi: 10.1016/j.jot.2019.05.003
49
ZHANG Y , HAO C , GUO W , et al. Co-culture of hWJMSCs and pACs in double biomimetic ACECM oriented scaffold enhances mechanical properties and accelerates articular cartilage regeneration in a caprine model[J]. Stem Cell Res Ther, 2020, 11 (1): 180.
doi: 10.1186/s13287-020-01670-2
50
XU W , YU A , LU X , et al. Design and performance evaluation of additively manufactured composite lattice structures of commercially pure Ti (CP-Ti)[J]. Bioact Mater, 2021, 6 (5): 1215- 1222.
doi: 10.1016/j.bioactmat.2020.10.005
51
HUANG X , CHEN Z , ZHAO G , et al. Combined culture experiment of mouse bone marrow mesenchymal stem cells and bioceramic scaffolds[J]. Exp Ther Med, 2020, 20 (5): 19.
52
KARAGEORGIOU V , KAPLAN D . Porosity of 3D biomaterial scaffolds and osteogenesis[J]. Biomaterials, 2005, 26 (27): 5474- 5491.
doi: 10.1016/j.biomaterials.2005.02.002
53
DI MARTINO A , SITTINGER M , RISBUD M V . Chitosan: a versatile biopolymer for orthopaedic tissue-engineering[J]. Biomaterials, 2005, 26 (30): 5983- 5990.
doi: 10.1016/j.biomaterials.2005.03.016
54
PARISI C , SALVATORE L , VESCHINI L , et al. Biomimetic gradient scaffold of collagen-hydroxyapatite for osteochondral regeneration[J]. J Tissue Eng, 2020, 11, 1- 13.
55
GOLAFSHAN N , VORNDRAN E , ZAHARIEVSKI S , et al. Tough magnesium phosphate-based 3D-printed implants induce bone regeneration in an equine defect model[J]. Biomaterials, 2020, 261, 120302.
doi: 10.1016/j.biomaterials.2020.120302
56
ZHAO C Y , ZHANG H F , CAI B , et al. Preparation of porous PLGA/Ti biphasic scaffold and osteochondral defect repair[J]. Biomaterials Science, 2013, 1 (7): 703- 710.
doi: 10.1039/c3bm00199g
57
CHEN J N , CHEN H A , LI P , et al. Simultaneous regeneration of articular cartilage and subchondral bone in vivo using MSCs induced by a spatially controlled gene delivery system in bilayered integrated scaffolds[J]. Biomaterials, 2011, 32 (21): 4793- 4805.
doi: 10.1016/j.biomaterials.2011.03.041
58
JIANG J , TANG A , ATESHIAN G A , et al. Bioactive stratified polymer ceramic-hydrogel scaffold for integrative osteochondral repair[J]. Ann Biomed Eng, 2010, 38 (6): 2183- 2196.
doi: 10.1007/s10439-010-0038-y
59
BITTNER S M , SMITH B T , DIAZ-GOMEZ L , et al. Fabrication and mechanical characterization of 3D printed vertical uniform and gradient scaffolds for bone and osteochondral tissue engineering[J]. Acta Biomater, 2019, 90, 37- 48.
doi: 10.1016/j.actbio.2019.03.041
60
DORMER N H , SINGH M , WANG L M , et al. Osteochondral interface tissue engineering using macroscopic gradients of bioactive signals[J]. Ann Biomed Eng, 2010, 38 (6): 2167- 2182.
doi: 10.1007/s10439-010-0028-0
61
LEVINGSTONE T J , MATSIKO A , DICKSON G R , et al. A biomimetic multi-layered collagen-based scaffold for osteochondral repair[J]. Acta Biomater, 2014, 10 (5): 1996- 2004.
doi: 10.1016/j.actbio.2014.01.005
62
DENG T Z , LV J , PANG J L , et al. Construction of tissue-engineered osteochondral composites and repair of large joint defects in rabbit[J]. J Tissue Eng Regen M, 2014, 8 (7): 546- 556.
63
GOTTERBARM T , BREUSCH S J , JUNG M , et al. Complete subchondral bone defect regeneration with a tricalcium phosphate collagen implant and osteoinductive growth factors: a randomized controlled study in Gottingen minipigs[J]. J Biomed Mater Res B, 2014, 102 (5): 933- 942.
doi: 10.1002/jbm.b.33074
64
QIAO Z , LIAN M , HAN Y , et al. Bioinspired stratified electrowritten fiber-reinforced hydrogel constructs with layer-specific induction capacity for functional osteochondral regeneration[J]. Biomaterials, 2021, 266, 120385.
doi: 10.1016/j.biomaterials.2020.120385
65
GELBER P E , BATISTA J , MILLAN-BILLI A , et al. Magnetic resonance evaluation of TruFit(R) plugs for the treatment of osteochondral lesions of the knee shows the poor characteristics of the repair tissue[J]. Knee, 2014, 21 (4): 827- 832.
doi: 10.1016/j.knee.2014.04.013
66
DELL'OSSO G , BOTTAI V , BUGELLI G , et al. The biphasic bioresorbable scaffold (Trufit((R))) in the osteochondral knee lesions: long-term clinical and MRI assessment in 30 patients[J]. Musculoskelet Surg, 2016, 100 (2): 93- 96.
doi: 10.1007/s12306-015-0383-y
67
PERDISA F , FILARDO G , DI MATTEO B , et al. Biological knee reconstruction: a case report of an olympic athlete[J]. Eur Rev Med Pharmacol Sci, 2014, 18 (Suppl 1)): 76- 80.
68
CHRISTENSEN B B , FOLDAGER C B , JENSEN J , et al. Poor osteochondral repair by a biomimetic collagen scaffold: 1-to 3-year clinical and radiological follow-up[J]. Knee Surg Sport Tr A, 2016, 24 (7): 2380- 2387.
doi: 10.1007/s00167-015-3538-3