Intra-articular treatment options for knee osteoarthritis

Abstract

Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called ‘stem’ cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks.

Key points

  • The cost and unclear effectiveness of hyaluronic acid and glucocorticoids have raised concerns over their broad use for osteoarthritis (OA)-related knee pain.

  • Self-reported parameters such as pain and stiffness are particularly responsive to intra-articular placebo, which poses challenges when attempting to ascribe clinical meaning to therapeutic interventions.

  • Estimates of the minimal (clinically) important difference for patient-reported outcomes can provide useful pretext when appraising the effectiveness of intra-articular therapies.

  • Lack of data, study heterogeneity and methodological limitations hinder our understanding of point-of-care injectable cell therapies such as platelet-rich plasma, bone marrow aspirate concentrate and adipose tissue-derived treatments.

  • The generally positive efficacy conclusions concerning mesenchymal ‘stem’ cell therapy for knee cartilage pathology might be overstated owing to selective outcome reporting.

  • A number of intra-articular therapeutic candidates for OA are currently in clinical development, including small-molecule therapies, biologic therapies, gene therapies and novel devices.

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Fig. 1: Intra-articular treatments for osteoarthritis.
Fig. 2: Intra-articular cell therapies.
Fig. 3: Intra-articular osteoarthritis therapy pipeline.

References

  1. 1.

    Sinusas, K. Osteoarthritis: diagnosis and treatment. Am. Fam. Physician 85, 49–56 (2012).

    PubMed  Google Scholar 

  2. 2.

    Liu-Bryan, R. Synovium and the innate inflammatory network in osteoarthritis progression. Curr. Rheumatol Rep. 15, 323 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Haseeb, A. & Haqqi, T. M. Immunopathogenesis of osteoarthritis. Clin. Immunol. 146, 185–196 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Aigner, T., Söder, S., Gebhard, P. M., McAlinden, A. & Haag, J. Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis — structure, chaos and senescence. Nat. Clin. Pract. Rheumatol. 3, 391–399 (2007).

    CAS  PubMed  Google Scholar 

  5. 5.

    Chevalier, X., Eymard, F. & Richette, P. Biologic agents in osteoarthritis: hopes and disappointments. Nat. Rev. Rheumatol. 9, 400–410 (2013).

    CAS  PubMed  Google Scholar 

  6. 6.

    Lories, R. J. & Luyten, F. P. The bone–cartilage unit in osteoarthritis. Nat. Rev. Rheumatol. 7, 43–49 (2011).

    CAS  Google Scholar 

  7. 7.

    Emami, A. et al. Toxicology evaluation of drugs administered via uncommon routes: intranasal, intraocular, intrathecal/intraspinal, and intra-articular. Int. J. Toxicol. 37, 4–27 (2018).

    CAS  PubMed  Google Scholar 

  8. 8.

    Evans, C. H., Kraus, V. B. & Setton, L. A. Progress in intra-articular therapy. Nat. Rev. Rheumatol. 10, 11–22 (2014).

    CAS  PubMed  Google Scholar 

  9. 9.

    Rousseau, J.-C. & Delmas, P. D. Biological markers in osteoarthritis. Nat. Clin. Pract. Rheumatol. 3, 346–356 (2007).

    CAS  PubMed  Google Scholar 

  10. 10.

    Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010).

    CAS  PubMed  Google Scholar 

  12. 12.

    Maudens, P., Jordan, O. & Allémann, E. Recent advances in intra-articular drug delivery systems for osteoarthritis therapy. Drug Discov. Today 23, 1761–1775 (2018).

    CAS  PubMed  Google Scholar 

  13. 13.

    Miller, R. E., Block, J. A. & Malfait, A.-M. What is new in pain modification in osteoarthritis? Rheumatology 58, 26 (2018).

    Google Scholar 

  14. 14.

    Nelson, A. E., Allen, K. D., Golightly, Y. M., Goode, A. P. & Jordan, J. M. A systematic review of recommendations and guidelines for the management of osteoarthritis: the chronic osteoarthritis management initiative of the U.S. bone and joint initiative. Semin. Arthritis Rheum. 43, 701–712 (2014).

    PubMed  Google Scholar 

  15. 15.

    Nguyen, C., Lefèvre-Colau, M.-M., Poiraudeau, S. & Rannou, F. Evidence and recommendations for use of intra-articular injections for knee osteoarthritis. Ann. Phys. Rehabil. Med. 59, 184–189 (2016).

    PubMed  Google Scholar 

  16. 16.

    Gerwin, N., Hops, C. & Lucke, A. Intraarticular drug delivery in osteoarthritis. Adv. Drug Deliv. Rev. 58, 226–242 (2006).

    CAS  PubMed  Google Scholar 

  17. 17.

    Habib, G. S. Systemic effects of intra-articular corticosteroids. Clin. Rheumatol. 28, 749–756 (2009).

    PubMed  Google Scholar 

  18. 18.

    Jackson, D. W., Evans, N. A. & Thomas, B. M. Accuracy of needle placement into the intra-articular space of the knee. J. Bone Joint Surg. Am. 84, 1522–1527 (2002).

    PubMed  Google Scholar 

  19. 19.

    Larsen, C. et al. Intra-articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J. Pharm. Sci. 97, 4622–4654 (2008).

    CAS  PubMed  Google Scholar 

  20. 20.

    Bannuru, R. R., Natov, N. S., Dasi, U. R., Schmid, C. H. & McAlindon, T. E. Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis — meta-analysis. Osteoarthr. Cartil. 19, 611–619 (2011).

    CAS  PubMed  Google Scholar 

  21. 21.

    Rosseland, L. A., Helgesen, K. G., Breivik, H. & Stubhaug, A. Moderate-to-severe pain after knee arthroscopy is relieved by intraarticular saline: a randomized controlled trial. Anesth. Analg. 98, 1546–1551 (2004).

    CAS  PubMed  Google Scholar 

  22. 22.

    Abhishek, A. & Doherty, M. Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthr. Cartil. 21, 1229–1235 (2013).

    CAS  PubMed  Google Scholar 

  23. 23.

    Bannuru, R. R. et al. Effectiveness and implications of alternative placebo treatments: a systematic review and network meta-analysis of osteoarthritis trials. Ann. Intern. Med. 163, 365–372 (2015).

    PubMed  Google Scholar 

  24. 24.

    Kirwan, J. R. & Rankin, E. Intra-articular therapy in osteoarthritis. Baillieres Clin. Rheumatol 11, 769–794 (1997).

    CAS  PubMed  Google Scholar 

  25. 25.

    Hameed, F. & Ihm, J. Injectable medications for osteoarthritis. PM R. 4, S75–S81 (2012).

    PubMed  Google Scholar 

  26. 26.

    Saltzman, B. M. et al. The therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: a meta-analysis of evidence level 1 studies. Am. J. Sports Med. 45, 2647–2653 (2017).

    PubMed  Google Scholar 

  27. 27.

    Sullivan, G. M. & Feinn, R. Using effect size — or why the P value is not enough. J. Grad. Med. Educ. 4, 279–282 (2012).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Jaeschke, R., Singer, J. & Guyatt, G. H. Measurement of health status: ascertaining the minimal clinically important difference. Control. Clin. Trials 10, 407–415 (1989).

    CAS  PubMed  Google Scholar 

  29. 29.

    Redelmeier, D. A. & Lorig, K. Assessing the clinical importance of symptomatic improvements. An illustration in rheumatology. Arch. Intern. Med. 153, 1337–1342 (1993).

    CAS  PubMed  Google Scholar 

  30. 30.

    Angst, F., Aeschlimann, A. & Angst, J. The minimal clinically important difference raised the significance of outcome effects above the statistical level, with methodological implications for future studies. J. Clin. Epidemiol. 82, 128–136 (2017).

    PubMed  Google Scholar 

  31. 31.

    McGlothlin, A. E. & Lewis, R. J. Minimal clinically important difference: defining what really matters to patients. JAMA 312, 1342–1343 (2014).

    CAS  PubMed  Google Scholar 

  32. 32.

    Devji, T. et al. Application of minimal important differences in degenerative knee disease outcomes: a systematic review and case study to inform BMJ Rapid Recommendations. BMJ Open 7, e015587 (2017).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Dworkin, R. H. et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J. Pain 9, 105–121 (2008).

    PubMed  Google Scholar 

  34. 34.

    Copay, A. G., Subach, B. R., Glassman, S. D., Polly, D. W. & Schuler, T. C. Understanding the minimum clinically important difference: a review of concepts and methods. Spine J. 7, 541–546 (2007).

    PubMed  Google Scholar 

  35. 35.

    King, M. T. A point of minimal important difference (MID): a critique of terminology and methods. Expert Rev. Pharmacoecon Outcomes Res. 11, 171–184 (2011).

    PubMed  Google Scholar 

  36. 36.

    Wright, A., Hannon, J., Hegedus, E. J. & Kavchak, A. E. Clinimetrics corner: a closer look at the minimal clinically important difference (MCID). J. Man. Manip. Ther. 20, 160–166 (2012).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Cook, C. E. Clinimetrics corner: the minimal clinically important change score (MCID): a necessary pretense. J. Man. Manip. Ther. 16, E82–E83 (2008).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Revicki, D., Hays, R. D., Cella, D. & Sloan, J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J. Clin. Epidemiol. 61, 102–109 (2008).

    PubMed  Google Scholar 

  39. 39.

    Bedard, N. A. et al. Impact of clinical practice guidelines on use of intra-articular hyaluronic acid and corticosteroid injections for knee osteoarthritis. J. Bone Joint Surg. Am. 100, 827–834 (2018).

    PubMed  Google Scholar 

  40. 40.

    Migliore, A. et al. The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap! Eur. Rev. Med. Pharmacol. Sci. 19, 1124–1129 (2015).

    CAS  PubMed  Google Scholar 

  41. 41.

    Jevsevar, D. S. et al. The American Academy of Orthopaedic Surgeons evidence-based guideline on: treatment of osteoarthritis of the knee, 2nd edition. J. Bone Joint Surg. Am. 95, 1885–1886 (2013).

    PubMed  Google Scholar 

  42. 42.

    Chao, J. et al. Inflammatory characteristics on ultrasound predict poorer longterm response to intraarticular corticosteroid injections in knee osteoarthritis. J. Rheumatol. 37, 650–655 (2010).

    CAS  PubMed  Google Scholar 

  43. 43.

    Gaffney, K., Ledingham, J. & Perry, J. D. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response. Ann. Rheum. Dis. 54, 379–381 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Raynauld, J.-P. et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 48, 370–377 (2003).

    CAS  PubMed  Google Scholar 

  45. 45.

    Jones, A. & Doherty, M. Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Ann. Rheum. Dis. 55, 829–832 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Caborn, D. et al. A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee. J. Rheumatol. 31, 333–343 (2004).

    CAS  PubMed  Google Scholar 

  47. 47.

    Arden, N. K. et al. A randomised controlled trial of tidal irrigation versus corticosteroid injection in knee osteoarthritis: the KIVIS Study. Osteoarthr. Cartil. 16, 733–739 (2008).

    CAS  PubMed  Google Scholar 

  48. 48.

    McAlindon, T. E. et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr. Cartil. 22, 363–388 (2014).

    CAS  PubMed  Google Scholar 

  49. 49.

    Bannuru, R. R. et al. Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum. 61, 1704–1711 (2009).

    CAS  PubMed  Google Scholar 

  50. 50.

    Bellamy, N. et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst. Rev. 2, CD005328 (2006).

    Google Scholar 

  51. 51.

    Jüni, P. et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst. Rev. 10, CD005328 (2015).

    Google Scholar 

  52. 52.

    National Institute for Health and Care Excellence. Osteoarthritis: Care and Management in Adults (NICE, 2014).

  53. 53.

    Hochberg, M. C. et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 64, 465–474 (2012).

    CAS  Google Scholar 

  54. 54.

    Wernecke, C., Braun, H. J. & Dragoo, J. L. The effect of intra-articular corticosteroids on articular cartilage: a systematic review. Orthop. J. Sports Med. 3, 2325967115581163 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Bedard, N. A. et al. The John N. Insall Award: do intraarticular injections increase the risk of infection after TKA? Clin. Orthop. Relat. Res. 475, 45–52 (2017).

    PubMed  Google Scholar 

  56. 56.

    McAlindon, T. E. et al. Effect of intra-articular triamcinolone versus saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 317, 1967–1975 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Cicuttini, F. M., Jones, G., Forbes, A. & Wluka, A. E. Rate of cartilage loss at two years predicts subsequent total knee arthroplasty: a prospective study. Ann. Rheum. Dis. 63, 1124–1127 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Hitzl, W. et al. Greater lateral femorotibial cartilage loss in osteoarthritis initiative participants with incident total knee arthroplasty: a prospective cohort study. Arthritis Care Res. 67, 1481–1486 (2015).

    Google Scholar 

  59. 59.

    Bannuru, R. R., Vaysbrot, E. E. & McIntyre, L. F. Did the American Academy of Orthopaedic Surgeons osteoarthritis guidelines miss the mark? Arthroscopy 30, 86–89 (2014).

    PubMed  Google Scholar 

  60. 60.

    Carlson, V. R. et al. Compliance with the AAOS guidelines for treatment of osteoarthritis of the knee: a survey of the American Association of Hip and Knee Surgeons. J. Am. Acad. Orthop. Surg. 26, 103–107 (2018).

    PubMed  Google Scholar 

  61. 61.

    Rutjes, A. W. S. et al. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann. Intern. Med. 157, 180–191 (2012).

    PubMed  Google Scholar 

  62. 62.

    Bellamy, N. et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst. Rev. 3, CD005321 (2006).

    Google Scholar 

  63. 63.

    Jevsevar, D., Donnelly, P., Brown, G. A. & Cummins, D. S. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J. Bone Joint Surg. Am. 97, 2047–2060 (2015).

    PubMed  Google Scholar 

  64. 64.

    Vannabouathong, C. et al. Nonoperative treatments for knee osteoarthritis: an evaluation of treatment characteristics and the intra-articular placebo effect: a systematic review. JBJS Rev. 6, e5 (2018).

    PubMed  Google Scholar 

  65. 65.

    Kapoor, M., Martel-Pelletier, J., Lajeunesse, D., Pelletier, J.-P. & Fahmi, H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol. 7, 33–42 (2011).

    CAS  PubMed  Google Scholar 

  66. 66.

    Martel-Pelletier, J. Pathophysiology of osteoarthritis. Osteoarthr. Cartil. 6, 374–376 (1998).

    CAS  PubMed  Google Scholar 

  67. 67.

    Ashraf, S. et al. Regulation of senescence associated signaling mechanisms in chondrocytes for cartilage tissue regeneration. Osteoarthr. Cartil. 24, 196–205 (2016).

    CAS  PubMed  Google Scholar 

  68. 68.

    Pettipher, E. R., Higgs, G. A. & Henderson, B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc. Natl Acad. Sci. USA 83, 8749–8753 (1986).

    CAS  PubMed  Google Scholar 

  69. 69.

    Kato, T. et al. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res. Ther. 16, R163 (2014).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Jacques, C., Gosset, M., Berenbaum, F. & Gabay, C. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation. Vitam. Horm. 74, 371–403 (2006).

    CAS  PubMed  Google Scholar 

  71. 71.

    Chevalier, X. et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 61, 344–352 (2009).

    CAS  PubMed  Google Scholar 

  72. 72.

    Kraus, V. B. et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthr. Cartil. 20, 271–278 (2012).

    CAS  PubMed  Google Scholar 

  73. 73.

    Goldring, S. R. & Goldring, M. B. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin. Orthop. Relat. Res. 427, S27–S36 (2004).

    Google Scholar 

  74. 74.

    Stannus, O. et al. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthr. Cartil. 18, 1441–1447 (2010).

    CAS  PubMed  Google Scholar 

  75. 75.

    Malfait, A. M. et al. Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation. Osteoarthr. Cartil. 17, 627–635 (2009).

    CAS  PubMed  Google Scholar 

  76. 76.

    Lindsley, H. B. et al. Treatment of knee osteoarthritis with intra-articular infliximab improves total WOMAC score. High baseline levels of synovial cellularity predict improvement [abstract FRI0304]. Ann. Rheum. Dis. 71 (Suppl. 3), 417 (2014).

    Google Scholar 

  77. 77.

    Ohtori, S. et al. Efficacy of direct injection of etanercept into knee joints for pain in moderate and severe knee osteoarthritis. Yonsei Med. J. 56, 1379 (2015).

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Wang, J. Efficacy and safety of adalimumab by intra-articular injection for moderate to severe knee osteoarthritis: an open-label randomized controlled trial. J. Int. Med. Res. 46, 326–334 (2018).

    CAS  PubMed  Google Scholar 

  79. 79.

    Hunter, D. J. et al. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet. Disord. 11, 232 (2010).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Lohmander, L. S. et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 66, 1820–1831 (2014).

    CAS  PubMed  Google Scholar 

  81. 81.

    Hall, M. P., Band, P. A., Meislin, R. J., Jazrawi, L. M. & Cardone, D. A. Platelet-rich plasma: current concepts and application in sports medicine. J. Am. Acad. Orthop. Surg. 17, 602–608 (2009).

    PubMed  Google Scholar 

  82. 82.

    Hsu, W. K. et al. Platelet-rich plasma in orthopaedic applications: evidence-based recommendations for treatment. J. Am. Acad. Orthop. Surg. 21, 739–471 (2013).

    PubMed  Google Scholar 

  83. 83.

    Andia, I. & Maffulli, N. Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat. Rev. Rheumatol. 9, 721–730 (2013).

    CAS  PubMed  Google Scholar 

  84. 84.

    Gutman, S. I. 510(k) summary: 3i CelSep centrifuge system. FDA https://www.accessdata.fda.gov/cdrh_docs/pdf/K994148.pdf (2000).

  85. 85.

    Melkerson, M. N. 510(k) summary. FDA https://www.accessdata.fda.gov/cdrh_docs/pdf8/K082333.pdf (2009).

  86. 86.

    Vaught, M. S. & Cole, B. J. Coding and reimbursement issues for platelet-rich plasma. Oper. Tech. Sports Med. 19, 185–189 (2011).

    Google Scholar 

  87. 87.

    Jones, I. A., Togashi, R. C. & Vangsness, C. T. The economics and regulation of PRP in the evolving field of orthopedic biologics. Curr. Rev. Musculoskelet. Med. 17, 602–608 (2018).

    Google Scholar 

  88. 88.

    Dhillon, R. S., Schwarz, E. M. & Maloney, M. D. Platelet-rich plasma therapy - future or trend? Arthritis Res. Ther. 14, 219 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Beitzel, K. et al. US definitions, current use, and FDA stance on use of platelet-rich plasma in sports medicine. J. Knee Surg. 28, 29–34 (2015).

    PubMed  Google Scholar 

  90. 90.

    Chahla, J. et al. A call for standardization in platelet-rich plasma preparation protocols and composition reporting: a systematic review of the clinical orthopaedic literature. J. Bone Joint Surg. Am. 99, 1769–1779 (2017).

    PubMed  Google Scholar 

  91. 91.

    Chen, X., Jones, I. A., Park, C. & Vangsness, C. T. The efficacy of platelet-rich plasma on tendon and ligament healing: a systematic review and meta-analysis with bias assessment. Am. J. Sports Med. 2016, 363546517743746 (2017).

    Google Scholar 

  92. 92.

    Khoshbin, A. et al. The efficacy of platelet-rich plasma in the treatment of symptomatic knee osteoarthritis: a systematic review with quantitative synthesis. Arthroscopy 29, 2037–2048 (2013).

    PubMed  Google Scholar 

  93. 93.

    Kanchanatawan, W. et al. Short-term outcomes of platelet-rich plasma injection for treatment of osteoarthritis of the knee. Knee Surg. Sports Traumatol. Arthrosc. 24, 1665–1677 (2016).

    PubMed  Google Scholar 

  94. 94.

    Tubach, F. et al. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann. Rheum. Dis. 64, 29–33 (2005).

    CAS  PubMed  Google Scholar 

  95. 95.

    Escobar, A. et al. Responsiveness and clinically important differences for the WOMAC and SF-36 after total knee replacement. Osteoarthr. Cartil. 15, 273–280 (2007).

    CAS  PubMed  Google Scholar 

  96. 96.

    Angst, F., Aeschlimann, A., Michel, B. A. & Stucki, G. Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. J. Rheumatol. 29, 131–138 (2002).

    PubMed  Google Scholar 

  97. 97.

    Chahla, J. et al. Concentrated bone marrow aspirate for the treatment of chondral injuries and osteoarthritis of the knee: a systematic review of outcomes. Orthop. J. Sports Med. 4, 2325967115625481 (2016).

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Bowen, J. E. Technical issues in harvesting and concentrating stem cells (bone marrow and adipose). PM R. 7, S8–S18 (2015).

    PubMed  Google Scholar 

  99. 99.

    McCarrel, T. & Fortier, L. Temporal growth factor release from platelet-rich plasma, trehalose lyophilized platelets, and bone marrow aspirate and their effect on tendon and ligament gene expression. J. Orthop. Res. 27, 1033–1042 (2009).

    CAS  PubMed  Google Scholar 

  100. 100.

    Turner, L. & Knoepfler, P. Selling stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell 19, 154–157 (2016).

    CAS  PubMed  Google Scholar 

  101. 101.

    Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

    CAS  PubMed  Google Scholar 

  102. 102.

    Aronowitz, J. A., Lockhart, R. A. & Hakakian, C. S. Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. Springerplus 4, 713 (2015).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Chirba, M. A., Sweetapple, B., Hannon, C. P. & Anderson, J. A. FDA regulation of adult stem cell therapies as used in sports medicine. J. Knee Surg. 28, 55–62 (2015).

    PubMed  Google Scholar 

  104. 104.

    Food and Drug Administration. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. FDA https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585403.pdf (2017).

  105. 105.

    Marks, P. & Gottlieb, S. Balancing safety and innovation for cell-based regenerative medicine. N. Engl. J. Med. 378, 954–959 (2018).

    PubMed  Google Scholar 

  106. 106.

    Kokai, L. E., Marra, K. & Rubin, J. P. Adipose stem cells: biology and clinical applications for tissue repair and regeneration. Transl Res. 163, 399–408 (2014).

    CAS  PubMed  Google Scholar 

  107. 107.

    Oberbauer, E. et al. Enzymatic and non-enzymatic isolation systems for adipose tissue-derived cells: current state of the art. Cell Regen (Lond.) 4, 7 (2015).

    Google Scholar 

  108. 108.

    Bourin, P. et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15, 641–648 (2013).

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Koh, Y.-G., Choi, Y.-J., Kwon, O.-R. & Kim, Y.-S. Second-look arthroscopic evaluation of cartilage lesions after mesenchymal stem cell implantation in osteoarthritic knees. Am. J. Sports Med. 42, 1628–1637 (2014).

    PubMed  Google Scholar 

  110. 110.

    Koh, Y.-G., Kwon, O.-R., Kim, Y. S., Choi, Y.-J. & Tak, D.-H. Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: 2-year follow-up of a prospective randomized trial. Arthroscopy 32, 97–109 (2016).

    PubMed  Google Scholar 

  111. 111.

    Pak, J. et al. Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications. J. Biomed. Sci. 24, 9 (2017).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Pers, Y.-M. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 5, 847–856 (2016).

    PubMed  PubMed Central  Google Scholar 

  113. 113.

    Fodor, P. B. & Paulseth, S. G. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet. Surg. J. 36, 229–236 (2016).

    PubMed  Google Scholar 

  114. 114.

    Mendicino, M., Bailey, A. M., Wonnacott, K., Puri, R. K. & Bauer, S. R. MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14, 141–145 (2014).

    CAS  PubMed  Google Scholar 

  115. 115.

    Freitag, J. et al. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review. BMC Musculoskelet. Disord. 17, 230 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Pas, H. I. et al. Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br. J. Sports Med. 51, 1125–1133 (2017).

    PubMed  Google Scholar 

  117. 117.

    McIntyre, J. A., Jones, I. A., Han, B. & Vangsness, C. T. Intra-articular mesenchymal stem cell therapy for the human joint: a systematic review. Am. J. Sports Med. 11, 036354651773584 (2017).

    Google Scholar 

  118. 118.

    Chahla, J. et al. Intra-articular cellular therapy for osteoarthritis and focal cartilage defects of the knee: a systematic review of the literature and study quality analysis. J. Bone Joint Surg. Am. 98, 1511–1521 (2016).

    PubMed  Google Scholar 

  119. 119.

    Pak, J., Lee, J. H., Park, K. S., Jeon, J. H. & Lee, S. H. Potential use of mesenchymal stem cells in human meniscal repair: current insights. Open Access J. Sports Med. 8, 33–38 (2017).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Caplan, A. I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).

    CAS  PubMed  Google Scholar 

  121. 121.

    Caplan, A. I. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 6, 1445–1451 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    CAS  PubMed  Google Scholar 

  123. 123.

    Horwitz, E. M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7, 393–395 (2005).

    CAS  PubMed  Google Scholar 

  124. 124.

    Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Stappenbeck, T. S. & Miyoshi, H. The role of stromal stem cells in tissue regeneration and wound repair. Science 324, 1666–1669 (2009).

    CAS  PubMed  Google Scholar 

  126. 126.

    Galipeau, J. & Krampera, M. The challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria. Cytotherapy 17, 125–127 (2015).

    PubMed  Google Scholar 

  127. 127.

    Marks, P. W., Witten, C. M. & Califf, R. M. Clarifying stem-cell therapy’s benefits and risks. N. Engl. J. Med. 376, 1007–1009 (2017).

    PubMed  Google Scholar 

  128. 128.

    Prockop, D. J. et al. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy 12, 576–578 (2010).

    PubMed  Google Scholar 

  129. 129.

    Toyserkani, N. M. et al. Concise review: a safety assessment of adipose-derived cell therapy in clinical trials: a systematic review of reported adverse events. Stem Cells Transl Med. 6, 1786–1794 (2017).

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Vega, A. et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation 99, 1681–1690 (2015).

    CAS  PubMed  Google Scholar 

  131. 131.

    Vangsness, C. T. J. et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J. Bone Joint Surg. Am. 96, 90–98 (2014).

    PubMed  Google Scholar 

  132. 132.

    Trounson, A. & McDonald, C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17, 11–22 (2015).

    CAS  PubMed  Google Scholar 

  133. 133.

    McIntyre, J. A., Jones, I. A., Danilkovich, A. & Vangsness, C. T. The placenta: applications in orthopaedic sports medicine. Am. J. Sports Med. 122, 363546517697682 (2017).

    Google Scholar 

  134. 134.

    Goldberg, A., Mitchell, K., Soans, J., Kim, L. & Zaidi, R. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J. Orthop. Surg. Res. 12, 39 (2017).

    PubMed  PubMed Central  Google Scholar 

  135. 135.

    Jones, I. A., Chen, X., Evseenko, D. & Vangsness, C. T. Nomenclature inconsistency and selective outcome reporting hinders our understanding of stem cell therapy for the knee. J. Bone Joint Surg. Am. (in the press).

  136. 136.

    Shkhyan, R. et al. Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann. Rheum. Dis. 77, 760–769 (2018).

    CAS  PubMed  Google Scholar 

  137. 137.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03513016 (2018).

  138. 138.

    Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Lozada, C. J. et al. A double-blind, randomized, saline-controlled study of the efficacy and safety of co-administered intra-articular injections of Tr14 and Ze14 for treatment of painful osteoarthritis of the knee: the MOZArT trial. Eur. J. Integ. Med. 13, 54–63 (2017).

    Google Scholar 

  140. 140.

    Lei, J., Priddy, L. B., Lim, J. J. & Koob, T. J. Dehydrated human amnion/chorion membrane (dHACM) allografts as a therapy for orthopedic tissue repair. Tech. Orthop. 32, 149–157 (2017).

    Google Scholar 

  141. 141.

    Lei, J., Priddy, L. B., Lim, J. J., Massee, M. & Koob, T. J. Identification of extracellular matrix components and biological factors in micronized dehydrated human amnion/chorion membrane. Adv. Wound Care (New Rochelle) 6, 43–53 (2017).

    Google Scholar 

  142. 142.

    Malarkey, M. A. Surgical biologics - untitled letter. FDA https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/complianceactivities/enforcement/untitledletters/ucm367184 (2013).

  143. 143.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03485157 (2018).

  144. 144.

    Willett, N. J. et al. Intra-articular injection of micronized dehydrated human amnion/chorion membrane attenuates osteoarthritis development. Arthritis Res. Ther. 16, R47 (2014).

    PubMed  PubMed Central  Google Scholar 

  145. 145.

    Shimonkevitz, R. et al. A diketopiperazine fragment of human serum albumin modulates T-lymphocyte cytokine production through RAP1. J. Trauma 64, 35–41 (2008).

    CAS  PubMed  Google Scholar 

  146. 146.

    Bar-Or, D. et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS ONE 9, e87910 (2014).

    PubMed  PubMed Central  Google Scholar 

  147. 147.

    Schwappach, J., Dryden, S. M. & Salottolo, K. M. Preliminary trial of intra-articular LMWF-5A for osteoarthritis of the knee. Orthopedics 40, e49–e53 (2017).

    PubMed  Google Scholar 

  148. 148.

    Cole, B., McGrath, B., Salottolo, K. & Bar-Or, D. LMWF-5A for the treatment of severe osteoarthritis of the knee: integrated analysis of safety and efficacy. Orthopedics 41, e77–e83 (2018).

    PubMed  Google Scholar 

  149. 149.

    Ampio Pharmaceuticals. Ampio pharmaceuticals reports positive results for both primary and secondary endpoints of pivotal phase 3 trial of Ampion™ in severe osteoarthritis-of-the knee (OAK). Ampiopharma https://ampiopharma.com/news/ampio-pharmaceuticals-reports-positive-results-primary-secondary-endpoints-pivotal-phase-3-trial-ampion-severe-osteoarthritis-knee-oak/ (2017).

  150. 150.

    Bar-Or, D. et al. Low molecular weight fraction of commercial human serum albumin induces morphologic and transcriptional changes of bone marrow-derived mesenchymal stem cells. Stem Cells Transl Med. 4, 945–955 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03349645 (2017).

  152. 152.

    Hangody, L. et al. Intraarticular injection of a cross-linked sodium hyaluronate combined with triamcinolone hexacetonide (Cingal) to provide symptomatic relief of osteoarthritis of the knee: a randomized, double-blind, placebo-controlled multicenter clinical trial. Cartilage 89, 1947603517703732 (2017).

    Google Scholar 

  153. 153.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02381652 (2015).

  154. 154.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03390036 (2018).

  155. 155.

    O’Shaughnessey, K. et al. Autologous protein solution prepared from the blood of osteoarthritic patients contains an enhanced profile of anti-inflammatory cytokines and anabolic growth factors. J. Orthopaed. Res. 32, 1349–1355 (2014).

    Google Scholar 

  156. 156.

    Hix, J. et al. An autologous anti-inflammatory protein solution yielded a favorable safety profile and significant pain relief in an open-label pilot study of patients with osteoarthritis. Biores Open Access 6, 151–158 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    King, W., Bendele, A., Marohl, T. & Woodell-May, J. Human blood-based anti-inflammatory solution inhibits osteoarthritis progression in a meniscal-tear rat study. J. Orthopaed. Res. 35, 2260–2268 (2017).

    CAS  Google Scholar 

  158. 158.

    Wanstrath, A. W. et al. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in a canine population. Vet. Surg. 45, 764–774 (2016).

    PubMed  Google Scholar 

  159. 159.

    van Drumpt, R. A. M., van der Weegen, W., King, W., Toler, K. & Macenski, M. M. Safety and treatment effectiveness of a single autologous protein solution injection in patients with knee osteoarthritis. Biores Open Access 5, 261–268 (2016).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Kon, E., Engebretsen, L., Verdonk, P., Nehrer, S. & Filardo, G. Clinical outcomes of knee osteoarthritis treated with an autologous protein solution injection: a 1-year pilot double-blinded randomized controlled trial. Am. J. Sports Med. 46, 171–180 (2018).

    PubMed  Google Scholar 

  161. 161.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02138890 (2016).

  162. 162.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02905240 (2018).

  163. 163.

    Dell’accio, F. & Cailotto, F. Pharmacological blockade of the WNT-beta-catenin signaling: a possible first-in-kind DMOAD. Osteoarthr. Cartil. 26, 4–6 (2018).

    PubMed  Google Scholar 

  164. 164.

    Usami, Y., Gunawardena, A. T., Iwamoto, M. & Enomoto-Iwamoto, M. Wnt signaling in cartilage development and diseases: lessons from animal studies. Lab. Invest. 96, 186–196 (2016).

    CAS  PubMed  Google Scholar 

  165. 165.

    Deshmukh, V. et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthr. Cartil. 26, 18–27 (2018).

    CAS  PubMed  Google Scholar 

  166. 166.

    Yasuhara, R. et al. Roles of β-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells. Lab. Invest. 91, 1739–1752 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Zhu, M. et al. Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 58, 2053–2064 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Yazici, Y. et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthr. Cartil. 25, 1598–1606 (2017).

    CAS  PubMed  Google Scholar 

  169. 169.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03122860 (2018).

  170. 170.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02536833 (2018).

  171. 171.

    Jeyanesh, R. S. et al. Results from a 52-week, phase 2a study of an intra-articular, Wnt pathway inhibitor, SM04690, for knee osteoarthritis. Samumed https://www.samumed.com/medium/image/the-orthobiologic-institute-tobi-annual-symposium-06072018_318/view.aspx (2018).

  172. 172.

    Roemer, F. W. et al. Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial. BMC Musculoskelet. Disord. 17, 267 (2016).

    PubMed  PubMed Central  Google Scholar 

  173. 173.

    Eckstein, F., Wirth, W., Guermazi, A., Maschek, S. & Aydemir, A. Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging. Arthritis Rheumatol. 67, 2916–2922 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01919164 (2018).

  175. 175.

    Hochberg, M. et al. Efficacy and safety of intra-articular sprifermin in symptomatic radiographic knee osteoarthritis: results of the 2-year primary analysis from a 5-year randomised, placebo-controlled, phase II study [abstract]. Arthritis Rheumatol. 69 (Suppl. 10), 1L (2017).

    Google Scholar 

  176. 176.

    Caterina, M. J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001).

    CAS  Google Scholar 

  177. 177.

    Simone, D. A., Nolano, M., Johnson, T., Wendelschafer-Crabb, G. & Kennedy, W. R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J. Neurosci. 18, 8947–8959 (1998).

    CAS  PubMed  Google Scholar 

  178. 178.

    Anand, P. & Bley, K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth. 107, 490–502 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Remadevi, R. & Szallisi, A. Adlea (ALGRX-4975), an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief. IDrugs 11, 120–132 (2008).

    CAS  PubMed  Google Scholar 

  180. 180.

    Stevens, R. et al. Efficacy and safety of CNTX-4975 in subjects with moderate to severe osteoarthritis knee pain: 24-week, randomized, double-blind, placebo-controlled, dose-ranging study. Ann. Rheum. Dis. 76 (Suppl. 2), 121–121 (2017).

    Google Scholar 

  181. 181.

    Hanson, P. D. CNTX-4975 administration in subjects with knee pain associated with osteoarthritis: results of the randomized, double-blind, placebo-controlled, phase 2b TRIUMPH study. availclinical https://www.availclinical.com/wp-content/uploads/2012/02/OA-Double-Blind-Study-Results.pdf (2017).

  182. 182.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03429049 (2018).

  183. 183.

    Lee, D. K. et al. Continuous transforming growth factor beta1 secretion by cell-mediated gene therapy maintains chondrocyte redifferentiation. Tissue Eng. 11, 310–318 (2005).

    CAS  PubMed  Google Scholar 

  184. 184.

    Ha, C.-W., Noh, M. J., Choi, K. B. & Lee, K. H. Initial phase I safety of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 in degenerative arthritis patients. Cytotherapy 14, 247–256 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Cherian, J. J. et al. Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-β1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthr. Cartil. 23, 2109–2118 (2015).

    CAS  PubMed  Google Scholar 

  186. 186.

    Guermazi, A. et al. Structural effects of intra-articular TGF-β1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial. BMC Musculoskelet. Disord. 18, 461 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Kim, M.-K. 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. 29, 48–59 (2018).

    CAS  PubMed  Google Scholar 

  188. 188.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03203330 (2018).

  189. 189.

    Food and Drug Administration. Drug approval package: ZILRETTA (triamcinolone acetonide). FDA https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208845Orig1s000TOC.cfm (2017).

  190. 190.

    Kraus, V. B. et al. Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA). Osteoarthr. Cartil. 26, 34–42 (2018).

    CAS  PubMed  Google Scholar 

  191. 191.

    Bodick, N. et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J. Bone Joint Surg. Am. 97, 877–888 (2015).

    PubMed  Google Scholar 

  192. 192.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01487161 (2018).

  193. 193.

    Conaghan, P. G. et al. Brief report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol. 70, 204–211 (2018).

    CAS  PubMed  Google Scholar 

  194. 194.

    Conaghan, P. G. et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. J. Bone Joint Surg. Am. 100, 666–677 (2018).

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Prockop, D. J. Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. Mol. Ther. 17, 939–946 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Bravery, C. A. et al. Potency assay development for cellular therapy products: an ISCT review of the requirements and experiences in the industry. Cytotherapy 15, 9–19 (2013).

    PubMed  Google Scholar 

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Acknowledgements

The work of the authors was supported by grants UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science (NCATS) of the US National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Nature Reviews Rheumatology thanks C. Evans, D. Hunter and A. Migliore for their contribution to the peer review of this work.

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Jones, I.A., Togashi, R., Wilson, M.L. et al. Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol 15, 77–90 (2019). https://doi.org/10.1038/s41584-018-0123-4

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