J Korean Orthop Assoc.  2019 Dec;54(6):478-489. 10.4055/jkoa.2019.54.6.478.

Current Update of Cartilage Regeneration Using Stem Cells in Osteoarthritis

• Seon JK
• Choi IS
• Ko JW

• KMID: 2469879
• DOI: http://doi.org/10.4055/jkoa.2019.54.6.478

Abstract

Osteoarthritis is a disease characterized by the progression of articular cartilage erosion, that increases pain during joint motion and reduces the ability to withstand mechanical stress, which in turn limits joint mobility and function. Damage to articular cartilage due to trauma or degenerative injury is considered a major cause of arthritis. Numerous studies and attempts have been made to regenerate articular cartilage. In the case of partial degenerative cartilage changes, microfracture and autologous chondrocyte implantation have been proposed as surgical treatment methods, but they have disadvantages such as insufficient mutual binding to the host cells, inaccurate cell delivery, and deterioration of healthy cartilage. Stem cell-based therapies have been developed to compensate for this. This review summarizes the drawbacks and consequences of various cartilage regeneration methods and describes the various attempts to treat cartilage damage. In addition, this review will discuss cartilage regeneration, particularly mesenchymal stem cell engineering-based therapies, and explore how to treat future cartilage regeneration using mesenchymal stem cells.

Keyword

osteoarthritis; cartilage injury; cartilage regeneration; mesenchymal stem cell

MeSH Terms

Arthritis
Cartilage*
Cartilage, Articular
Chondrocytes
Joints
Mesenchymal Stromal Cells
Osteoarthritis*
Regeneration*
Stem Cells*
Stress, Mechanical

Figure

• 

  Figure 1 Extracellular matrix of articular cartilage.

• 

  Figure 2 Cartilage regeneration method. (A) Focal cartilage damage, (B) chondroplasty, (C) microfracture, (D) autologous chondrocyte implantation, (E) matrix assisted autologous chondrocyte implantation.

• 

  Figure 3 BioSeed C (BioTissue Technologies GmbH).

• 

  Figure 4 NeoCart (Histogenics Corporation), Novocart (B. Braun-Tetec), CaReS (Ars Arthro, Esslingen).

• 

  Figure 5 Human umbilical cord blood-derived stem cell therapy.

Reference

1. Gupta S, Hawker GA, Laporte A, Croxford R, Coyte PC. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology (Oxford). 2005; 44:1531–1537.

2. Barbour KE, Helmick CG, Boring M, Zhang X, Lu H, Holt JB. Prevalence of doctor-diagnosed arthritis at state and county levels - United States, 2014. MMWR Morb Mortal Wkly Rep. 2016; 65:489–494.

3. Sophia Fox AJ, Bedi A, Rodeo SA. The basic science of articular cartilage: structure, composition, and function. Sports Health. 2009; 1:461–468.

4. Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol. 2015; 11:21–34.

5. Kon E, Filardo G, Berruto M, et al. Articular cartilage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture. Am J Sports Med. 2011; 39:2549–2557.

6. Rodrigo JJ, Steadman JR, Silliman JF, Fulstone HA. Improvement in full-thickness chondral defect healing in the human knee after debridement and microfracture using continuous passive motion. Am J Knee Surg. 1994; 7:109–116.

7. Knutsen G, Drogset JO, Engebretsen L, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007; 89:2105–2112.

8. Miller BS, Steadman JR, Briggs KK, Rodrigo JJ, Rodkey WG. Patient satisfaction and outcome after microfracture of the degenerative knee. J Knee Surg. 2004; 17:13–17.

9. Kreuz PC, Erggelet C, Steinwachs MR, et al. Is microfracture of chondral defects in the knee associated with different results in patients aged 40 years or younger? Arthroscopy. 2006; 22:1180–1186.

10. Kreuz PC, Steinwachs MR, Erggelet C, et al. Results after microfracture of full-thickness chondral defects in different compartments in the knee. Osteoarthritis Cartilage. 2006; 14:1119–1125.

11. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med. 2009; 37:2053–2063.

12. Gudas R, Gudaitė A, Mickevičius T, 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; 29:89–97.

13. Park YB, Ha CW, Rhim JH, Lee HJ. Stem cell therapy for articular cartilage repair: review of the entity of cell populations used and the result of the clinical application of each entity. Am J Sports Med. 2018; 46:2540–2552.

14. Knutsen G, Drogset JO, Engebretsen L, et al. A randomized multicenter trial comparing autologous chondrocyte implantation with microfracture: long-term follow-up at 14 to 15 years. J Bone Joint Surg Am. 2016; 98:1332–1339.

15. Ruta DJ, Villarreal AD, Richardson DR. Orthopedic Surgical Options for Joint Cartilage Repair and Restoration. Phys Med Rehabil Clin N Am. 2016; 27:1019–1042.

16. Riboh JC, Cvetanovich GL, Cole BJ, Yanke AB. Comparative efficacy of cartilage repair procedures in the knee: a network meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2017; 25:3786–3799.

17. Krych AJ, Pareek A, King AH, Johnson NR, Stuart MJ, Williams RJ 3rd. Return to sport after the surgical management of articular cartilage lesions in the knee: a meta-analysis. Knee Surg Sports Traumatol Arthrosc. 2017; 25:3186–3196.

18. Ebert JR, Fallon M, Wood DJ, Janes GC. A prospective clinical and radiological evaluation at 5 years after arthroscopic matrix-induced autologous chondrocyte implantation. Am J Sports Med. 2017; 45:59–69.

19. Kon E, Verdonk P, Condello V, et al. Matrix-assisted autologous chondrocyte transplantation for the repair of cartilage defects of the knee: systematic clinical data review and study quality analysis. Am J Sports Med. 2009; 37 Suppl 1:156S–166S.

20. Kon E, Delcogliano M, Filardo G, Montaperto C, Marcacci M. Second generation issues in cartilage repair. Sports Med Arthrosc Rev. 2008; 16:221–229.

21. Grigolo B, Lisignoli G, Piacentini A, et al. Evidence for redifferentiation of human chondrocytes grown on a hyaluronan-based biomaterial (HYAff 11): molecular, immunohistochemical and ultrastructural analysis. Biomaterials. 2002; 23:1187–1195.

22. Irion VH, Flanigan DC. New and emerging techniques in cartilage repair: other scaffold-based cartilage treatment options. Oper Tech Sports Med. 2013; 21:125–137.

23. Crawford DC, Heveran CM, Cannon WD Jr, Foo LF, Potter HG. An autologous cartilage tissue implant NeoCart for treatment of grade III chondral injury to the distal femur: prospective clinical safety trial at 2 years. Am J Sports Med. 2009; 37:1334–1343.

24. Gobbi A, Karnatzikos G, Scotti C, Mahajan V, Mazzucco L, Grigolo B. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage. 2011; 2:286–299.

25. Cole BJ, Farr J, Winalski CS, et al. Outcomes after a single-stage procedure for cell-based cartilage repair: a prospective clinical safety trial with 2-year follow-up. Am J Sports Med. 2011; 39:1170–1179.

26. Rai V, Dilisio MF, Dietz NE, Agrawal DK. Recent strategies in cartilage repair: a systemic review of the scaffold development and tissue engineering. J Biomed Mater Res A. 2017; 105:2343–2354.

27. Matricali GA, Dereymaeker GP, Luyten FP. Donor site morbidity after articular cartilage repair procedures: a review. Acta Orthop Belg. 2010; 76:669–674.

28. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284:143–147.

29. De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001; 44:1928–1942.

30. Guilak F, Estes BT, Diekman BO, Moutos FT, Gimble JM. 2010 Nicolas Andry Award: multipotent adult stem cells from adipose tissue for musculoskeletal tissue engineering. Clin Orthop Relat Res. 2010; 468:2530–2540.

31. Trubiani O, Orsini G, Caputi S, Piatelli A. Adult mesenchymal stem cells in dental research: a new approach for tissue engineering. Int J Immunopathol Pharmacol. 2006; 19:451–460.

32. Danišovič L, Lesný P, Havlas V, et al. Chondrogenic differentiation of human bone marrow and adipose tissue-derived mesenchymal stem cells. J Appl Biomed. 2007; 5:139–150.

33. Koga H, Shimaya M, Muneta T, et al. Local adherent technique for transplanting mesenchymal stem cells as a potential treatment of cartilage defect. Arthritis Res Ther. 2008; 10:R84.

34. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage. 2002; 10:199–206.

35. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant. 2004; 13:595–600.

36. Adachi N, Ochi M, Deie M, Ito Y. Transplant of mesenchymal stem cells and hydroxyapatite ceramics to treat severe osteochondral damage after septic arthritis of the knee. J Rheumatol. 2005; 32:1615–1618.

37. Kuroda R, Ishida K, Matsumoto T, et al. Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthritis Cartilage. 2007; 15:226–231.

38. Wakitani S, Nawata M, Tensho K, Okabe T, Machida H, Ohgushi H. Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J Tissue Eng Regen Med. 2007; 1:74–79.

39. Adachi N, Ochi M, Deie M, Ishikawa M, Ito Y. Osteonecrosis of the knee treated with a tissue-engineered cartilage and bone implant. A case report. J Bone Joint Surg Am. 2007; 89:2752–2757.

40. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008; 11:343–353.

41. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses. 2008; 71:900–908.

42. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med. 2010; 38:1110–1116.

43. Haleem AM, Singergy AA, Sabry D, et al. The clinical use of human culture-expanded autologous bone marrow mesenchymal stem cells transplanted on platelet-rich fibrin glue in the treatment of articular cartilage defects: a pilot study and preliminary results. Cartilage. 2010; 1:253–261.

44. Wakitani S, Okabe T, Horibe S, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 2011; 5:146–150.

45. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011; 14:211–215.

46. Emadedin M, Aghdami N, Taghiyar L, et al. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 2012; 15(7):422–428.

47. Lee KB, Wang VT, Chan YH, Hui JH. A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid: a prospective comparative study on safety and short-term efficacy. Ann Acad Med Singapore. 2012; 41:511–517.

48. Teo BJ, Buhary K, Tai BC, Hui JH. Cell-based therapy improves function in adolescents and young adults with patellar osteochondritis dissecans. Clin Orthop Relat Res. 2013; 471:1152–1158.

49. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy. 2013; 29:2020–2028.

50. Orozco L, Munar A, Soler R, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation. 2013; 95:1535–1541.

51. Davatchi F, Sadeghi Abdollahi B, Mohyeddin M, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2016; 19:219–225.

52. de Windt TS, Vonk LA, Slaper-Cortenbach IC, et al. Allogeneic mesenchymal stem cells stimulate cartilage regeneration and are safe for single-stage cartilage repair in humans upon mixture with recycled autologous chondrons. Stem Cells. 2017; 35:256–264.

53. Yamasaki S, Mera H, Itokazu M, Hashimoto Y, Wakitani S. Cartilage repair with autologous bone marrow mesenchymal stem cell transplantation: review of preclinical and clinical studies. Cartilage. 2014; 5:196–202.

54. Ha CW, Park YB, Kim SH, Lee HJ. Intra-articular mesenchymal stem cells in osteoarthritis of the knee: a systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy. 2019; 35:277–288.e2.

55. Medical Advisory Secretariat. Osteogenic protein-1 for long bone nonunion: an evidence-based analysis. Ont Health Technol Assess Ser. 2005; 5:1–57.

56. Jäger M, Jelinek EM, Wess KM, et al. Bone marrow concentrate: a novel strategy for bone defect treatment. Curr Stem Cell Res Ther. 2009; 4:34–43.

57. Sampson S, Smith J, Vincent H, Aufiero D, Zall M, Botto-van-Bemden A. Intra-articular bone marrow concentrate injection protocol: short-term efficacy in osteoarthritis. Regen Med. 2016; 11:511–520.

58. Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O'Connor MI. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017; 45:82–90.

59. Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res Int. 2014; 2014:370621.

60. Shariatzadeh M, Song J, Wilson SL. The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis. Cell Tissue Res. 2019; 378:399–410.

61. Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014; 32:1254–1266.

62. Pers YM, Rackwitz L, Ferreira R, et al. ADIPOA Consortium. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016; 5:847–856.

63. Song Y, Du H, Dai C, et al. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. Regen Med. 2018; 13:295–307.

64. Pak J, Chang JJ, Lee JH, Lee SH. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet Disord. 2013; 14:337.

65. Bui KH-T, Duong TD, Nguyen NT, et al. Symptomatic knee osteoarthritis treatment using autologous adipose derived stem cells and platelet-rich plasma: a clinical study. Biomed Res Ther. 2014; 1:2–8.

66. Koh YG, Kwon OR, Kim YS, Choi YJ, Tak DH. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Arthroscopy. 2016; 32:97–109.

67. Kim YS, Lee M, Koh YG. Additional mesenchymal stem cell injection improves the outcomes of marrow stimulation combined with supramalleolar osteotomy in varus ankle osteoarthritis: short-term clinical results with second-look arthroscopic evaluation. J Exp Orthop. 2016; 3:12.

68. Fodor PB, Paulseth SG. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet Surg J. 2016; 36:229–236.

69. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151:264–269. W64.

70. Kim YS, Koh YG. Injection of mesenchymal stem cells as a supplementary strategy of marrow stimulation improves cartilage regeneration after lateral sliding calcaneal osteotomy for varus ankle osteoarthritis: clinical and second-look arthroscopic results. Arthroscopy. 2016; 32:878–889.

71. Kim YS, Kwon OR, Choi YJ, Suh DS, Heo DB, Koh YG. Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis. Am J Sports Med. 2015; 43:2738–2746.

72. Park YB, Ha CW, Lee CH, Yoon YC, Park YG. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Transl Med. 2017; 6:613–621.

73. Matas J, Orrego M, Amenabar D, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med. 2019; 8:215–224.

74. Flynn A, Barry F, O'Brien T. UC blood-derived mesenchymal stromal cells: an overview. Cytotherapy. 2007; 9:717–726.

75. Park YB, Ha CW, Lee CH, Yoon YC, Park YG. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Transl Med. 2017; 6:613–621.