Research progress of different cell seeding densities and cell ratios in cartilage tissue engineering_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

XIE Huifeng ^1,2 , ZHOU Wei ^1,2 ,  BAI Bo ^1,2 ,  ZHANG Shujiang ^1,2

1. Department of Orthopedics, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Guangdong, 510120, P. R. China;
2. Guangdong Key Laboratory of Orthopedic Technology and Implanted Materials, Guangzhou Guangdong, 510120, P. R. China;

Corresponding author：

BAI Bo, Email: drbobai@139.com; ZHANG Shujiang, Email: drzhangsj@gzhmu.edu.cn

Keywords：

Cartilage tissue engineering; articular chondrocytes; bone marrow mesenchymal stem cells; co-culture; seeding density; cell ratio

DOI：

10.7507/1002-1892.202110091

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the research progress of different cell seeding densities and cell ratios in cartilage tissue engineering. Methods The literature about tissue engineered cartilage constructed with three-dimensional scaffold was extensively reviewed, and the seeding densities and ratios of most commonly used seed cells were summarized. Results Articular chondrocytes (ACHs) and bone marrow mesenchymal stem cells (BMSCs) are the most commonly used seed cells, and they can induce hyaline cartilage formation in vitro and in vivo. Cell seeding density and cell ratio both play important roles in cartilage formation. Tissue engineered cartilage with good quality can be produced when the cell seeding density of ACHs or BMSCs reaches or exceeds that in normal articular cartilage. Under the same culture conditions, the ability of pure BMSCs to build hyaline cartilage is weeker than that of pure ACHs or co-culture of both. Conclusion Due to the effect of scaffold materials, growth factors, and cell passages, optimal cell seeding density and cell ratio need further study.

Citation： XIE Huifeng, ZHOU Wei, BAI Bo, ZHANG Shujiang. Research progress of different cell seeding densities and cell ratios in cartilage tissue engineering. Chinese Journal of Reparative and Reconstructive Surgery, 2022, 36(4): 470-478. doi: 10.7507/1002-1892.202110091 Copy

1.	Newman AP. Articular cartilage repair. Am J Sports Med, 1998, 26(2): 309-324.
2.	Li YY, Cheng HW, Cheung KM, et al. Mesenchymal stem cell-collagen microspheres for articular cartilage repair: cell density and differentiation status. Acta Biomater, 2014, 10(5): 1919-1929.
3.	McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA, 2017, 317(19): 1967-1975.
4.	Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: Results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med, 2019, 47(2): 347-354.
5.	Meheux CJ, McCulloch PC, Lintner DM, et al. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review. Arthroscopy, 2016, 32(3): 495-505.
6.	Frehner F, Benthien JP. Microfracture: State of the art in cartilage surgery? Cartilage, 2018, 9(4): 339-345.
7.	Nie X, Chuah YJ, Zhu W, et al. Decellularized tissue engineered hyaline cartilage graft for articular cartilage repair. Biomaterials, 2020, 235: 119821. doi: 10.1016/j.biomaterials.2020.119821.
8.	Kwon H, Brown WE, Lee CA, et al. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat Rev Rheumatol, 2019, 15(9): 550-570.
9.	Campos Y, Almirall A, Fuentes G, et al. Tissue engineering: An alternative to repair cartilage. Tissue Eng Part B Rev, 2019, 25(4): 357-373.
10.	Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med, 1999, 331(14): 889-895.
11.	Murawski CD, Kennedy JG. Operative treatment of osteochondral lesions of the talus. J Bone Joint Surg (Am), 2013, 95(11): 1045-1054.
12.	Tan AR, Hung CT. Concise review: Mesenchymal stem cells for functional cartilage tissue engineering: Taking cues from chondrocyte-based constructs. Stem Cells Transl Med, 2017, 6(4): 1295-1303.
13.	Matricali GA, Dereymaeker GP, Luyten FP. Donor site morbidity after articular cartilage repair procedures: a review. Acta Orthop Belg, 2010, 76(5): 669-674.
14.	Cao C, Zhang Y, Ye Y, et al. Effects of cell phenotype and seeding density on the chondrogenic capacity of human osteoarthritic chondrocytes in type I collagen scaffolds. J Orthop Surg Res, 2020, 15(1): 120. doi: 10.1186/s13018-020-01617-6.
15.	Duan L, Ma B, Liang Y, et al. Cytokine networking of chondrocyte dedifferentiation in vitro and its implications for cell-based cartilage therapy. Am J Transl Res, 2015, 7(2): 194-208.
16.	Ma B, Leijten JC, Wu L, et al. Gene expression profiling of dedifferentiated human articular chondrocytes in monolayer culture. Osteoarthritis Cartilage, 2013, 21(4): 599-603.
17.	Caron MM, Emans PJ, Coolsen MM, et al. Redifferentiation of dedifferentiated human articular chondrocytes: comparison of 2D and 3D cultures. Osteoarthritis Cartilage, 2012, 20(10): 1170-1178.
18.	Augello A, De Bari C. The regulation of differentiation in mesenchymal stem cells. Hum Gene Ther, 2010, 21(10): 1226-1238.
19.	Mesallati T, Buckley CT, Kelly DJ. A comparison of self-assembly and hydrogel encapsulation as a means to engineer functional cartilaginous grafts using culture expanded chondrocytes. Tissue Eng Part C Methods, 2014, 20(1): 52-63.
20.	Ponticiello MS, Schinagl RM, Kadiyala S, et al. Gelatin-based resorbable sponge as a carrier matrix for human mesenchymal stem cells in cartilage regeneration therapy. J Biomed Mater Res, 2000, 52(2): 246-255.
21.	Kavalkovich KW, Boynton RE, Murphy JM, et al. Chondrogenic differentiation of human mesenchymal stem cells within an alginate layer culture system. In Vitro Cell Dev Biol Anim, 2002, 38(8): 457-466.
22.	Tang J, Peng R, Ding J. The regulation of stem cell differentiation by cell-cell contact on micropatterned material surfaces. Biomaterials, 2010, 31(9): 2470-2476.
23.	Levorson EJ, Mountziaris PM, Hu O, et al. Cell-derived polymer/extracellular matrix composite scaffolds for cartilage regeneration, Part 1: investigation of cocultures and seeding densities for improved extracellular matrix deposition. Tissue Eng Part C Methods, 2014, 20(4): 340-357.
24.	Mo XT, Guo SC, Xie HQ, et al. Variations in the ratios of co-cultured mesenchymal stem cells and chondrocytes regulate the expression of cartilaginous and osseous phenotype in alginate constructs. Bone, 2009, 45(1): 42-51.
25.	Meretoja VV, Dahlin RL, Kasper FK, et al. Enhanced chondrogenesis in co-cultures with articular chondrocytes and mesenchymal stem cells. Biomaterials, 2012, 33(27): 6362-6369.
26.	Ko CY, Ku KL, Yang SR, et al. In vitro and in vivo co-culture of chondrocytes and bone marrow stem cells in photocrosslinked PCL-PEG-PCL hydrogels enhances cartilage formation. J Tissue Eng Regen Med, 2016, 10(10): E485-E496.
27.	Sabatino MA, Santoro R, Gueven S, et al. Cartilage graft engineering by co-culturing primary human articular chondrocytes with human bone marrow stromal cells. J Tissue Eng Regen Med, 2015, 9(12): 1394-1403.
28.	Bosnakovski D, Mizuno M, Kim G, et al. Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells (MSCs) in different hydrogels: influence of collagen type Ⅱ extracellular matrix on MSC chondrogenesis. Biotechnol Bioeng, 2006, 93(6): 1152-1163.
29.	Quinn TM, Häuselmann HJ, Shintani N, et al. Cell and matrix morphology in articular cartilage from adult human knee and ankle joints suggests depth-associated adaptations to biomechanical and anatomical roles. Osteoarthritis Cartilage, 2013, 21(12): 1904-1912.
30.	Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health, 2009, 1(6): 461-468.
31.	Mansfield JC, Bell JS, Winlove CP. The micromechanics of the superficial zone of articular cartilage. Osteoarthritis Cartilage, 2015, 23(10): 1806-1816.
32.	Charlier E, Deroyer C, Ciregia F, et al. Chondrocyte dedifferentiation and osteoarthritis (OA). Biochem Pharmacol, 2019, 165: 49-65.
33.	Mauck RL, Seyhan SL, Ateshian GA, et al. Influence of seeding density and dynamic deformational loading on the developing structure/function relationships of chondrocyte-seeded agarose hydrogels. Ann Biomed Eng, 2002, 30(8): 1046-1056.
34.	Saini S, Wick TM. Concentric cylinder bioreactor for production of tissue engineered cartilage: effect of seeding density and hydrodynamic loading on construct development. Biotechnol Prog, 2003, 19(2): 510-521.
35.	Iwasa J, Ochi M, Uchio Y, et al. Effects of cell density on proliferation and matrix synthesis of chondrocytes embedded in atelocollagen gel. Artif Organs, 2003, 27(3): 249-255.
36.	Moretti M, Wendt D, Dickinson SC, et al. Effects of in vitro preculture on in vivo development of human engineered cartilage in an ectopic model. Tissue Eng, 2005, 11(9-10): 1421-1428.
37.	Williams GM, Klein TJ, Sah RL. Cell density alters matrix accumulation in two distinct fractions and the mechanical integrity of alginate-chondrocyte constructs. Acta Biomater, 2005, 1(6): 625-633.
38.	Mahmoudifar N, Doran PM. Effect of seeding and bioreactor culture conditions on the development of human tissue-engineered cartilage. Tissue Eng, 2006, 12(6): 1675-1685.
39.	Wang Y, Blasioli DJ, Kim HJ, et al. Cartilage tissue engineering with silk scaffolds and human articular chondrocytes. Biomaterials, 2006, 27(25): 4434-4442.
40.	Kelly DJ, Crawford A, Dickinson SC, et al. Biochemical markers of the mechanical quality of engineered hyaline cartilage. J Mater Sci Mater Med, 2007, 18(2): 273-281.
41.	Yen CN, Lin YR, Chang MD, et al. Use of porous alginate sponges for substantial chondrocyte expansion and matrix production: effects of seeding density. Biotechnol Prog, 2008, 24(2): 452-457.
42.	Bernstein P, Dong M, Graupner S, et al. Sox9 expression of alginate-encapsulated chondrocytes is stimulated by low cell density. J Biomed Mater Res A, 2009, 91(3): 910-918.
43.	Francioli SE, Candrian C, Martin K, et al. Effect of three-dimensional expansion and cell seeding density on the cartilage-forming capacity of human articular chondrocytes in type Ⅱ collagen sponges. J Biomed Mater Res A, 2010, 95(3): 924-931.
44.	Wan LQ, Jiang J, Miller DE, et al. Matrix deposition modulates the viscoelastic shear properties of hydrogel-based cartilage grafts. Tissue Eng Part A, 2011, 17(7-8): 1111-1122.
45.	Cui X, Breitenkamp K, Lotz M, et al. Synergistic action of fibroblast growth factor-2 and transforming growth factor-beta1 enhances bioprinted human neocartilage formation. Biotechnol Bioeng, 2012, 109(9): 2357-2368.
46.	Ren X, Wang F, Chen C, et al. Engineering zonal cartilage through bioprinting collagen type Ⅱ hydrogel constructs with biomimetic chondrocyte density gradient. BMC Musculoskelet Disord, 2016, 17: 301. doi: 10.1186/s12891-016-1130-8.
47.	Cigan AD, Roach BL, Nims RJ, et al. High seeding density of human chondrocytes in agarose produces tissue-engineered cartilage approaching native mechanical and biochemical properties. J Biomech, 2016, 49(9): 1909-1917.
48.	Lam T, Dehne T, Krüger JP, et al. Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue-engineered cartilage. J Biomed Mater Res B Appl Biomater, 2019, 107(8): 2649-2657.
49.	Somoza RA, Welter JF, Correa D, et al. Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations. Tissue Eng Part B Rev, 2014, 20(6): 596-608.
50.	Huang CY, Reuben PM, D’Ippolito G, et al. Chondrogenesis of human bone marrow-derived mesenchymal stem cells in agarose culture. Anat Rec A Discov Mol Cell Evol Biol, 2004, 278(1): 428-436.
51.	Hui TY, Cheung KM, Cheung WL, et al. In vitro chondrogenic differentiation of human mesenchymal stem cells in collagen microspheres: influence of cell seeding density and collagen concentration. Biomaterials, 2008, 29(22): 3201-3212.
52.	Li Z, Kupcsik L, Yao SJ, et al. Chondrogenesis of human bone marrow mesenchymal stem cells in fibrin-polyurethane composites. Tissue Eng Part A, 2009, 15(7): 1729-1737.
53.	Buxton AN, Bahney CS, Yoo JU, et al. Temporal exposure to chondrogenic factors modulates human mesenchymal stem cell chondrogenesis in hydrogels. Tissue Eng Part A, 2011, 17(3-4): 371-380.
54.	Zhang L, Yuan T, Guo L, et al. An in vitro study of collagen hydrogel to induce the chondrogenic differentiation of mesenchymal stem cells. J Biomed Mater Res A, 2012, 100(10): 2717-2725.
55.	Olderøy MØ, Lilledahl MB, Beckwith MS, et al. Biochemical and structural characterization of neocartilage formed by mesenchymal stem cells in alginate hydrogels. PLoS One, 2014, 9(3): e91662. doi: 10.1371/journal.pone.0091662.
56.	Bean AC, Tuan RS. Fiber diameter and seeding density influence chondrogenic differentiation of mesenchymal stem cells seeded on electrospun poly(ε-caprolactone) scaffolds. Biomed Mater, 2015, 10(1): 015018. doi: 10.1088/1748-6041/10/1/015018.
57.	Pustlauk W, Paul B, Brueggemeier S, et al. Modulation of chondrogenic differentiation of human mesenchymal stem cells in jellyfish collagen scaffolds by cell density and culture medium. J Tissue Eng Regen Med, 2017, 11(6): 1710-1722.
58.	Li X, Teng Y, Liu J, et al. Chondrogenic differentiation of BMSCs encapsulated in chondroinductive polysaccharide/collagen hybrid hydrogels. J Mater Chem B, 2017, 5(26): 5109-5119.
59.	Sun AX, Lin H, Fritch MR, et al. Chondrogenesis of human bone marrow mesenchymal stem cells in 3-dimensional, photocrosslinked hydrogel constructs: Effect of cell seeding density and material stiffness. Acta Biomater, 2017, 58: 302-311.
60.	Kim M, Erickson IE, Huang AH, et al. Donor variation and optimization of human mesenchymal stem cell chondrogenesis in hyaluronic acid. Tissue Eng Part A, 2018, 24(21-22): 1693-1703.
61.	Little CJ, Bawolin NK, Chen X. Mechanical properties of natural cartilage and tissue-engineered constructs. Tissue Eng Part B Rev, 2011, 17(4): 213-227.
62.	Wu L, Leijten JC, Georgi N, et al. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A, 2011, 17(9-10): 1425-1436.
63.	Wu L, Prins HJ, Helder MN, et al. Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng Part A, 2012, 18(15-16): 1542-1551.
64.	Fu Y, Karbaat L, Wu L, et al. Trophic effects of mesenchymal stem cells in tissue regeneration. Tissue Eng Part B Rev, 2017, 23(6): 515-528.

1. Newman AP. Articular cartilage repair. Am J Sports Med, 1998, 26(2): 309-324.
2. Li YY, Cheng HW, Cheung KM, et al. Mesenchymal stem cell-collagen microspheres for articular cartilage repair: cell density and differentiation status. Acta Biomater, 2014, 10(5): 1919-1929.
3. McAlindon TE, LaValley MP, Harvey WF, et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA, 2017, 317(19): 1967-1975.
4. Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: Results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med, 2019, 47(2): 347-354.
5. Meheux CJ, McCulloch PC, Lintner DM, et al. Efficacy of intra-articular platelet-rich plasma injections in knee osteoarthritis: A systematic review. Arthroscopy, 2016, 32(3): 495-505.
6. Frehner F, Benthien JP. Microfracture: State of the art in cartilage surgery? Cartilage, 2018, 9(4): 339-345.
7. Nie X, Chuah YJ, Zhu W, et al. Decellularized tissue engineered hyaline cartilage graft for articular cartilage repair. Biomaterials, 2020, 235: 119821. doi: 10.1016/j.biomaterials.2020.119821.
8. Kwon H, Brown WE, Lee CA, et al. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat Rev Rheumatol, 2019, 15(9): 550-570.
9. Campos Y, Almirall A, Fuentes G, et al. Tissue engineering: An alternative to repair cartilage. Tissue Eng Part B Rev, 2019, 25(4): 357-373.
10. Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med, 1999, 331(14): 889-895.
11. Murawski CD, Kennedy JG. Operative treatment of osteochondral lesions of the talus. J Bone Joint Surg (Am), 2013, 95(11): 1045-1054.
12. Tan AR, Hung CT. Concise review: Mesenchymal stem cells for functional cartilage tissue engineering: Taking cues from chondrocyte-based constructs. Stem Cells Transl Med, 2017, 6(4): 1295-1303.
13. Matricali GA, Dereymaeker GP, Luyten FP. Donor site morbidity after articular cartilage repair procedures: a review. Acta Orthop Belg, 2010, 76(5): 669-674.
14. Cao C, Zhang Y, Ye Y, et al. Effects of cell phenotype and seeding density on the chondrogenic capacity of human osteoarthritic chondrocytes in type I collagen scaffolds. J Orthop Surg Res, 2020, 15(1): 120. doi: 10.1186/s13018-020-01617-6.
15. Duan L, Ma B, Liang Y, et al. Cytokine networking of chondrocyte dedifferentiation in vitro and its implications for cell-based cartilage therapy. Am J Transl Res, 2015, 7(2): 194-208.
16. Ma B, Leijten JC, Wu L, et al. Gene expression profiling of dedifferentiated human articular chondrocytes in monolayer culture. Osteoarthritis Cartilage, 2013, 21(4): 599-603.
17. Caron MM, Emans PJ, Coolsen MM, et al. Redifferentiation of dedifferentiated human articular chondrocytes: comparison of 2D and 3D cultures. Osteoarthritis Cartilage, 2012, 20(10): 1170-1178.
18. Augello A, De Bari C. The regulation of differentiation in mesenchymal stem cells. Hum Gene Ther, 2010, 21(10): 1226-1238.
19. Mesallati T, Buckley CT, Kelly DJ. A comparison of self-assembly and hydrogel encapsulation as a means to engineer functional cartilaginous grafts using culture expanded chondrocytes. Tissue Eng Part C Methods, 2014, 20(1): 52-63.
20. Ponticiello MS, Schinagl RM, Kadiyala S, et al. Gelatin-based resorbable sponge as a carrier matrix for human mesenchymal stem cells in cartilage regeneration therapy. J Biomed Mater Res, 2000, 52(2): 246-255.
21. Kavalkovich KW, Boynton RE, Murphy JM, et al. Chondrogenic differentiation of human mesenchymal stem cells within an alginate layer culture system. In Vitro Cell Dev Biol Anim, 2002, 38(8): 457-466.
22. Tang J, Peng R, Ding J. The regulation of stem cell differentiation by cell-cell contact on micropatterned material surfaces. Biomaterials, 2010, 31(9): 2470-2476.
23. Levorson EJ, Mountziaris PM, Hu O, et al. Cell-derived polymer/extracellular matrix composite scaffolds for cartilage regeneration, Part 1: investigation of cocultures and seeding densities for improved extracellular matrix deposition. Tissue Eng Part C Methods, 2014, 20(4): 340-357.
24. Mo XT, Guo SC, Xie HQ, et al. Variations in the ratios of co-cultured mesenchymal stem cells and chondrocytes regulate the expression of cartilaginous and osseous phenotype in alginate constructs. Bone, 2009, 45(1): 42-51.
25. Meretoja VV, Dahlin RL, Kasper FK, et al. Enhanced chondrogenesis in co-cultures with articular chondrocytes and mesenchymal stem cells. Biomaterials, 2012, 33(27): 6362-6369.
26. Ko CY, Ku KL, Yang SR, et al. In vitro and in vivo co-culture of chondrocytes and bone marrow stem cells in photocrosslinked PCL-PEG-PCL hydrogels enhances cartilage formation. J Tissue Eng Regen Med, 2016, 10(10): E485-E496.
27. Sabatino MA, Santoro R, Gueven S, et al. Cartilage graft engineering by co-culturing primary human articular chondrocytes with human bone marrow stromal cells. J Tissue Eng Regen Med, 2015, 9(12): 1394-1403.
28. Bosnakovski D, Mizuno M, Kim G, et al. Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells (MSCs) in different hydrogels: influence of collagen type Ⅱ extracellular matrix on MSC chondrogenesis. Biotechnol Bioeng, 2006, 93(6): 1152-1163.
29. Quinn TM, Häuselmann HJ, Shintani N, et al. Cell and matrix morphology in articular cartilage from adult human knee and ankle joints suggests depth-associated adaptations to biomechanical and anatomical roles. Osteoarthritis Cartilage, 2013, 21(12): 1904-1912.
30. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health, 2009, 1(6): 461-468.
31. Mansfield JC, Bell JS, Winlove CP. The micromechanics of the superficial zone of articular cartilage. Osteoarthritis Cartilage, 2015, 23(10): 1806-1816.
32. Charlier E, Deroyer C, Ciregia F, et al. Chondrocyte dedifferentiation and osteoarthritis (OA). Biochem Pharmacol, 2019, 165: 49-65.
33. Mauck RL, Seyhan SL, Ateshian GA, et al. Influence of seeding density and dynamic deformational loading on the developing structure/function relationships of chondrocyte-seeded agarose hydrogels. Ann Biomed Eng, 2002, 30(8): 1046-1056.
34. Saini S, Wick TM. Concentric cylinder bioreactor for production of tissue engineered cartilage: effect of seeding density and hydrodynamic loading on construct development. Biotechnol Prog, 2003, 19(2): 510-521.
35. Iwasa J, Ochi M, Uchio Y, et al. Effects of cell density on proliferation and matrix synthesis of chondrocytes embedded in atelocollagen gel. Artif Organs, 2003, 27(3): 249-255.
36. Moretti M, Wendt D, Dickinson SC, et al. Effects of in vitro preculture on in vivo development of human engineered cartilage in an ectopic model. Tissue Eng, 2005, 11(9-10): 1421-1428.
37. Williams GM, Klein TJ, Sah RL. Cell density alters matrix accumulation in two distinct fractions and the mechanical integrity of alginate-chondrocyte constructs. Acta Biomater, 2005, 1(6): 625-633.
38. Mahmoudifar N, Doran PM. Effect of seeding and bioreactor culture conditions on the development of human tissue-engineered cartilage. Tissue Eng, 2006, 12(6): 1675-1685.
39. Wang Y, Blasioli DJ, Kim HJ, et al. Cartilage tissue engineering with silk scaffolds and human articular chondrocytes. Biomaterials, 2006, 27(25): 4434-4442.
40. Kelly DJ, Crawford A, Dickinson SC, et al. Biochemical markers of the mechanical quality of engineered hyaline cartilage. J Mater Sci Mater Med, 2007, 18(2): 273-281.
41. Yen CN, Lin YR, Chang MD, et al. Use of porous alginate sponges for substantial chondrocyte expansion and matrix production: effects of seeding density. Biotechnol Prog, 2008, 24(2): 452-457.
42. Bernstein P, Dong M, Graupner S, et al. Sox9 expression of alginate-encapsulated chondrocytes is stimulated by low cell density. J Biomed Mater Res A, 2009, 91(3): 910-918.
43. Francioli SE, Candrian C, Martin K, et al. Effect of three-dimensional expansion and cell seeding density on the cartilage-forming capacity of human articular chondrocytes in type Ⅱ collagen sponges. J Biomed Mater Res A, 2010, 95(3): 924-931.
44. Wan LQ, Jiang J, Miller DE, et al. Matrix deposition modulates the viscoelastic shear properties of hydrogel-based cartilage grafts. Tissue Eng Part A, 2011, 17(7-8): 1111-1122.
45. Cui X, Breitenkamp K, Lotz M, et al. Synergistic action of fibroblast growth factor-2 and transforming growth factor-beta1 enhances bioprinted human neocartilage formation. Biotechnol Bioeng, 2012, 109(9): 2357-2368.
46. Ren X, Wang F, Chen C, et al. Engineering zonal cartilage through bioprinting collagen type Ⅱ hydrogel constructs with biomimetic chondrocyte density gradient. BMC Musculoskelet Disord, 2016, 17: 301. doi: 10.1186/s12891-016-1130-8.
47. Cigan AD, Roach BL, Nims RJ, et al. High seeding density of human chondrocytes in agarose produces tissue-engineered cartilage approaching native mechanical and biochemical properties. J Biomech, 2016, 49(9): 1909-1917.
48. Lam T, Dehne T, Krüger JP, et al. Photopolymerizable gelatin and hyaluronic acid for stereolithographic 3D bioprinting of tissue-engineered cartilage. J Biomed Mater Res B Appl Biomater, 2019, 107(8): 2649-2657.
49. Somoza RA, Welter JF, Correa D, et al. Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations. Tissue Eng Part B Rev, 2014, 20(6): 596-608.
50. Huang CY, Reuben PM, D’Ippolito G, et al. Chondrogenesis of human bone marrow-derived mesenchymal stem cells in agarose culture. Anat Rec A Discov Mol Cell Evol Biol, 2004, 278(1): 428-436.
51. Hui TY, Cheung KM, Cheung WL, et al. In vitro chondrogenic differentiation of human mesenchymal stem cells in collagen microspheres: influence of cell seeding density and collagen concentration. Biomaterials, 2008, 29(22): 3201-3212.
52. Li Z, Kupcsik L, Yao SJ, et al. Chondrogenesis of human bone marrow mesenchymal stem cells in fibrin-polyurethane composites. Tissue Eng Part A, 2009, 15(7): 1729-1737.
53. Buxton AN, Bahney CS, Yoo JU, et al. Temporal exposure to chondrogenic factors modulates human mesenchymal stem cell chondrogenesis in hydrogels. Tissue Eng Part A, 2011, 17(3-4): 371-380.
54. Zhang L, Yuan T, Guo L, et al. An in vitro study of collagen hydrogel to induce the chondrogenic differentiation of mesenchymal stem cells. J Biomed Mater Res A, 2012, 100(10): 2717-2725.
55. Olderøy MØ, Lilledahl MB, Beckwith MS, et al. Biochemical and structural characterization of neocartilage formed by mesenchymal stem cells in alginate hydrogels. PLoS One, 2014, 9(3): e91662. doi: 10.1371/journal.pone.0091662.
56. Bean AC, Tuan RS. Fiber diameter and seeding density influence chondrogenic differentiation of mesenchymal stem cells seeded on electrospun poly(ε-caprolactone) scaffolds. Biomed Mater, 2015, 10(1): 015018. doi: 10.1088/1748-6041/10/1/015018.
57. Pustlauk W, Paul B, Brueggemeier S, et al. Modulation of chondrogenic differentiation of human mesenchymal stem cells in jellyfish collagen scaffolds by cell density and culture medium. J Tissue Eng Regen Med, 2017, 11(6): 1710-1722.
58. Li X, Teng Y, Liu J, et al. Chondrogenic differentiation of BMSCs encapsulated in chondroinductive polysaccharide/collagen hybrid hydrogels. J Mater Chem B, 2017, 5(26): 5109-5119.
59. Sun AX, Lin H, Fritch MR, et al. Chondrogenesis of human bone marrow mesenchymal stem cells in 3-dimensional, photocrosslinked hydrogel constructs: Effect of cell seeding density and material stiffness. Acta Biomater, 2017, 58: 302-311.
60. Kim M, Erickson IE, Huang AH, et al. Donor variation and optimization of human mesenchymal stem cell chondrogenesis in hyaluronic acid. Tissue Eng Part A, 2018, 24(21-22): 1693-1703.
61. Little CJ, Bawolin NK, Chen X. Mechanical properties of natural cartilage and tissue-engineered constructs. Tissue Eng Part B Rev, 2011, 17(4): 213-227.
62. Wu L, Leijten JC, Georgi N, et al. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A, 2011, 17(9-10): 1425-1436.
63. Wu L, Prins HJ, Helder MN, et al. Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng Part A, 2012, 18(15-16): 1542-1551.
64. Fu Y, Karbaat L, Wu L, et al. Trophic effects of mesenchymal stem cells in tissue regeneration. Tissue Eng Part B Rev, 2017, 23(6): 515-528.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress of different cell seeding densities and cell ratios in cartilage tissue engineering

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