Skip to main content

Advertisement

SpringerLink
Log in

Minimally Invasive Cellular Therapies for Osteoarthritis Treatment

  • Review
  • Published:
Regenerative Engineering and Translational Medicine Aims and scope Submit manuscript

Abstract

Osteoarthritis (OA) is a chronic degenerative disease characterized by multiple pathological conditions such as synovitis, degeneration of the articular cartilage, subchondral bone remodeling, and osteophyte formation. Local chronic inflammation response induces degradation of cartilage and the poor regenerative ability of articular cartilage due to its avascular nature and limited regeneration of chondrocytes affecting the microenvironment of the joint. Current clinical treatments provide temporal pain relief but have failed to treat OA pathogenesis. In addition, surgical invasive methods have the risk of adverse complications such as long-term pain and increased morbidity. Therefore, there is a need to develop novel therapeutic strategies to prevent adverse effects seen in current surgical approaches. Minimally invasive therapies have been explored to overcome the limitations of conventional OA therapies. In recent years, cellular-based therapies have been employed to suppress inflammation and promote cartilage regeneration by using progenitor cells and stem cells including induced pluripotent stem cells (iPSCs) and genetically modified cells. The present review summarizes the status of cellular-based therapy for OA treatment. We suggest that minimally invasive intervention in the microenvironment of the joint may overcome the current limitation for OA treatment.

Lay Summary

Osteoarthritis is a chronic degenerative disease for which many therapies are insufficient in treating disease pathogenesis and instead provide transient symptomatic relieves such as pain and inflammation. Those treatments that do target the progression of the disease include surgical intervention and, depending on the age of the patient, these procedures may not even be an option. Minimally invasive cellular-based therapies help to lower the financial burden and attenuate disease progression rather than providing temporary relief of the symptoms. These cellular therapies are reviewed in this manuscript.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum. 2009;60(12):3546–53. https://doi.org/10.1002/art.24984.

    Article  Google Scholar 

  2. Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis: articular cartilage and subchondral bone. Ann N Y Acad Sci. 2010;1192(1):230–7. https://doi.org/10.1111/j.1749-6632.2009.05240.x.

    Article  CAS  Google Scholar 

  3. Glyn-Jones S, Palmer AJR, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87. https://doi.org/10.1016/S0140-6736(14)60802-3.

  4. Karuppal R. Current concepts in the articular cartilage repair and regeneration. J Orthop. 2017;14(2):A1–3. https://doi.org/10.1016/j.jor.2017.05.001.

    Article  Google Scholar 

  5. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil. 2014;22(3):363–88. https://doi.org/10.1016/j.joca.2014.01.003.

  6. Escobar Ivirico JL, Bhattacharjee M, Kuyinu E, Nair LS, Laurencin CT. Regenerative engineering for knee osteoarthritis treatment: biomaterials and cell-based technologies. Engineering. 2017;3(1):16–27. https://doi.org/10.1016/J.ENG.2017.01.003.

    Article  Google Scholar 

  7. Trigkilidas D, Anand A. The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain. Ann R Coll Surg Engl. 2013;95(8):545–51. https://doi.org/10.1308/rcsann.2013.95.8.545.

    Article  CAS  Google Scholar 

  8. Vines J, Aliprantis A, Gomoll A, Farr J. Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg. 2015;29(06):443–50. https://doi.org/10.1055/s-0035-1569481.

    Article  Google Scholar 

  9. Browne JE, Branch TP. Surgical alternatives for treatment of articular cartilage lesions. J Am Acad Orthop Surg. 2000;8(3):180–9. https://doi.org/10.5435/00124635-200005000-00005.

    Article  CAS  Google Scholar 

  10. Oussedik S, Tsitskaris K, Parker D. Treatment of articular cartilage lesions of the knee by microfracture or autologous chondrocyte implantation: a systematic review. Arthrosc J Arthrosc Relat Surg. 2015;31(4):732–44. https://doi.org/10.1016/j.arthro.2014.11.023.

    Article  Google Scholar 

  11. Steinwachs M, Kreuz PC. Autologous chondrocyte implantation in chondral defects of the knee with a type I/III collagen membrane: a prospective study with a 3-year follow-up. Arthrosc J Arthrosc Relat Surg. 2007;23(4):381–7. https://doi.org/10.1016/j.arthro.2006.12.003.

    Article  Google Scholar 

  12. Memtsoudis SG, Ma Y, Chiu Y-L, Poultsides L, Gonzalez Della Valle A, Mazumdar M. Bilateral total knee arthroplasty: risk factors for major morbidity and mortality. Anesth Analg. 2011;113(4):784–90. https://doi.org/10.1213/ANE.0b013e3182282953.

    Article  Google Scholar 

  13. Beswick AD, Wylde V, Gooberman-Hill R, Blom A, Dieppe P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open. 2012;2(1):e000435. https://doi.org/10.1136/bmjopen-2011-000435.

    Article  Google Scholar 

  14. 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(2):229–36. https://doi.org/10.1093/asj/sjv135.

    Article  Google Scholar 

  15. Seol D, McCabe DJ, Choe H, Zheng H, Yu Y, Jang K, et al. Chondrogenic progenitor cells respond to cartilage injury. Arthritis Rheum. 2012;64(11):3626–37. https://doi.org/10.1002/art.34613.

  16. Quesenberry PJ, Colvin G, Dooner G, Dooner M, Aliotta JM, Johnson K. The stem cell continuum: cell cycle, injury, and phenotype lability. Ann N Y Acad Sci. 2007;1106(1):20–9. https://doi.org/10.1196/annals.1392.016.

    Article  Google Scholar 

  17. Im G-I, Kim H-J. Electroporation-mediated gene transfer of SOX trio to enhance chondrogenesis in adipose stem cells. Osteoarthr Cartil. 2011;19(4):449–57. https://doi.org/10.1016/j.joca.2011.01.005.

    Article  Google Scholar 

  18. Lee l-M, Im G-I. SOX trio-co-transduced adipose stem cells in fibrin gel to enhance cartilage repair and delay the progression of osteoarthritis in the rat. Biomaterials. 2012;33(7):2016–24. https://doi.org/10.1016/j.biomaterials.2011.11.050.

    Article  CAS  Google Scholar 

  19. Zhang X, Mao Z, Yu C. Suppression of early experimental osteoarthritis by gene transfer of interleukin-1 receptor antagonist and interleukin-10. J Orthop Res. 2004;22(4):742–50. https://doi.org/10.1016/j.orthres.2003.12.007.

    Article  CAS  Google Scholar 

  20. Ilas DC, Churchman SM, McGonagle D, Jones E. Targeting subchondral bone mesenchymal stem cell activities for intrinsic joint repair in osteoarthritis. Future Sci OA. 2017;3(4):FSO228. https://doi.org/10.4155/fsoa-2017-0055.

    Article  CAS  Google Scholar 

  21. Hernigou P, Auregan JC, Dubory A, Flouzat-Lachaniette CH, Chevallier N, Rouard H. Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee. Int Orthop. 2018;42(11):2563–71. https://doi.org/10.1007/s00264-018-3916-9.

    Article  Google Scholar 

  22. Hernigou P, Delambre J, Quiennec S, Poignard A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: a prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. Int Orthop. 2020. https://doi.org/10.1007/s00264-020-04571-4.

  23. ter Huurne M, Schelbergen R, Blattes R, Blom A, de Munter W, Grevers LC, et al. Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis. Arthritis Rheum. 2012;64(11):3604–13. https://doi.org/10.1002/art.34626.

  24. Diekman BO, Wu CL, Louer CR, Furman BD, Huebner JL, Kraus VB, et al. Intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents posttraumatic arthritis. Cell Transplant. 2013;22(8):1395–408. https://doi.org/10.3727/096368912X653264.

  25. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med. 2010;38(6):1117–24. https://doi.org/10.1177/0363546509357915.

    Article  Google Scholar 

  26. Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan DC. Failures, re-operations, and complications after autologous chondrocyte implantation – a systematic review. Osteoarthr Cartil. 2011;19(7):779–91. https://doi.org/10.1016/j.joca.2011.02.010.

    Article  CAS  Google Scholar 

  27. Williams R, et al. Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS One. 2010;5(10):e13246. https://doi.org/10.1371/journal.pone.0013246.

    Article  CAS  Google Scholar 

  28. Alsalameh S, Amin R, Gemba T, Lotz M. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 2004;50(5):1522–32. https://doi.org/10.1002/art.20269.

    Article  Google Scholar 

  29. Koelling S, Kruegel J, Irmer M, Path JR, Sadowski B, Miro X, et al. Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell. 2009;4(4):324–35. https://doi.org/10.1016/j.stem.2009.01.015.

  30. Jiang Y, Tuan RS. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nat Rev Rheumatol. 2015;11(4):206–12. https://doi.org/10.1038/nrrheum.2014.200.

    Article  Google Scholar 

  31. Marcus P, De Bari C, Dell’Accio F, Archer CW. Articular chondroprogenitor cells maintain chondrogenic potential but fail to form a functional matrix when implanted into muscles of SCID mice. CARTILAGE. 2014;5(4):231–40. https://doi.org/10.1177/1947603514541274.

    Article  CAS  Google Scholar 

  32. Frisbie DD, McCarthy HE, Archer CW, Barrett MF, McIlwraith CW. Evaluation of articular cartilage progenitor cells for the repair of articular defects in an equine model. J Bone Jt Surg. 2015;97(6):484–93. https://doi.org/10.2106/JBJS.N.00404.

    Article  Google Scholar 

  33. Vizoso F, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. Int J Mol Sci. 2017;18(9):1852. https://doi.org/10.3390/ijms18091852.

    Article  CAS  Google Scholar 

  34. Docheva D, Popov C, Mutschler W, Schieker M. Human mesenchymal stem cells in contact with their environment: surface characteristics and the integrin system. J Cell Mol Med. 2007;11(1):21–38. https://doi.org/10.1111/j.1582-4934.2007.00001.x.

    Article  CAS  Google Scholar 

  35. Deans RJ, Moseley AB. Mesenchymal stem cells. Exp Hematol. 2000;28(8):875–84. https://doi.org/10.1016/S0301-472X(00)00482-3.

    Article  CAS  Google Scholar 

  36. Tran C, Damaser MS. Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev. 2015;82–83:1–11. https://doi.org/10.1016/j.addr.2014.10.007.

    Article  CAS  Google Scholar 

  37. Armiento AR, Alini M, Stoddart MJ. Articular fibrocartilage - why does hyaline cartilage fail to repair? Adv Drug Deliv Rev. 2019;146:289–305. https://doi.org/10.1016/j.addr.2018.12.015.

    Article  CAS  Google Scholar 

  38. Mueller MB, Tuan RS. Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cells. Arthritis Rheum. 2008;58(5):1377–88. https://doi.org/10.1002/art.23370.

    Article  CAS  Google Scholar 

  39. Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;10(3):244–58. https://doi.org/10.1016/j.stem.2012.02.005.

    Article  CAS  Google Scholar 

  40. Katsuda T, Kosaka N, Takeshita F, Ochiya T. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. PROTEOMICS. 2013;13(10–11):1637–53. https://doi.org/10.1002/pmic.201200373.

    Article  CAS  Google Scholar 

  41. Legaki E, Roubelakis MG, Theodoropoulos GE, Lazaris A, Kollia A, Karamanolis G, et al. Therapeutic potential of secreted molecules derived from human amniotic fluid Mesenchymal stem/stroma cells in a mice model of colitis. Stem Cell Rev Rep. 2016;12(5):604–12. https://doi.org/10.1007/s12015-016-9677-1.

  42. Zubkova ES, Beloglazova IB, Makarevich PI, Boldyreva MA, Sukhareva OY, Shestakova MV, et al. Regulation of adipose tissue stem cells angiogenic potential by tumor necrosis factor-alpha: regulation of adipose tissue stem cells. J Cell Biochem. 2016;117(1):180–96. https://doi.org/10.1002/jcb.25263.

  43. Braga Osorio Gomes Salgado AJ, et al. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther. 2010;5(2):103–10. https://doi.org/10.2174/157488810791268564.

    Article  Google Scholar 

  44. Lin L, Du L. The role of secreted factors in stem cells-mediated immune regulation. Cell Immunol. 2018;326:24–32. https://doi.org/10.1016/j.cellimm.2017.07.010.

    Article  CAS  Google Scholar 

  45. 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;2018:1–22. https://doi.org/10.1155/2018/9079538.

  46. Ioannidis JPA, Kim BYS, Trounson A. How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation. Nat Biomed Eng. 2018;2(11):797–809. https://doi.org/10.1038/s41551-018-0314-y.

    Article  CAS  Google Scholar 

  47. Gregory MH, Capito N, Kuroki K, Stoker AM, Cook JL, Sherman SL. A review of translational animal models for knee osteoarthritis. Arthritis. 2012;2012:1–14. https://doi.org/10.1155/2012/764621.

    Article  Google Scholar 

  48. Thysen S, Luyten FP, Lories RJU. Targets, models and challenges in osteoarthritis research. Dis Model Mech. 2015;8(1):17–30. https://doi.org/10.1242/dmm.016881.

    Article  CAS  Google Scholar 

  49. Cope PJ, Ourradi K, Li Y, Sharif M. Models of osteoarthritis: the good, the bad and the promising. Osteoarthr Cartil. 2019;27(2):230–9. https://doi.org/10.1016/j.joca.2018.09.016.

    Article  CAS  Google Scholar 

  50. McCoy AM. Animal models of osteoarthritis: comparisons and key considerations. Vet Pathol. 2015;52(5):803–18. https://doi.org/10.1177/0300985815588611.

    Article  CAS  Google Scholar 

  51. Bapat S, Hubbard D, Munjal A, Hunter M, Fulzele S. Pros and cons of mouse models for studying osteoarthritis. Clin Transl Med. 2018;7(1):36. https://doi.org/10.1186/s40169-018-0215-4.

    Article  Google Scholar 

  52. Kuyinu EL, Narayanan G, Nair LS, Laurencin CT. Animal models of osteoarthritis: classification, update, and measurement of outcomes. J Orthop Surg. 2016;11(1):19. https://doi.org/10.1186/s13018-016-0346-5.

    Article  Google Scholar 

  53. Leijten JCH, Georgi N, Wu L, van Blitterswijk CA, Karperien M. Cell sources for articular cartilage repair strategies: shifting from monocultures to cocultures. Tissue Eng Part B Rev. 2013;19(1):31–40. https://doi.org/10.1089/ten.teb.2012.0273.

    Article  CAS  Google Scholar 

  54. Caplan AI. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol. 2007;213(2):341–7. https://doi.org/10.1002/jcp.21200.

    Article  CAS  Google Scholar 

  55. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45(11):e54. https://doi.org/10.1038/emm.2013.94.

    Article  CAS  Google Scholar 

  56. Jin H, Bae Y, Kim M, Kwon SJ, Jeon H, Choi S, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013;14(9):17986–8001. https://doi.org/10.3390/ijms140917986.

    Article  Google Scholar 

  57. Wu M, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8(1):5014. https://doi.org/10.1038/s41598-018-23396-1.

    Article  CAS  Google Scholar 

  58. Koyama N, Okubo Y, Nakao K, Osawa K, Fujimura K, Bessho K. Pluripotency of mesenchymal cells derived from synovial fluid in patients with temporomandibular joint disorder. Life Sci. 2011;89(19–20):741–7. https://doi.org/10.1016/j.lfs.2011.09.005.

    Article  CAS  Google Scholar 

  59. Heo JS, Choi Y, Kim H-S, Kim HO. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int J Mol Med. 2016;37(1):115–25. https://doi.org/10.3892/ijmm.2015.2413.

    Article  Google Scholar 

  60. Dominici M, le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. https://doi.org/10.1080/14653240600855905.

  61. 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(3):399–410. https://doi.org/10.1007/s00441-019-03069-9.

    Article  Google Scholar 

  62. Pittenger MF. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7. https://doi.org/10.1126/science.284.5411.143.

    Article  CAS  Google Scholar 

  63. Kasir R, Vernekar VN, Laurencin CT. Regenerative engineering of cartilage using adipose-derived stem cells. Regen Eng Transl Med. 2015;1(1–4):42–9. https://doi.org/10.1007/s40883-015-0005-0.

    Article  Google Scholar 

  64. Mohamed-Ahmed S, et al. Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res Ther. 2018;9(1):168. https://doi.org/10.1186/s13287-018-0914-1.

    Article  CAS  Google Scholar 

  65. Mei L, et al. Culture-expanded allogenic adipose tissue-derived stem cells attenuate cartilage degeneration in an experimental rat osteoarthritis model. PLoS One. 2017;12(4):e0176107. https://doi.org/10.1371/journal.pone.0176107.

    Article  CAS  Google Scholar 

  66. Desando G, et al. Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. Arthritis Res Ther. 2013;15(1):R22. https://doi.org/10.1186/ar4156.

    Article  CAS  Google Scholar 

  67. Sato M, et al. Direct transplantation of mesenchymal stem cells into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis Res Ther. 2012;14(1):R31. https://doi.org/10.1186/ar3735.

    Article  CAS  Google Scholar 

  68. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48(12):3464–74. https://doi.org/10.1002/art.11365.

    Article  Google Scholar 

  69. Ude CC, et al. Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model. PLoS One. 2014;9(6):e98770. https://doi.org/10.1371/journal.pone.0098770.

    Article  CAS  Google Scholar 

  70. Al Faqeh H, Nor Hamdan BMY, Chen HC, Aminuddin BS, Ruszymah BHI. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012;47(6):458–64. https://doi.org/10.1016/j.exger.2012.03.018.

    Article  Google Scholar 

  71. Lee KBL, Hui JHP, Song IC, Ardany L, Lee EH. Injectable mesenchymal stem cell therapy for large cartilage defects-a porcine model. Stem Cells. 2007;25(11):2964–71. https://doi.org/10.1634/stemcells.2006-0311.

    Article  Google Scholar 

  72. Frisbie DD, Kisiday JD, Kawcak CE, Werpy NM, McIlwraith CW. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. J Orthop Res. 2009;27(12):1675–80. https://doi.org/10.1002/jor.20933.

    Article  Google Scholar 

  73. Segawa Y, Muneta T, Makino H, Nimura A, Mochizuki T, Ju YJ, et al. Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profiles. J Orthop Res. 2009;27(4):435–41. https://doi.org/10.1002/jor.20786.

  74. Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005;52(8):2521–9. https://doi.org/10.1002/art.21212.

    Article  Google Scholar 

  75. Morito T, Muneta T, Hara K, Ju YJ, Mochizuki T, Makino H, et al. Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology. 2008;47(8):1137–43. https://doi.org/10.1093/rheumatology/ken114.

  76. Sekiya I, Ojima M, Suzuki S, Yamaga M, Horie M, Koga H, et al. Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J Orthop Res. 2012;30(6):943–9. https://doi.org/10.1002/jor.22029.

  77. Neybecker P, et al. In vitro and in vivo potentialities for cartilage repair from human advanced knee osteoarthritis synovial fluid-derived mesenchymal stem cells. Stem Cell Res Ther. 2018;9(1):329. https://doi.org/10.1186/s13287-018-1071-2.

  78. Ozeki N, Muneta T, Koga H, Nakagawa Y, Mizuno M, Tsuji K, et al. Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthr Cartil. 2016;24(6):1061–70. https://doi.org/10.1016/j.joca.2015.12.018.

  79. Hatsushika D, Muneta T, Nakamura T, Horie M, Koga H, Nakagawa Y, et al. Repetitive allogeneic intraarticular injections of synovial mesenchymal stem cells promote meniscus regeneration in a porcine massive meniscus defect model. Osteoarthr Cartil. 2014;22(7):941–50. https://doi.org/10.1016/j.joca.2014.04.028.

    Article  CAS  Google Scholar 

  80. Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9(1):12. https://doi.org/10.1186/1478-811X-9-12.

    Article  CAS  Google Scholar 

  81. Contentin R, Demoor M, Concari M, Desancé M, Audigié 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. https://doi.org/10.1007/s12015-019-09914-2.

  82. Wu K-C, Chang Y-H, Liu H-W, Ding D-C. Transplanting human umbilical cord mesenchymal stem cells and hyaluronate hydrogel repairs cartilage of osteoarthritis in the minipig model. Tzu Chi Med J. 2019;31(1):11. https://doi.org/10.4103/tcmj.tcmj_87_18.

    Article  CAS  Google Scholar 

  83. Trounson A, DeWitt ND. Pluripotent stem cells progressing to the clinic. Nat Rev Mol Cell Biol. 2016;17(3):194–200. https://doi.org/10.1038/nrm.2016.10.

    Article  CAS  Google Scholar 

  84. Tabar V, Studer L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet. 2014;15(2):82–92. https://doi.org/10.1038/nrg3563.

    Article  CAS  Google Scholar 

  85. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292(5819):154–6. https://doi.org/10.1038/292154a0.

    Article  CAS  Google Scholar 

  86. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci. 1981;78(12):7634–8. https://doi.org/10.1073/pnas.78.12.7634.

    Article  CAS  Google Scholar 

  87. Thomson JA. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7. https://doi.org/10.1126/science.282.5391.1145.

    Article  CAS  Google Scholar 

  88. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. https://doi.org/10.1016/j.cell.2006.07.024.

    Article  CAS  Google Scholar 

  89. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. https://doi.org/10.1016/j.cell.2007.11.019.

  90. Martin U. Therapeutic application of pluripotent stem cells: challenges and risks. Front Med. 2017;4:229. https://doi.org/10.3389/fmed.2017.00229.

    Article  Google Scholar 

  91. Wakitani S, Aoki H, Harada Y, Sonobe M, Morita Y, Mu Y, et al. Embryonic stem cells form articular cartilage, not teratomas, in osteochondral defects of rat joints. Cell Transplant. 2004;13(4):331–6. https://doi.org/10.3727/000000004783983891.

  92. Saito T, et al. Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells. Biomed Res. 2015;36(3):179–86. https://doi.org/10.2220/biomedres.36.179.

    Article  Google Scholar 

  93. Manunta A, et al. The use of embryonic cells in the treatment of osteochondral defects of the knee: an ovine in vivo study. Joints. 2016;04(02):070–9. https://doi.org/10.11138/jts/2016.4.2.070.

    Article  Google Scholar 

  94. 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(3):343–53.

  95. 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(6):900–8. https://doi.org/10.1016/j.mehy.2008.06.042.

    Article  CAS  Google Scholar 

  96. Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, et al. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 2012;15(7):422–8.

  97. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. preliminary report of four patients: mesenchymal stem cell therapy for knee osteoarthritis. Int J Rheum Dis. 2011;14(2):211–5. https://doi.org/10.1111/j.1756-185X.2011.01599.x.

    Article  Google Scholar 

  98. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transp J. 2013;95(12):1535–41. https://doi.org/10.1097/TP.0b013e318291a2da.

  99. Soler R, Orozco L, Munar A, Huguet M, López R, Vives J, et al. Final results of a phase I–II trial using ex vivo expanded autologous mesenchymal stromal cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee. 2016;23(4):647–54. https://doi.org/10.1016/j.knee.2015.08.013.

  100. Koh Y-G, Choi Y-J, Kwon S-K, Kim Y-S, Yeo J-E. Clinical results and second-look arthroscopic findings after treatment with adipose-derived stem cells for knee osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2015;23(5):1308–16. https://doi.org/10.1007/s00167-013-2807-2.

    Article  Google Scholar 

  101. Schiavone Panni A, Vasso M, Braile A, Toro G, de Cicco A, Viggiano D, et al. Preliminary results of autologous adipose-derived stem cells in early knee osteoarthritis: identification of a subpopulation with greater response. Int Orthop. 2019;43(1):7–13. https://doi.org/10.1007/s00264-018-4182-6.

  102. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial: IA injection of MSCs for knee osteoarthritis. Stem Cells. 2014;32(5):1254–66. https://doi.org/10.1002/stem.1634.

  103. Freitag J, Bates D, Wickham J, Shah K, Huguenin L, Tenen A, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14(3):213–30. https://doi.org/10.2217/rme-2018-0161.

  104. Emadedin M, Ghorbani Liastani M, Fazeli R, Mohseni F, Moghadasali R, Mardpour S, et al. Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, ankle, or hip osteoarthritis. Arch Iran Med. 2015;18(6):336–44.

    Google Scholar 

  105. Lamo-Espinosa JM, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016;14(1):246. https://doi.org/10.1186/s12967-016-0998-2.

    Article  CAS  Google Scholar 

  106. Garay-Mendoza D, Villarreal-Martínez L, Garza-Bedolla A, Pérez-Garza DM, Acosta-Olivo C, Vilchez-Cavazos F, et al. The effect of intra-articular injection of autologous bone marrow stem cells on pain and knee function in patients with osteoarthritis. Int J Rheum Dis. 2018;21(1):140–7. https://doi.org/10.1111/1756-185X.13139.

  107. Al-Najar M, et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. J Orthop Surg. 2017;12(1):190. https://doi.org/10.1186/s13018-017-0689-6.

    Article  Google Scholar 

  108. Vega A, Martín-Ferrero MA, del Canto F, Alberca M, García V, Munar A, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681–90. https://doi.org/10.1097/TP.0000000000000678.

  109. Gupta PK, et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016;18(1):301. https://doi.org/10.1186/s13075-016-1195-7.

    Article  Google Scholar 

  110. Jo CH, Chai JW, Jeong EC, Oh S, Shin JS, Shim H, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study. Am J Sports Med. 2017;45(12):2774–83. https://doi.org/10.1177/0363546517716641.

  111. Pers Y-M, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial: ASCs for severe OA of the knee. Stem Cells Transl Med. 2016;5(7):847–56. https://doi.org/10.5966/sctm.2015-0245.

  112. Koh Y-G, Choi Y-J. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 2012;19(6):902–7. https://doi.org/10.1016/j.knee.2012.04.001.

    Article  Google Scholar 

  113. Koh YG, Choi YJ, Kwon OR, Kim YS. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am J Sports Med. 2014;42(7):1628–37. https://doi.org/10.1177/0363546514529641.

    Article  Google Scholar 

  114. 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. Arthrosc J Arthrosc Relat Surg. 2016;32(5):878–89. https://doi.org/10.1016/j.arthro.2016.01.020.

    Article  Google Scholar 

  115. Kim YS, Lee HJ, Choi YJ, Kim YI, Koh YG. Does an injection of a stromal vascular fraction containing adipose-derived mesenchymal stem cells influence the outcomes of marrow stimulation in osteochondral lesions of the talus?: a clinical and magnetic resonance imaging study. Am J Sports Med. 2014;42(10):2424–34. https://doi.org/10.1177/0363546514541778.

    Article  Google Scholar 

  116. Kim YS, Choi YJ, Koh YG. Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes. Am J Sports Med. 2015;43(9):2293–301. https://doi.org/10.1177/0363546515588317.

    Article  Google Scholar 

  117. Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I. Mesenchymal stem cell-based therapy for cartilage repair: a review. Knee Surg Sports Traumatol Arthrosc. 2009;17(11):1289–97. https://doi.org/10.1007/s00167-009-0782-4.

    Article  Google Scholar 

  118. 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(1):74–9. https://doi.org/10.1002/term.8.

    Article  Google Scholar 

  119. Vinardell T, Sheehy EJ, Buckley CT, Kelly DJ. A comparison of the functionality and in vivo phenotypic stability of cartilaginous tissues engineered from different stem cell sources. Tissue Eng Part A. 2012;18(11–12):1161–70. https://doi.org/10.1089/ten.tea.2011.0544.

    Article  CAS  Google Scholar 

  120. Yong S-B, Chung JY, Song Y, Kim Y-H. Recent challenges and advances in genetically-engineered cell therapy. J Pharm Investig. 2018;48(2):199–208. https://doi.org/10.1007/s40005-017-0381-1.

    Article  CAS  Google Scholar 

  121. Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911. https://doi.org/10.1038/s41467-018-04252-2.

    Article  CAS  Google Scholar 

  122. Mahboudi H, Soleimani M, Enderami SE, Kehtari M, Ardeshirylajimi A, Eftekhary M, et al. Enhanced chondrogenesis differentiation of human induced pluripotent stem cells by MicroRNA-140 and transforming growth factor beta 3 (TGFβ3). Biologicals. 2018;52:30–6. https://doi.org/10.1016/j.biologicals.2018.01.005.

  123. Matsumoto T, Cooper GM, Gharaibeh B, Meszaros LB, Li G, Usas A, et al. Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble flt-1. Arthritis Rheum. 2009;60(5):1390–405. https://doi.org/10.1002/art.24443.

  124. Peng B-Y, et al. Non-invasive in vivo molecular imaging of intra-articularly transplanted immortalized bone marrow stem cells for osteoarthritis treatment. Oncotarget. 2017;8(57):97153–64. https://doi.org/10.18632/oncotarget.21315.

    Article  Google Scholar 

  125. Noh MJ, Copeland RO, Yi Y, Choi KB, Meschter C, Hwang S, et al. Pre-clinical studies of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 (TG-C). Cytotherapy. 2010;12(3):384–93. https://doi.org/10.3109/14653240903470639.

  126. Ha C-W, Noh MJ, Choi KB, Lee KH. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy. 2012;14(2):247–56. https://doi.org/10.3109/14653249.2011.629645.

    Article  CAS  Google Scholar 

  127. Lee MC, Ha CW, Elmallah RK, Cherian JJ, Cho JJ, Kim TW, et al. A placebo-controlled randomised trial to assess the effect of TGF-ß1-expressing chondrocytes in patients with arthritis of the knee. Bone Jt J. 2015;97-B(7):924–32. https://doi.org/10.1302/0301-620X.97B7.35852.

  128. Kim M-K, Ha CW, in Y, Cho SD, Choi ES, Ha JK, et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum Gene Ther Clin Dev. 2018;29(1):48–59. https://doi.org/10.1089/humc.2017.249.

  129. Roseti L, Desando G, Cavallo C, Petretta M, Grigolo B. Articular cartilage regeneration in osteoarthritis. Cells. 2019;8(11):1305. https://doi.org/10.3390/cells8111305.

    Article  CAS  Google Scholar 

  130. Dicks A, Wu C-L, Steward N, Adkar SS, Gersbach CA, Guilak F. Prospective isolation of chondroprogenitors from human iPSCs based on cell surface markers identified using a CRISPR-Cas9-generated reporter. Stem Cell Res Ther. 2020;11(1):66. https://doi.org/10.1186/s13287-020-01597-8.

    Article  CAS  Google Scholar 

  131. Li X, Guo W, Zha K, Jing X, Wang M, Zhang Y, et al. Enrichment of CD146 + adipose-derived stem cells in combination with articular cartilage extracellular matrix scaffold promotes cartilage regeneration. Theranostics. 2019;9(17):5105–21. https://doi.org/10.7150/thno.33904.

  132. Madry H, Cucchiarini M. Gene therapy for human osteoarthritis: principles and clinical translation. Expert Opin Biol Ther. 2016;16(3):331–46. https://doi.org/10.1517/14712598.2016.1124084.

    Article  CAS  Google Scholar 

  133. Jia Z, et al. Repair of articular cartilage defects with intra-articular injection of autologous rabbit synovial fluid-derived mesenchymal stem cells. J Transl Med. 2018;16(1):123. https://doi.org/10.1186/s12967-018-1485-8.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Connecticut Convergence Institute for Translation in Regenerative Engineering, University of Connecticut Health, Farmington, CT, USA

    Shiv Shah, Takayoshi Otsuka, Maumita Bhattacharjee & Cato T. Laurencin

  2. Raymond and Beverly Sackler Center for Biomedical, Biological, Physical and Engineering Sciences, The University of Connecticut Health, 263 Farmington Ave, Farmington, CT, 06030, USA

    Shiv Shah, Takayoshi Otsuka, Maumita Bhattacharjee & Cato T. Laurencin

  3. Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT, USA

    Shiv Shah, Takayoshi Otsuka, Maumita Bhattacharjee & Cato T. Laurencin

  4. Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT, USA

    Shiv Shah & Cato T. Laurencin

  5. Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA

    Cato T. Laurencin

  6. Department of Materials Science and Engineering, University of Connecticut, Storrs, CT, USA

    Cato T. Laurencin

  7. Institute of Materials Science, University of Connecticut, Storrs, CT, USA

    Cato T. Laurencin

  8. Department of Craniofacial Sciences, School of Dental Medicine, University of Connecticut Health, Farmington, CT, USA

    Cato T. Laurencin

Authors
  1. Shiv Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takayoshi Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maumita Bhattacharjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cato T. Laurencin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cato T. Laurencin.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shah, S., Otsuka, T., Bhattacharjee, M. et al. Minimally Invasive Cellular Therapies for Osteoarthritis Treatment. Regen. Eng. Transl. Med. 7, 76–90 (2021). https://doi.org/10.1007/s40883-020-00184-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40883-020-00184-w

Keywords

Search

Navigation