Biochemical Aspects of Scaffolds for Cartilage Tissue Engineering; from Basic Science to Regenerative Medicine

Document Type : CURRENT CONCEPTS REVIEW

Authors

1 1 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. 2 Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran 3 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Orthopedic Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pharmaceutics, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

4 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran. 2 Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran

Abstract

Chondral defects are frequent and important causes of pain and disability. Cartilage has limited self-repair and 
regeneration capacity. The ideal approach for articular cartilage defects is the regeneration of hyaline cartilage with 
sustainable symptom-free constructs. Tissue engineering provides new strategies for the regeneration of functional 
cartilage tissue through optimized scaffolds with architectural, mechanical, and biochemical properties similar to the 
native cartilage tissue. In this review, the basic science of cartilage structure, interactions between proteins, stem cells, 
as well as biomaterials, scaffold characteristics and fabrication methods, as well as current and potential therapies in 
regenerative medicine will be discussed mostly from a biochemical point of view. Furthermore, the recent trends in 
scaffold-based therapies and supplementary factors in cartilage tissue engineering will be considered. 
Level of evidence: I

Keywords


1. Casanellas I, Garcia-Lizarribar A, Lagunas A, Samitier 
J. Producing 3D Biomimetic Nanomaterials for 
Musculoskeletal System Regeneration. Front Bioeng 
Biotechnol. 2018;6:128.
2. Hunziker EB, Quinn TM, Hauselmann HJ. Quantitative 
structural organization of normal adult human 
articular cartilage. Osteoarthritis Cartilage. 
2002;10(7):564-72.
3. Murphy L, Helmick CG. The impact of osteoarthritis in 
the United States: a population-health perspective: A 
population-based review of the fourth most common 
cause of hospitalization in U.S. adults. Orthop Nurs. 
2012;31(2):85-91.
4. Vilela CA, da Silva Morais A, Pina S, Oliveira JM, 
Correlo VM, Reis RL, et al. Clinical Trials and 
Management of Osteochondral Lesions. Adv Exp Med 
Biol. 2018;1058:391-413.
5. Bicho D, Pina S, Reis RL, Oliveira JM. Commercial 
Products for Osteochondral Tissue Repair and 
Regeneration. Adv Exp Med Biol. 2018;1058:415-28.
6. Buckwalter JA, Mankin HJ. Articular cartilage: 
degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect. 1998;47:487-
504.
7. Buckwalter JA, Mankin HJ. Articular cartilage: tissue 
design and chondrocyte-matrix interactions. Instr 
Course Lect. 1998;47:477-86.
8. Camp CL, Stuart MJ, Krych AJ. Current concepts of 
articular cartilage restoration techniques in the knee. 
Sports Health. 2014;6(3):265-73.
9. Gudas R, Gudaite A, Mickevicius T, Masiulis N, 
Simonaityte R, Cekanauskas E, et al. Comparison 
of osteochondral autologous transplantation, 
microfracture, or debridement techniques in articular 
cartilage lesions associated with anterior cruciate 
ligament injury: a prospective study with a 3-year 
follow-up. Arthroscopy. 2013;29(1):89-97.
10.Richter DL, Schenck RC, Jr., Wascher DC, Treme G. 
Knee Articular Cartilage Repair and Restoration 
Techniques: A Review of the Literature. Sports Health. 
2016;8(2):153-60.
11.Oliver-Welsh L, Griffin JW, Meyer MA, Gitelis ME, Cole 
BJ. Deciding How Best to Treat Cartilage Defects. 
Orthopedics. 2016;39(6):343-50.
12.Mason C, Dunnill P. A brief definition of regenerative 
medicine. Regen Med. 2008;3(1):1-5.
13.Decker RS. Articular cartilage and joint development 
from embryogenesis to adulthood. InSeminars in cell 
& developmental biology 2017 (Vol. 62, pp. 50-56). 
Academic Press.
14.Zhang L, Hu J, Athanasiou KA. The role of tissue 
engineering in articular cartilage repair and 
regeneration. Crit Rev Biomed Eng. 2009;37(1-2):1-57.
15.Jorgensen AEM, Kjaer M, Heinemeier KM. The Effect 
of Aging and Mechanical Loading on the Metabolism 
of Articular Cartilage. J Rheumatol. 2017;44(4):410-7.
16.Elder BD, Athanasiou KA. Hydrostatic pressure 
in articular cartilage tissue engineering: from 
chondrocytes to tissue regeneration. Tissue Eng Part 
B Rev. 2009;15(1):43-53.
17.Zhu M, Li W, Dong X, Yuan X, Midgley AC, Chang H, et al. 
In vivo engineered extracellular matrix scaffolds with 
instructive niches for oriented tissue regeneration. 
Nature communications. 2019;10(1):1-4.
18.Sundelacruz S, Kaplan DL. Stem cell-and scaffoldbased tissue engineering approaches to osteochondral 
regenerative medicine. InSeminars in cell & 
developmental biology 2009 (Vol. 20, No. 6, pp. 646-
655). Academic Press..
19.Humphrey JD, Dufresne ER, Schwartz MA. 
Mechanotransduction and extracellular matrix 
homeostasis. Nat Rev Mol Cell Biol. 2014;15(12):802-
12.
20.Alford JW, Cole BJ. Cartilage restoration, part 1: basic 
science, historical perspective, patient evaluation, and 
treatment options. Am J Sports Med. 2005;33(2):295-
306.
21.Patel JM, Wise BC, Bonnevie ED, Mauck RL. A 
Systematic Review and Guide to Mechanical Testing 
for Articular Cartilage Tissue Engineering. Tissue Eng 
Part C Methods. 2019;25(10):593-608.
22.Yamashita A, Tamamura Y, Morioka M, Karagiannis P, 
Shima N, Tsumaki N. Considerations in hiPSC-derived 
cartilage for articular cartilage repair. Inflammation 
and Regeneration. 2018;38(1):1-7..
23.Tatari H. The structure, physiology, and biomechanics 
of articular cartilage: injury and repair. Acta 
orthopaedica et traumatologica turcica. 2007;41:1-5.
24.Yari D, Ehsanbakhsh Z, Validad MH, Langroudi 
FH. Association of TIMP-1 and COL4A4 Gene 
Polymorphisms with Keratoconus in an Iranian 
Population. J Ophthalmic Vis Res. 2020;15(3):299-
307.
25.Moradi A, Ataollahi F, Sayar K, Pramanik S, Chong PP, 
Khalil AA, et al. Chondrogenic potential of physically 
treated bovine cartilage matrix derived porous 
scaffolds on human dermal fibroblast cells. J Biomed 
Mater Res A. 2016;104(1):245-56.
26.Mehlhorn AT, Niemeyer P, Kaiser S, Finkenzeller G, 
Stark GB, Sudkamp NP, et al. Differential expression 
pattern of extracellular matrix molecules during 
chondrogenesis of mesenchymal stem cells from 
bone marrow and adipose tissue. Tissue Eng. 
2006;12(10):2853-62.
27.Vincent TL, Wann AK. Mechanoadaptation: articular 
cartilage through thick and thin. The Journal of 
physiology. 2019;597(5):1271-81..
28.Roughley PJ, Lee ER. Cartilage proteoglycans: 
structure and potential functions. Microsc Res Tech. 
1994;28(5):385-97.
29.Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate 
proteoglycans. Cold Spring Harbor perspectives in 
biology. 2011;3(7):a004952.
30.Neves MI, Araújo M, Moroni L, da Silva RM, Barrias 
CC. Glycosaminoglycan-inspired biomaterials for 
the development of bioactive hydrogel networks. 
Molecules. 2020;25(4):978.
31.Iozzo RV, Schaefer L. Proteoglycan form and function: 
A comprehensive nomenclature of proteoglycans. 
Matrix Biol. 2015;42:11-55.
32.Driessen BJH, Logie C, Vonk LA. Cellular 
reprogramming for clinical cartilage repair. Cell Biol 
Toxicol. 2017;33(4):329-49.
33.Wilusz RE, Sanchez-Adams J, Guilak F. The structure 
and function of the pericellular matrix of articular 
cartilage. Matrix Biol. 2014;39:25-32.
34.Carballo CB, Nakagawa Y, Sekiya I, Rodeo SA. Basic 
Science of Articular Cartilage. Clin Sports Med. 
2017;36(3):413-25.
35.Bolton MC, Dudhia J, Bayliss MT. Age-related changes 
in the synthesis of link protein and aggrecan in human 
articular cartilage: implications for aggregate stability. 
Biochem J. 1999;337(1):77-82.
36.Price JS, Waters JG, Darrah C, Pennington C, Edwards 
DR, Donell ST, et al. The role of chondrocyte senescence 
in osteoarthritis. Aging Cell. 2002;1(1):57-65.
37.Saravani R, Yari D, Saravani S, Hasanian-Langroudi 
F. Correlation between the COL4A3, MMP-9, and 
TIMP-1 polymorphisms and risk of keratoconus. Jpn 
J Ophthalmol. 2017;61(3):218-22.
38.Brittberg M, Lindahl A, Nilsson A, Ohlsson C, 
Isaksson O, Peterson L. Treatment of deep cartilage 
defects in the knee with autologous chondrocyte and transplantation. Instr Course Lect. 1998;47:487-
504.
7. Buckwalter JA, Mankin HJ. Articular cartilage: tissue 
design and chondrocyte-matrix interactions. Instr 
Course Lect. 1998;47:477-86.
8. Camp CL, Stuart MJ, Krych AJ. Current concepts of 
articular cartilage restoration techniques in the knee. 
Sports Health. 2014;6(3):265-73.
9. Gudas R, Gudaite A, Mickevicius T, Masiulis N, 
Simonaityte R, Cekanauskas E, et al. Comparison 
of osteochondral autologous transplantation, 
microfracture, or debridement techniques in articular 
cartilage lesions associated with anterior cruciate 
ligament injury: a prospective study with a 3-year 
follow-up. Arthroscopy. 2013;29(1):89-97.
10.Richter DL, Schenck RC, Jr., Wascher DC, Treme G. 
Knee Articular Cartilage Repair and Restoration 
Techniques: A Review of the Literature. Sports Health. 
2016;8(2):153-60.
11.Oliver-Welsh L, Griffin JW, Meyer MA, Gitelis ME, Cole 
BJ. Deciding How Best to Treat Cartilage Defects. 
Orthopedics. 2016;39(6):343-50.
12.Mason C, Dunnill P. A brief definition of regenerative 
medicine. Regen Med. 2008;3(1):1-5.
13.Decker RS. Articular cartilage and joint development 
from embryogenesis to adulthood. InSeminars in cell 
& developmental biology 2017 (Vol. 62, pp. 50-56). 
Academic Press.
14.Zhang L, Hu J, Athanasiou KA. The role of tissue 
engineering in articular cartilage repair and 
regeneration. Crit Rev Biomed Eng. 2009;37(1-2):1-57.
15.Jorgensen AEM, Kjaer M, Heinemeier KM. The Effect 
of Aging and Mechanical Loading on the Metabolism 
of Articular Cartilage. J Rheumatol. 2017;44(4):410-7.
16.Elder BD, Athanasiou KA. Hydrostatic pressure 
in articular cartilage tissue engineering: from 
chondrocytes to tissue regeneration. Tissue Eng Part 
B Rev. 2009;15(1):43-53.
17.Zhu M, Li W, Dong X, Yuan X, Midgley AC, Chang H, et al. 
In vivo engineered extracellular matrix scaffolds with 
instructive niches for oriented tissue regeneration. 
Nature communications. 2019;10(1):1-4.
18.Sundelacruz S, Kaplan DL. Stem cell-and scaffoldbased tissue engineering approaches to osteochondral 
regenerative medicine. InSeminars in cell & 
developmental biology 2009 (Vol. 20, No. 6, pp. 646-
655). Academic Press..
19.Humphrey JD, Dufresne ER, Schwartz MA. 
Mechanotransduction and extracellular matrix 
homeostasis. Nat Rev Mol Cell Biol. 2014;15(12):802-
12.
20.Alford JW, Cole BJ. Cartilage restoration, part 1: basic 
science, historical perspective, patient evaluation, and 
treatment options. Am J Sports Med. 2005;33(2):295-
306.
21.Patel JM, Wise BC, Bonnevie ED, Mauck RL. A 
Systematic Review and Guide to Mechanical Testing 
for Articular Cartilage Tissue Engineering. Tissue Eng 
Part C Methods. 2019;25(10):593-608.
22.Yamashita A, Tamamura Y, Morioka M, Karagiannis P, 
Shima N, Tsumaki N. Considerations in hiPSC-derived 
cartilage for articular cartilage repair. Inflammation 
and Regeneration. 2018;38(1):1-7..
23.Tatari H. The structure, physiology, and biomechanics 
of articular cartilage: injury and repair. Acta 
orthopaedica et traumatologica turcica. 2007;41:1-5.
24.Yari D, Ehsanbakhsh Z, Validad MH, Langroudi 
FH. Association of TIMP-1 and COL4A4 Gene 
Polymorphisms with Keratoconus in an Iranian 
Population. J Ophthalmic Vis Res. 2020;15(3):299-
307.
25.Moradi A, Ataollahi F, Sayar K, Pramanik S, Chong PP, 
Khalil AA, et al. Chondrogenic potential of physically 
treated bovine cartilage matrix derived porous 
scaffolds on human dermal fibroblast cells. J Biomed 
Mater Res A. 2016;104(1):245-56.
26.Mehlhorn AT, Niemeyer P, Kaiser S, Finkenzeller G, 
Stark GB, Sudkamp NP, et al. Differential expression 
pattern of extracellular matrix molecules during 
chondrogenesis of mesenchymal stem cells from 
bone marrow and adipose tissue. Tissue Eng. 
2006;12(10):2853-62.
27.Vincent TL, Wann AK. Mechanoadaptation: articular 
cartilage through thick and thin. The Journal of 
physiology. 2019;597(5):1271-81..
28.Roughley PJ, Lee ER. Cartilage proteoglycans: 
structure and potential functions. Microsc Res Tech. 
1994;28(5):385-97.
29.Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate 
proteoglycans. Cold Spring Harbor perspectives in 
biology. 2011;3(7):a004952.
30.Neves MI, Araújo M, Moroni L, da Silva RM, Barrias 
CC. Glycosaminoglycan-inspired biomaterials for 
the development of bioactive hydrogel networks. 
Molecules. 2020;25(4):978.
31.Iozzo RV, Schaefer L. Proteoglycan form and function: 
A comprehensive nomenclature of proteoglycans. 
Matrix Biol. 2015;42:11-55.
32.Driessen BJH, Logie C, Vonk LA. Cellular 
reprogramming for clinical cartilage repair. Cell Biol 
Toxicol. 2017;33(4):329-49.
33.Wilusz RE, Sanchez-Adams J, Guilak F. The structure 
and function of the pericellular matrix of articular 
cartilage. Matrix Biol. 2014;39:25-32.
34.Carballo CB, Nakagawa Y, Sekiya I, Rodeo SA. Basic 
Science of Articular Cartilage. Clin Sports Med. 
2017;36(3):413-25.
35.Bolton MC, Dudhia J, Bayliss MT. Age-related changes 
in the synthesis of link protein and aggrecan in human 
articular cartilage: implications for aggregate stability. 
Biochem J. 1999;337(1):77-82.
36.Price JS, Waters JG, Darrah C, Pennington C, Edwards 
DR, Donell ST, et al. The role of chondrocyte senescence 
in osteoarthritis. Aging Cell. 2002;1(1):57-65.
37.Saravani R, Yari D, Saravani S, Hasanian-Langroudi 
F. Correlation between the COL4A3, MMP-9, and 
TIMP-1 polymorphisms and risk of keratoconus. Jpn 
J Ophthalmol. 2017;61(3):218-22.
38.Brittberg M, Lindahl A, Nilsson A, Ohlsson C, 
Isaksson O, Peterson L. Treatment of deep cartilage 
defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331(14):889-95. 39.Lepperdinger G, Brunauer R, Jamnig A, Laschober G, 
Kassem M. Controversial issue: is it safe to employ 
mesenchymal stem cells in cell-based therapies? Exp 
Gerontol. 2008;43(11):1018-23.
40.Mendelson A, Frank E, Allred C, Jones E, Chen M, Zhao 
W, et al. Chondrogenesis by chemotactic homing of 
synovium, bone marrow, and adipose stem cells in 
vitro. FASEB J. 2011;25(10):3496-504.
41.Lo Monaco M, Merckx G, Ratajczak J, Gervois P, 
Hilkens P, Clegg P, et al. Stem Cells for Cartilage Repair: 
Preclinical Studies and Insights in Translational 
Animal Models and Outcome Measures. Stem Cells 
Int. 2018;2018:9079538.
42.Wang M, Yuan Z, Ma N, Hao C, Guo W, Zou G, et al. 
Advances and Prospects in Stem Cells for Cartilage 
Regeneration. Stem Cells Int. 2017;2017:4130607.
43.Jacob G, Shimomura K, Krych AJ, Nakamura N. The 
Meniscus Tear: A Review of Stem Cell Therapies. Cells. 
2019;9(1).
44.Gur-Cohen S, Yang H, Baksh SC, Miao Y, Levorse 
J, Kataru RP, et al. Stem cell-driven lymphatic 
remodeling coordinates tissue regeneration. Science. 
2019;366(6470):1218-25.
45.Wang WG, Lou SQ, Ju XD, Xia K, Xia JH. In vitro 
chondrogenesis of human bone marrow-derived 
mesenchymal progenitor cells in monolayer culture: 
activation by transfection with TGF-beta2. Tissue Cell. 
2003;35(1):69-77.
46.Caplan AI. Adult mesenchymal stem cells for tissue 
engineering versus regenerative medicine. J Cell 
Physiol. 2007;213(2):341-7.
47.Mahmoudifar N, Doran PM. Chondrogenic 
differentiation of human adipose-derived stem cells in 
polyglycolic acid mesh scaffolds under dynamic culture 
conditions. Biomaterials. 2010;31(14):3858-67.
48.Pievani A, Scagliotti V, Russo FM, Azario I, Rambaldi 
B, Sacchetti B, et al. Comparative analysis of 
multilineage properties of mesenchymal stromal 
cells derived from fetal sources shows an advantage 
of mesenchymal stromal cells isolated from cord 
blood in chondrogenic differentiation potential. 
Cytotherapy. 2014;16(7):893-905.
49.Wang SJ, Jiang D, Zhang ZZ, Huang AB, Qi YS, Wang 
HJ, et al. Chondrogenic Potential of Peripheral 
Blood Derived Mesenchymal Stem Cells Seeded on 
Demineralized Cancellous Bone Scaffolds. Sci Rep. 
2016;6:36400.
50.Zuliani CC, Bombini MF, Andrade KC, Mamoni R, 
Pereira AH, Coimbra IB. Micromass cultures are 
effective for differentiation of human amniotic fluid 
stem cells into chondrocytes. Clinics (Sao Paulo). 
2018;73:e268.
51.Longoni A, Utomo L, van Hooijdonk IE, Bittermann GK, 
Vetter VC, Kruijt Spanjer EC, et al. The chondrogenic 
differentiation potential of dental pulp stem cells. Eur 
Cell Mater. 2020;39:121-35.
52.To K, Zhang B, Romain K, Mak C, Khan W. SynoviumDerived Mesenchymal Stem Cell Transplantation in 
Cartilage Regeneration: A PRISMA Review of in vivo 
Studies. Front Bioeng Biotechnol. 2019;7:314.
53.Andriamanalijaona R, Duval E, Raoudi M, Lecourt S, 
Vilquin JT, Marolleau JP, et al. Differentiation potential 
of human muscle-derived cells towards chondrogenic 
phenotype in alginate beads culture. Osteoarthritis 
Cartilage. 2008;16(12):1509-18.
54.Huang JI, Kazmi N, Durbhakula MM, Hering TM, Yoo 
JU, Johnstone B. Chondrogenic potential of progenitor 
cells derived from human bone marrow and adipose 
tissue: a patient-matched comparison. J Orthop Res. 
2005;23(6):1383-9.
55.Contentin R, Demoor M, Concari M, Desance M, Audigie 
F, Branly T, et al. Comparison of the Chondrogenic 
Potential of Mesenchymal Stem Cells Derived from 
Bone Marrow and Umbilical Cord Blood Intended 
for Cartilage Tissue Engineering. Stem Cell Rev Rep. 
2020;16(1):126-43.
56.Silva JC, Udangawa RN, Chen J, Mancinelli CD, 
Garrudo FFF, Mikael PE, et al. Kartogenin-loaded 
coaxial PGS/PCL aligned nanofibers for cartilage 
tissue engineering. Mater Sci Eng C Mater Biol Appl. 
2020;107:110291.
57.Moura CS, Silva JC, Faria S, Fernandes PR, da Silva 
CL, Cabral JMS, et al. Chondrogenic differentiation 
of mesenchymal stem/stromal cells on 3D porous 
poly (epsilon-caprolactone) scaffolds: Effects 
of material alkaline treatment and chondroitin 
sulfate supplementation. J Biosci Bioeng. 
2020;129(6):756-64.
58.Kohli N, Wright KT, Sammons RL, Jeys L, Snow 
M, Johnson WE. An In Vitro Comparison of the 
Incorporation, Growth, and Chondrogenic Potential 
of Human Bone Marrow versus Adipose Tissue 
Mesenchymal Stem Cells in Clinically Relevant 
Cell Scaffolds Used for Cartilage Repair. Cartilage. 
2015;6(4):252-63.
59.Satue M, Schuler C, Ginner N, Erben RG. Intraarticularly injected mesenchymal stem cells promote 
cartilage regeneration, but do not permanently 
engraft in distant organs. Sci Rep. 2019;9(1):10153.
60.Secunda R, Vennila R, Mohanashankar AM, 
Rajasundari M, Jeswanth S, Surendran R. Isolation, 
expansion and characterisation of mesenchymal 
stem cells from human bone marrow, adipose tissue, 
umbilical cord blood and matrix: a comparative study. 
Cytotechnology. 2015;67(5):793-807.
61.Baghaei K, Hashemi SM, Tokhanbigli S, Asadi Rad A, 
Assadzadeh-Aghdaei H, Sharifian A, et al. Isolation, 
differentiation, and characterization of mesenchymal 
stem cells from human bone marrow. Gastroenterol 
Hepatol Bed Bench. 2017;10(3):208-13.
62.Grskovic B, Ruzicka K, Karimi A, Qujeq D, Muller MM. 
Cell cycle analysis of the CD133+ and CD133- cells 
isolated from umbilical cord blood. Clin Chim Acta. 
2004;343(1-2):173-8.
63.Park D, Lim J, Park JY, Lee SH. Concise Review: Stem Cell 
Microenvironment on a Chip: Current Technologies 
for Tissue Engineering and Stem Cell Biology. Stem 
Cells Transl Med. 2015;4(11):1352-68.
64.Jansen KA, Donato DM, Balcioglu HE, Schmidt T, Danen 
EH, Koenderink GH. A guide to mechanobiology: 
Where biology and physics meet. Biochim Biophys 
Acta. 2015;1853(11 Pt B):3043-52. 65.Kim IG, Gil CH, Seo J, Park SJ, Subbiah R, Jung TH, et 
al. Mechanotransduction of human pluripotent stem 
cells cultivated on tunable cell-derived extracellular 
matrix. Biomaterials. 2018;150:100-11.
66.Johnson VL, Hunter DJ. The epidemiology of 
osteoarthritis. Best Pract Res Clin Rheumatol. 
2014;28(1):5-15.
67.Hattori T, Muller C, Gebhard S, Bauer E, Pausch F, 
Schlund B, et al. SOX9 is a major negative regulator 
of cartilage vascularization, bone marrow formation 
and endochondral ossification. Development. 
2010;137(6):901-11.
68.Schnabel M, Marlovits S, Eckhoff G, Fichtel I, Gotzen L, 
Vecsei V, et al. Dedifferentiation-associated changes in 
morphology and gene expression in primary human 
articular chondrocytes in cell culture. Osteoarthritis 
Cartilage. 2002;10(1):62-70.
69.69. Zou J, Bai B, Yao Y. Progress of Co-culture 
Systems in Cartilage Regeneration. Expert Opin Biol 
Ther. 2018;18(11):1151-8.
70.70. Benya PD, Shaffer JD. Dedifferentiated 
chondrocytes reexpress the differentiated collagen 
phenotype when cultured in agarose gels. Cell. 
1982;30(1):215-24.
71.Okubo R, Asawa Y, Watanabe M, Nagata S, Nio 
M, Takato T, et al. Proliferation medium in threedimensional culture of auricular chondrocytes 
promotes effective cartilage regeneration in vivo. 
Regen Ther. 2019;11:306-15.
72.Jin GZ, Kim HW. Efficacy of collagen and 
alginate hydrogels for the prevention of rat 
chondrocyte dedifferentiation. J Tissue Eng. 
2018;9:2041731418802438.
73.Puetzer JL, Petitte JN, Loboa EG. Comparative review 
of growth factors for induction of three-dimensional 
in vitro chondrogenesis in human mesenchymal stem 
cells isolated from bone marrow and adipose tissue. 
Tissue Eng Part B Rev. 2010;16(4):435-44.
74.Schumann D, Kujat R, Nerlich M, Angele P. 
Mechanobiological conditioning of stem cells for 
cartilage tissue engineering. Biomed Mater Eng. 
2006;16(4 Suppl):S37-52.
75.Zhang S, Vijayavenkataraman S, Lu WF, Fuh JYH. 
A review on the use of computational methods 
to characterize, design, and optimize tissue 
engineering scaffolds, with a potential in 3D printing 
fabrication. J Biomed Mater Res B Appl Biomater. 
2019;107(5):1329-51.
76.Jafari M, Paknejad Z, Rad MR, Motamedian SR, Eghbal 
MJ, Nadjmi N, et al. Polymeric scaffolds in tissue 
engineering: a literature review. J Biomed Mater Res 
B Appl Biomater. 2017;105(2):431-59.
77.Chai Q, Jiao Y, Yu X. Hydrogels for Biomedical 
Applications: Their Characteristics and the 
Mechanisms behind Them. Gels. 2017;3(1).
78.Bordbar S, Lotfi Bakhshaiesh N, Khanmohammadi 
M, Sayahpour FA, Alini M, Baghaban Eslaminejad 
M. Production and evaluation of decellularized 
extracellular matrix hydrogel for cartilage 
regeneration derived from knee cartilage. J Biomed 
Mater Res A. 2020;108(4):938-46.
79.Thompson WR, Scott A, Loghmani MT, Ward SR, 
Warden SJ. Understanding Mechanobiology: Physical 
Therapists as a Force in Mechanotherapy and 
Musculoskeletal Regenerative Rehabilitation. Phys 
Ther. 2016;96(4):560-9.
80.Marrella A, Lee TY, Lee DH, Karuthedom S, Syla 
D, Chawla A, et al. Engineering vascularized and 
innervated bone biomaterials for improved skeletal 
tissue regeneration. Mater Today (Kidlington). 
2018;21(4):362-76.
81.Hersel U, Dahmen C, Kessler H. RGD modified 
polymers: biomaterials for stimulated cell adhesion 
and beyond. Biomaterials. 2003;24(24):4385-415.
82.Amann E, Wolff P, Breel E, van Griensven M, Balmayor 
ER. Hyaluronic acid facilitates chondrogenesis 
and matrix deposition of human adipose derived 
mesenchymal stem cells and human chondrocytes cocultures. Acta Biomater. 2017;52:130-44.
83.Cheng A, Schwartz Z, Kahn A, Li X, Shao Z, Sun M, 
et al. Advances in Porous Scaffold Design for Bone 
and Cartilage Tissue Engineering and Regeneration. 
Tissue Eng Part B Rev. 2019;25(1):14-29.
84.Liu W, Thomopoulos S, Xia Y. Electrospun nanofibers 
for regenerative medicine. Adv Healthc Mater. 
2012;1(1):10-25.
85.Amiri N, Rozbeh Z, Afrough T, Sajadi Tabassi SA, 
Moradi A, Movaffagh J. Optimization of ChitosanGelatin Nanofibers Production: Investigating the 
Effect of Solution Properties and Working Parameters 
on Fibers Diameter. BioNanoScience. 2018;8(3):778-
89.
86.Amiri N, Moradi A, Tabasi SAS, Movaffagh J. Modeling 
and process optimization of electrospinning of 
chitosan-collagen nanofiber by response surface 
methodology. Materials Research Express. 2018; 
5(4):045404.
87.Braghirolli DI, Steffens D, Pranke P. Electrospinning 
for regenerative medicine: a review of the main topics. 
Drug Discov Today. 2014;19(6):743-53.
88.Kundu B, Rajkhowa R, Kundu SC, Wang X. Silk fibroin 
biomaterials for tissue regenerations. Adv Drug Deliv 
Rev. 2013;65(4):457-70.
89.Friess W. Collagen--biomaterial for drug delivery. Eur 
J Pharm Biopharm. 1998;45(2):113-36.
90.Ma PX, Zhang R. Synthetic nano-scale fibrous 
extracellular matrix. J Biomed Mater Res. 
1999;46(1):60-72.
91.Garcia Y, Wilkins B, Collighan RJ, Griffin M, Pandit 
A. Towards development of a dermal rudiment for 
enhanced wound healing response. Biomaterials. 
2008;29(7):857-68.
92.Movaffagh J, Fazly Bazzaz BS, Yazdi AT, Sajadi-Tabassi 
A, Azizzadeh M, Najafi E, et al. Wound Healing and 
Antimicrobial Effects of Chitosan-hydrogel/Honey 
Compounds in a Rat Full-thickness Wound Model. 
Wounds. 2019;31(9):228-35.
93.Stokols S, Tuszynski MH. Freeze-dried agarose 
scaffolds with uniaxial channels stimulate and guide 
linear axonal growth following spinal cord injury. 
Biomaterials. 2006;27(3):443-51.
94.Bozkurt A, Lassner F, O’Dey D, Deumens R, Bocker  A, Schwendt T, et al. The role of microstructured and 
interconnected pore channels in a collagen-based 
nerve guide on axonal regeneration in peripheral 
nerves. Biomaterials. 2012;33(5):1363-75.
95.Ghassemi T, Saghatolslami N, Matin MM, Gheshlaghi 
R, Moradi A. CNT-decellularized cartilage hybrids 
for tissue engineering applications. Biomed Mater. 
2017;12(6):065008.
96.Rowland CR, Lennon DP, Caplan AI, Guilak F. The 
effects of crosslinking of scaffolds engineered from 
cartilage ECM on the chondrogenic differentiation of 
MSCs. Biomaterials. 2013;34(23):5802-12.
97.Shen W, Chen X, Hu Y, Yin Z, Zhu T, Hu J, et al. Longterm effects of knitted silk-collagen sponge scaffold 
on anterior cruciate ligament reconstruction 
and osteoarthritis prevention. Biomaterials. 
2014;35(28):8154-63.
98.Qujeq D, Abassi R, Faeizi F, Parsian H, Faraji AS, Taheri 
H, et al. Effect of granulocyte colony-stimulating factor 
administration on tissue regeneration due to carbon 
tetrachloride-induced liver damage in experimental 
model. Toxicol Ind Health. 2013;29(6):498-503.
99.Drury JL, Mooney DJ. Hydrogels for tissue engineering: 
scaffold design variables and applications. 
Biomaterials. 2003;24(24):4337-51.
100. Zhou Y, Liang K, Zhao S, Zhang C, Li J, Yang H, et al. 
Photopolymerized maleilated chitosan/methacrylated 
silk fibroin micro/nanocomposite hydrogels as 
potential scaffolds for cartilage tissue engineering. Int 
J Biol Macromol. 2018;108:383-90.
101. Burdick JA, Chung C, Jia X, Randolph MA, Langer 
R. Controlled degradation and mechanical behavior 
of photopolymerized hyaluronic acid networks. 
Biomacromolecules. 2005;6(1):386-91.
102. Joanne P, Kitsara M, Boitard SE, Naemetalla H, 
Vanneaux V, Pernot M, et al. Nanofibrous clinical-grade 
collagen scaffolds seeded with human cardiomyocytes 
induces cardiac remodeling in dilated cardiomyopathy. 
Biomaterials. 2016;80:157-68.
103. Miao Z, Lu Z, Wu H, Liu H, Li M, Lei D, et al. 
Collagen, agarose, alginate, and Matrigel hydrogels as 
cell substrates for culture of chondrocytes in vitro: A 
comparative study. J Cell Biochem. 2017.
104. Stoppel WL, Ghezzi CE, McNamara SL, Black 
LD, 3rd, Kaplan DL. Clinical applications of naturally 
derived biopolymer-based scaffolds for regenerative 
medicine. Ann Biomed Eng. 2015;43(3):657-80.
105. Chan G, Mooney DJ. New materials for tissue 
engineering: towards greater control over the biological 
response. Trends Biotechnol. 2008;26(7):382-92.
106. Cheng CW, Solorio LD, Alsberg E. Decellularized 
tissue and cell-derived extracellular matrices 
as scaffolds for orthopaedic tissue engineering. 
Biotechnol Adv. 2014;32(2):462-84.
107. Morris AH, Stamer DK, Kyriakides TR. The host 
response to naturally-derived extracellular matrix 
biomaterials. Semin Immunol. 2017;29:72-91.
108. Hoshiba T, Lu H, Kawazoe N, Chen G. 
Decellularized matrices for tissue engineering. Expert 
Opin Biol Ther. 2010;10(12):1717-28.
109. Gupta SK, Mishra NC, Dhasmana A. 
Decellularization Methods for Scaffold Fabrication. 
Methods Mol Biol. 2018;1577:1-10.
110. Kim YS, Majid M, Melchiorri AJ, Mikos AG. 
Applications of decellularized extracellular matrix in 
bone and cartilage tissue engineering. Bioeng Transl 
Med. 2019;4(1):83-95.
111. Johnson TD, Hill RC, Dzieciatkowska M, Nigam 
V, Behfar A, Christman KL, et al. Quantification 
of decellularized human myocardial matrix: A 
comparison of six patients. Proteomics Clin Appl. 
2016;10(1):75-83.
112. Sanchez PL, Fernandez-Santos ME, Costanza S, 
Climent AM, Moscoso I, Gonzalez-Nicolas MA, et al. 
Acellular human heart matrix: A critical step toward 
whole heart grafts. Biomaterials. 2015;61:279-89.
113. VeDepo MC, Buse EE, Quinn RW, Williams TD, 
Detamore MS, Hopkins RA, et al. Species-specific 
effects of aortic valve decellularization. Acta Biomater. 
2017;50:249-58.
114. Pellegata AF, Asnaghi MA, Stefani I, Maestroni A, 
Maestroni S, Dominioni T, et al. Detergent-enzymatic 
decellularization of swine blood vessels: insight on 
mechanical properties for vascular tissue engineering. 
Biomed Res Int. 2013;2013:918753.
115. Ghassemi T, Saghatoleslami N, Mahdavi-Shahri 
N, Matin MM, Gheshlaghi R, Moradi A. A comparison 
study of different decellularization treatments on 
bovine articular cartilage. J Tissue Eng Regen Med. 
2019;13(10):1861-71.
116. Moradi A, Pramanik S, Ataollahi F, Abdul Khalil 
A, Kamarul T, Pingguan-Murphy B. A comparison 
study of different physical treatments on cartilage 
matrix derived porous scaffolds for tissue 
engineering applications. Sci Technol Adv Mater. 
2014;15(6):065001.
117. Garrigues NW, Little D, Sanchez-Adams J, Ruch 
DS, Guilak F. Electrospun cartilage-derived matrix 
scaffolds for cartilage tissue engineering. J Biomed 
Mater Res A. 2014;102(11):3998-4008.
118. Cheng NC, Estes BT, Young TH, Guilak F. Genipincrosslinked cartilage-derived matrix as a scaffold for 
human adipose-derived stem cell chondrogenesis. 
Tissue Eng Part A. 2013;19(3-4):484-96.
119. Cheng NC, Estes BT, Young TH, Guilak F. 
Engineered cartilage using primary chondrocytes 
cultured in a porous cartilage-derived matrix. Regen 
Med. 2011;6(1):81-93.
120. Mao Y, Block T, Singh-Varma A, Sheldrake A, 
Leeth R, Griffey S, et al. Extracellular matrix derived 
from chondrocytes promotes rapid expansion of 
human primary chondrocytes in vitro with reduced 
dedifferentiation. Acta Biomater. 2019;85:75-83.
121. Fermor HL, McLure SW, Taylor SD, Russell SL, 
Williams S, Fisher J, et al. Biological, biochemical and 
biomechanical characterisation of articular cartilage 
from the porcine, bovine and ovine hip and knee. 
Biomed Mater Eng. 2015;25(4):381-95.
122. Taylor SD, Tsiridis E, Ingham E, Jin Z, Fisher J, 
Williams S. Comparison of human and animal femoral 
head chondral properties and geometries. Proc Inst 
Mech Eng H. 2012;226(1):55-62. 123. Palmese LL, Thapa RK, Sullivan MO, Kiick KL. 
Hybrid hydrogels for biomedical applications. Curr 
Opin Chem Eng. 2019;24:143-57.
124. Grover GN, Rao N, Christman KL. Myocardial 
matrix-polyethylene glycol hybrid hydrogels for tissue 
engineering. Nanotechnology. 2014;25(1):014011.
125. Mansour JM, Welter JF. Multimodal evaluation 
of tissue-engineered cartilage. J Med Biol Eng. 
2013;33(1):1-16.
126. Zhou S, Wang Y, Zhang K, Cao N, Yang R, Huang 
J, et al. The Fabrication and Evaluation of a Potential 
Biomaterial Produced with Stem Cell Sheet Technology 
for Future Regenerative Medicine. Stem Cells Int. 
2020;2020:9567362.
127. Vincourt JB, Lionneton F, Kratassiouk G, 
Guillemin F, Netter P, Mainard D, et al. Establishment of 
a reliable method for direct proteome characterization 
of human articular cartilage. Mol Cell Proteomics. 
2006;5(10):1984-95.
128. De Ceuninck F, Marcheteau E, Berger S, Caliez 
A, Dumont V, Raes M, et al. Assessment of some tools 
for the characterization of the human osteoarthritic 
cartilage proteome. J Biomol Tech. 2005;16(3):256-65.
129. Gaudet AD, Popovich PG. Extracellular matrix 
regulation of inflammation in the healthy and injured 
spinal cord. Exp Neurol. 2014;258:24-34.
130. Acharya C, Yik JH, Kishore A, Van Dinh V, Di 
Cesare PE, Haudenschild DR. Cartilage oligomeric 
matrix protein and its binding partners in the cartilage 
extracellular matrix: interaction, regulation and role in 
chondrogenesis. Matrix Biol. 2014;37:102-11.
131. Oh CD, Lu Y, Liang S, Mori-Akiyama Y, Chen D, 
de Crombrugghe B, et al. SOX9 regulates multiple 
genes in chondrocytes, including genes encoding ECM 
proteins, ECM modification enzymes, receptors, and 
transporters. PLoS One. 2014;9(9):e107577.
132. Tew SR, Clegg PD, Brew CJ, Redmond CM, 
Hardingham TE. SOX9 transduction of a human 
chondrocytic cell line identifies novel genes regulated 
in primary human chondrocytes and in osteoarthritis. 
Arthritis Res Ther. 2007;9(5):R107.
133. Henry SP, Liang S, Akdemir KC, de Crombrugghe 
B. The postnatal role of Sox9 in cartilage. J Bone Miner 
Res. 2012;27(12):2511-25.
134. Kim Y, Murao H, Yamamoto K, Deng JM, Behringer 
RR, Nakamura T, et al. Generation of transgenic mice 
for conditional overexpression of Sox9. J Bone Miner 
Metab. 2011;29(1):123-9.
135. Taheem DK, Foyt DA, Loaiza S, Ferreira SA, Ilic D, 
Auner HW, et al. Differential Regulation of Human Bone 
Marrow Mesenchymal Stromal Cell Chondrogenesis 
by Hypoxia Inducible Factor-1alpha Hydroxylase 
Inhibitors. Stem Cells. 2018;36(9):1380-92.
136. Jahr H, Gunes S, Kuhn AR, Nebelung S, Pufe T. 
Bioreactor-Controlled Physoxia Regulates TGF-beta 
Signaling to Alter Extracellular Matrix Synthesis by 
Human Chondrocytes. Int J Mol Sci. 2019;20(7).
137. Markway BD, Cho H, Johnstone B. Hypoxia 
promotes redifferentiation and suppresses markers 
of hypertrophy and degeneration in both healthy 
and osteoarthritic chondrocytes. Arthritis Res Ther. 
2013;15(4):R92.
138. Schrobback K, Malda J, Crawford RW, Upton 
Z, Leavesley DI, Klein TJ. Effects of oxygen on zonal 
marker expression in human articular chondrocytes. 
Tissue Eng Part A. 2012;18(9-10):920-33.
139. Milner PI, Wilkins RJ, Gibson JS. The role of 
mitochondrial reactive oxygen species in pH regulation 
in articular chondrocytes. Osteoarthritis Cartilage. 
2007;15(7):735-42.
140. Yari D, Saravani R, Saravani S, Ebrahimian K, 
Galavi HR. Genetic Polymorphisms of Catalase and 
Glutathione Peroxidase-1 in Keratoconus. Iran J Public 
Health. 2018;47(10):1567-74.
141. Das RH, van Osch GJ, Kreukniet M, Oostra J, 
Weinans H, Jahr H. Effects of individual control of pH 
and hypoxia in chondrocyte culture. J Orthop Res. 
2010;28(4):537-45.
142. Mitchell AC, Briquez PS, Hubbell JA, Cochran JR. 
Engineering growth factors for regenerative medicine 
applications. Acta Biomater. 2016;30:1-12.
143. Belair DG, Le NN, Murphy WL. Design of growth 
factor sequestering biomaterials. Chem Commun 
(Camb). 2014;50(99):15651-68.
144. Thielen NGM, van der Kraan PM, van Caam 
APM. TGFbeta/BMP Signaling Pathway in Cartilage 
Homeostasis. Cells. 2019;8(9).
145. Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, 
et al. Transforming growth factor-beta in stem cells 
and tissue homeostasis. Bone Res. 2018;6:2.
146. Coricor G, Serra R. TGF-beta regulates 
phosphorylation and stabilization of Sox9 protein 
in chondrocytes through p38 and Smad dependent 
mechanisms. Sci Rep. 2016;6:38616.
147. Badlani N, Oshima Y, Healey R, Coutts R, 
Amiel D. Use of bone morphogenic protein-7 as a 
treatment for osteoarthritis. Clin Orthop Relat Res. 
2009;467(12):3221-9.
148. Shi S, Mercer S, Eckert GJ, Trippel SB. 
Regulation of articular chondrocyte catabolic 
genes by growth factor interaction. J Cell Biochem. 
2019;120(7):11127-39.
149. Shi S, Mercer S, Eckert GJ, Trippel SB. Growth 
factor transgenes interactively regulate articular 
chondrocytes. J Cell Biochem. 2013;114(4):908-19.
150. Li J, Dong S. The Signaling Pathways Involved 
in Chondrocyte Differentiation and Hypertrophic 
Differentiation. Stem Cells Int. 2016;2016:2470351.
151. Wang Y, Fan X, Xing L, Tian F. Wnt signaling: 
a promising target for osteoarthritis therapy. Cell 
Commun Signal. 2019;17(1):97.
152. Gao Y, Liu S, Huang J, Guo W, Chen J, Zhang 
L, et al. The ECM-cell interaction of cartilage 
extracellular matrix on chondrocytes. Biomed Res Int. 
2014;2014:648459.
153. Mas-Moruno C, Fraioli R, Rechenmacher F, 
Neubauer S, Kapp TG, Kessler H. alphavbeta3- or 
alpha5beta1-Integrin-Selective Peptidomimetics 
for Surface Coating. Angew Chem Int Ed Engl. 
2016;55(25):7048-67.
154. Jansen KA, Atherton P, Ballestrem C. 
Mechanotransduction at the cell-matrix interface.  Semin Cell Dev Biol. 2017;71:75-83.
155. Hu X, Margadant FM, Yao M, Sheetz MP. Molecular 
stretching modulates mechanosensing pathways. 
Protein Sci. 2017;26(7):1337-51.
156. Johnstone B, Alini M, Cucchiarini M, Dodge GR, 
Eglin D, Guilak F, et al. Tissue engineering for articular 
cartilage repair--the state of the art. Eur Cell Mater. 
2013;25:248-67.
157. Di Bella C, Duchi S, O’Connell CD, Blanchard 
R, Augustine C, Yue Z, et al. In situ handheld threedimensional bioprinting for cartilage regeneration. J 
Tissue Eng Regen Med. 2018;12(3):611-21.
158. Khan IM, Gilbert SJ, Singhrao SK, Duance VC, 
Archer CW. Cartilage integration: evaluation of the 
reasons for failure of integration during cartilage 
repair. A review. Eur Cell Mater. 2008;16:26-39.
159. Yang YH, Ard MB, Halper JT, Barabino GA. Type 
I collagen-based fibrous capsule enhances integration 
of tissue-engineered cartilage with native articular 
cartilage. Ann Biomed Eng. 2014;42(4):716-26.
160. Pabbruwe MB, Esfandiari E, Kafienah W, Tarlton 
JF, Hollander AP. Induction of cartilage integration by a 
chondrocyte/collagen-scaffold implant. Biomaterials. 
2009;30(26):4277-86.
161. Yang YK, Ogando CR, Barabino GA. In Vitro 
Evaluation of the Influence of Substrate Mechanics on 
Matrix-Assisted Human Chondrocyte Transplantation. 
J Funct Biomater. 2020;11(1).
162. Gurusinghe S, Strappe P. Gene modification of 
mesenchymal stem cells and articular chondrocytes 
to enhance chondrogenesis. Biomed Res Int. 
2014;2014:369528.
163. Celik E, Bayram C, Denkbas EB. Chondrogenesis 
of human mesenchymal stem cells by microRNA 
loaded triple polysaccharide nanoparticle system. 
Mater Sci Eng C Mater Biol Appl. 2019;102:756-63.
164. Jimenez G, Venkateswaran S, Lopez-Ruiz E, 
Peran M, Pernagallo S, Diaz-Monchon JJ, et al. A 
soft 3D polyacrylate hydrogel recapitulates the 
cartilage niche and allows growth-factor free tissue 
engineering of human articular cartilage. Acta 
Biomater. 2019;90:146-56.
165. Takada E, Mizuno S. Reproduction of 
Characteristics of Extracellular Matrices in Specific 
Longitudinal Depth Zone Cartilage within Spherical 
Organoids in Response to Changes in Osmotic 
Pressure. Int J Mol Sci. 2018;19(5).
166. Yeung P, Cheng KH, Yan CH, Chan BP. Collagen 
microsphere based 3D culture system for human 
osteoarthritis chondrocytes (hOACs). Sci Rep. 
2019;9(1):12453.
167. Udomluck N, Kim SH, Cho H, Park JY, Park H. 
Three-dimensional cartilage tissue regeneration 
system harnessing goblet-shaped microwells 
containing biocompatible hydrogel. Biofabrication. 
2019;12(1):015019.
168. Saraswat R, Ratnayake I, Perez EC, Schutz 
WM, Zhu Z, Ahrenkiel SP, et al. Micropatterned 
Biphasic Nanocomposite Platform for Maintaining 
Chondrocyte Morphology. ACS Appl Mater Interfaces. 
2020;12(13):14814-24.
169. Yan X, Chen YR, Song YF, Yang M, Ye J, Zhou G, et al. 
Scaffold-Based Gene Therapeutics for Osteochondral 
Tissue Engineering. Front Pharmacol. 2019;10:1534.
170. Cong L, Zhu Y, Tu G. A bioinformatic analysis 
of microRNAs role in osteoarthritis. Osteoarthritis 
Cartilage. 2017;25(8):1362-71.
171. Wolock SL, Krishnan I, Tenen DE, Matkins V, 
Camacho V, Patel S, et al. Mapping Distinct Bone 
Marrow Niche Populations and Their Differentiation 
Paths. Cell Rep. 2019;28(2):302-11 e5.
172. Huynh N, Kelly N, Katz D, Pham M, Guilak F. 
Single Cell RNA Sequencing Reveals Heterogeneity 
of Human MSC Chondrogenesis: Lasso Regularized 
Logistic Regression to Identify Gene and Regulatory 
Signatures. bioRxiv. 2019:854406
173. Zhang B, Gao L, Ma L, Luo Y, Yang H, Cui Z. 3D 
Bioprinting: A Novel Avenue for Manufacturing 
Tissues and Organs. Engineering. 2019;5(4):777-94.
174. Derby B. Printing and prototyping of tissues and 
scaffolds. Science. 2012;338(6109):921-6.
175. Henrionnet C, Pourchet L, Neybecker P, 
Messaoudi O, Gillet P, Loeuille D, et al. Combining 
Innovative Bioink and Low Cell Density for the 
Production of 3D-Bioprinted Cartilage Substitutes: A 
Pilot Study. Stem Cells International. 2020;2020:1-16.
176. Francis SL, Di Bella C, Wallace GG, Choong 
PFM. Cartilage Tissue Engineering Using Stem Cells 
and Bioprinting Technology-Barriers to Clinical 
Translation. Front Surg. 2018;5:70.
177. Ruiz-Cantu L, Gleadall A, Faris C, Segal J, 
Shakesheff K, Yang J. Multi-material 3D bioprinting of 
porous constructs for cartilage regeneration. Mater Sci 
Eng C Mater Biol Appl. 2020;109:110578.
178. Antich C, de Vicente J, Jimenez G, Chocarro C, 
Carrillo E, Montanez E, et al. Bio-inspired hydrogel 
composed of hyaluronic acid and alginate as a 
potential bioink for 3D bioprinting of articular 
cartilage engineering constructs. Acta Biomater. 
2020;106:114-23.
179. Zhao Z, Fan C, Chen F, Sun Y, Xia Y, Ji A, et al. 
Progress in Articular Cartilage Tissue Engineering: 
A Review on Therapeutic Cells and Macromolecular 
Scaffolds. Macromol Biosci. 2020;20(2):e1900278.
180. Semba J, Mieloch A, Rybka J. Introduction 
to the state-of-the-art 3D bioprinting methods, 
design, and applications in orthopedics. Bioprinting. 
2019;18:e00070 




Volume 10, Issue 3
March 2022
Pages 229-244
  • Receive Date: 18 February 2021
  • Revise Date: 15 December 2021
  • Accept Date: 19 January 2022
  • First Publish Date: 15 February 2022