A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis

Christopher J Centeno, Hasan Al-Sayegh, Jamil Bashir, Shaun Goodyear, Michael D Freeman, Christopher J Centeno, Hasan Al-Sayegh, Jamil Bashir, Shaun Goodyear, Michael D Freeman

Abstract

Background: Prior studies describing the treatment of symptomatic knee osteoarthritis with injections of bone marrow concentrate have provided encouraging results. The relationship between the cellular dose contained within the bone marrow concentrate and efficacy of the treatment, however, is unclear. In the present study we describe clinical outcomes for symptomatic knee osteoarthritis in relation to higher and lower cell concentrations contained within a bone marrow concentrate treatment protocol.

Methods: Data from an ongoing patient registry was culled to identify 373 patients that received bone marrow concentrate injections for the treatment of 424 osteoarthritic knee joints. The clinical scales for these patients were assessed at baseline and then tracked post-procedure at 1, 3, 6 and 12 months, and annually thereafter. Tracked outcomes included the numeric pain scale; a lower extremity functional questionnaire; an International Knee Documentation Committee scale; and a subjective improvement rating scale. Using pain and functional outcome measures, a receiver operating characteristic analysis was used to define an optimal clinical outcome threshold at which bone marrow nucleated cell count could be divided into either a lower or higher cell count group within a treatment protocol.

Results: The lower and higher cell count groups were defined using a threshold of 4 × 10(8) cells. There were 224 and 185 knee joints treated in the lower (≤4 × 10(8)) and higher (>4 × 10(8)) cell count groups respectively. Most joints were diagnosed with early stage knee osteoarthritis. Both the lower and higher cell count groups demonstrated significant positive results with the treatment for all of the pain and functional metrics. The higher cell count group reported lower post treatment numeric pain scale values, in comparison with the lower cell count group (1.6 vs. 3.2; P < 0.001). No significant differences were detected for the other metrics, however.

Conclusions: Improved function and reduced pain was observed in patients treated with a bone marrow concentrate protocol regardless of cellular dose; however, patients receiving a higher concentration of cells reported a better pain outcome in comparison with the lower dose group. These preliminary findings suggest that cell dose may be an important factor governing clinical outcomes in autologous bone marrow concentrate treatment of knee osteoarthritis. Further studies using a larger patient population may help elucidate these findings.

Figures

Fig. 1
Fig. 1
Sensitivity and specificity for composite pain and functional improvement as predicted by the nucleated cell count and examined by the receiver operating characteristics curve analysis
Fig. 2
Fig. 2
Nucleated cell count of the study population. Lower nucleated cell count group was categorized as ≤ 4 × 108 cells; whereas in the higher cell count group, there were > 4 × 108 nucleated cells

References

    1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58(1):26–35. doi: 10.1002/art.23176.
    1. Agency for Healthcare Research and Quality. Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP). 2014 July 17; Available from: .
    1. Schairer WW, Zhang AL, Feeley BT. Hospital readmissions after primary shoulder arthroplasty. J Shoulder Elbow Surg. 2014.
    1. Urquhart DM, Hanna FS, Brennan SL, Wluka AE, Leder K, Cameron PA, et al. Incidence and risk factors for deep surgical site infection after primary total hip arthroplasty: a systematic review. J Arthroplasty. 2010;25(8):1216–22. doi: 10.1016/j.arth.2009.08.011.
    1. Sihvonen R, Paavola M, Malmivaara A, Itälä A, Joukainen A, Nurmi H, et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med. 2013;369(26):2515–24. doi: 10.1056/NEJMoa1305189.
    1. Dhillon MS, Behera P, Patel S, Shetty V. Orthobiologics and platelet rich plasma. Indian J Orthop. 2014;48(1):1–9. doi: 10.4103/0019-5413.125477.
    1. Filardo G, Kon E, Di Martino A, Di Matteo B, Merli ML, Cenacchi A, et al. Platelet-rich plasma vs hyaluronic acid to treat knee degenerative pathology: study design and preliminary results of a randomized controlled trial. BMC Musculoskelet Disord. 2012;13:229. doi: 10.1186/1471-2474-13-229.
    1. 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. doi: 10.1155/2014/370621.
    1. Williams AR, Hare JM. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109(8):923–40. doi: 10.1161/CIRCRESAHA.111.243147.
    1. Zhang Y, Wang F, Chen J, Ning Z, Yang L. Bone marrow-derived mesenchymal stem cells versus bone marrow nucleated cells in the treatment of chondral defects. Int Orthop. 2012;36(5):1079–86. doi: 10.1007/s00264-011-1362-z.
    1. Ikehara A, Maeda H, Kimura T, Saito S, Ochiai AA. Bone marrow-derived macrophages are associated with androgen modulated prostate regeneration. Prostate. 2012;72(1):1–11. doi: 10.1002/pros.21399.
    1. Sesia SB, Duhr R, Medeiros, da Cunha C, Todorov A, Schaeren S, Padovan E, et al. Anti-inflammatory/tissue repair macrophages enhance the cartilage-forming capacity of human bone marrow-derived mesenchymal stromal cells. J Cell Physiol. 2015;230(6):1258–69. doi: 10.1002/jcp.24861.
    1. Bashir J, Sherman A, Lee H, Kaplan L, Hare JM. Mesenchymal stem cell therapies in the treatment of musculoskeletal diseases. PM R. 2014;6(1):61–9. doi: 10.1016/j.pmrj.2013.05.007.
    1. Grigolo B, Lisignoli G, Desando G, Cavallo C, Marconi E, Tschon M, et al. Osteoarthritis treated with mesenchymal stem cells on hyaluronan-based scaffold in rabbit. Tissue Eng Part C Methods. 2009;15(4):647–58. doi: 10.1089/ten.tec.2008.0569.
    1. Horie M, Sekiya I, Muneta T, Ichinose S, Matsumoto K, Saito H, et al. Intra-articular Injected synovial stem cells differentiate into meniscal cells directly and promote meniscal regeneration without mobilization to distant organs in rat massive meniscal defect. Stem Cells. 2009;27(4):878–87. doi: 10.1634/stemcells.2008-0616.
    1. Lee KB, Hui JH, 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. doi: 10.1634/stemcells.2006-0311.
    1. Hernigou P, Poignard A, Beaujean F, Rouard F. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am. 2005;87(7):1430–7. doi: 10.2106/JBJS.D.02215.
    1. Zhang YZ, Da WM. Experimental study of platelet-rich plasma optimizing mesenchymal stem cells culture. Zhonghua Xue Ye Xue Za Zhi. 2006;27(6):403–5.
    1. D'Esposito V, Passaretti F, Perruolo G, Ambrosio MR, Valentino R, Oriente F, et al. Platelet-rich plasma increases growth and motility of adipose tissue-derived mesenchymal stem cells and controls adipocyte secretory function. J Cell Biochem. 2015.
    1. Augustyniak E, Trzeciak T, Richter M, Kaczmarczyk J, Suchorska W. The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration. Int Orthop. 2015;39(5):995–1003. doi: 10.1007/s00264-014-2619-0.
    1. Bouwmeester W, Fechter MM, Heymans MW, Twisk JW, Ebeling LJ, Brand A, et al. Prediction of nucleated cells in bone marrow stem cell products by donor characteristics: a retrospective single centre analysis. Vox Sang. 2010;98(3 Pt 1):e276–83. doi: 10.1111/j.1423-0410.2009.01281.x.
    1. Premer C, Blum A, Bellio MA, Schulman IH, Hurwitz BE, Parker M, et al. Allogeneic mesenchymal stem cells restore endothelial function in heart failure by stimulating endothelial progenitor cells. EBioMedicine. 2015;2(5):467–75. doi: 10.1016/j.ebiom.2015.03.020.
    1. Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells. 2015;33(1):146–56. doi: 10.1002/stem.1845.
    1. Mundy LN, Ishihara A, Wellman ML, Bertone AL. Evaluation of the ability of a gravitational filtration system to enhance recovery of equine bone marrow elements. Am J Vet Res. 2015;76(6):561–9. doi: 10.2460/ajvr.76.6.561.
    1. 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.
    1. Li P, Li SH, Wu J, Zang WF, Dhingra S, Sun L. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008;11(3):343–53.
    1. 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. doi: 10.1016/j.mehy.2008.06.042.
    1. Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, et al. Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther. 2011;6(4):368–78.
    1. Centeno C, Schultz JR, Cheever M, Freeman M, Robinson B, Faulkner SJ. A Case Series of Percutaneeous Treatment of Non-Union Fractures with Autologous, Culture Expanded, Bone Marrow Dervied, Mesenchymal Stem Cells and Platelet Lysate. Journal of Bioengineering & Biomedical Science. 2011;Special Issue, S2-007.
    1. Centeno CJ, Freeman MD. Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. Wiener Medizinische Wochenschriff. 2014;164(5-6):83–7.
    1. Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of Autologous Bone Marrow Concentrate for Knee Osteoarthritis with and without Adipose Graft. BioMed Research International. 2014;2014:9. doi: 10.1155/2014/370621.
    1. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494–502. doi: 10.1136/ard.16.4.494.
    1. Sowers M, Karvonen-Gutierrez CA, Jacobson JA, Jiang Y, Yosef M. Associations of anatomical measures from MRI with radiographically defined knee osteoarthritis score, pain, and physical functioning. J Bone Joint Surg Am. 2011;93(3):241–51. doi: 10.2106/JBJS.I.00667.
    1. Childs JD, Piva SR, Fritz JM. Responsiveness of the numeric pain rating scale in patients with low back pain. Spine (Phila Pa 1976) 2005;30(11):1331–4. doi: 10.1097/01.brs.0000164099.92112.29.
    1. Binkley JM, Stratford PW, Lott SA, Riddle DL. The Lower Extremity Functional Scale (LEFS): scale development, measurement properties, and clinical application. North American Orthopaedic Rehabilitation Research Network. Phys Ther. 1999;79(4):371–83.
    1. Collins NJ, Misra D, Felson DT, Crossley KM, Roos EM. Measures of knee function: International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS), Knee Outcome Survey Activities of Daily Living Scale (KOS-ADL), Lysholm Knee Scoring Scale, Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Activity Rating Scale (ARS), and Tegner Activity Score (TAS) Arthritis Care Res (Hoboken) 2011;63(Suppl 11):S208–28. doi: 10.1002/acr.20632.
    1. Bornes TD, Adesida AB, Jomha NM. Mesenchymal stem cells in the treatment of traumatic articular cartilage defects: a comprehensive review. Arthritis Res Ther. 2014;16(5):432. doi: 10.1186/s13075-014-0432-1.
    1. Farrar JT, Young JP, Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149–58. doi: 10.1016/S0304-3959(01)00349-9.
    1. Song F, Tang J, Geng R, Hu H, Zhu C, Cui W, et al. Comparison of the efficacy of bone marrow mononuclear cells and bone mesenchymal stem cells in the treatment of osteoarthritis in a sheep model. Int J Clin Exp Pathol. 2014;7(4):1415–26.
    1. Wang W, Cao W. Treatment of osteoarthritis with mesenchymal stem cells. Sci China Life Sci. 2014..
    1. Vangsness CT, Jr, Farr J, 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M, 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. 2014;96(2):90–8. doi: 10.2106/JBJS.M.00058.
    1. Singh A, Goel SC, Gupta KK, Kumar M, Arun GR, Patil H, et al. The role of stem cells in osteoarthritis: an experimental study in rabbits. Bone Joint Res. 2014;3(2):32–7. doi: 10.1302/2046-3758.32.2000187.
    1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7. doi: 10.1126/science.284.5411.143.
    1. Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-beta secretion. J Clin Invest. 2015.
    1. Raeissadat SA, Rayegani SM, Hassanabadi H, Fathi M, Ghorbani E, Babaee M, et al. Knee Osteoarthritis Injection Choices: Platelet- Rich Plasma (PRP) Versus Hyaluronic Acid (A one-year randomized clinical trial) Clin Med Insights Arthritis Musculoskelet Disord. 2015;8:1–8.
    1. Gobbi A, Lad D, Karnatzikos G. The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2014;23(8):2170–7. doi: 10.1007/s00167-014-2987-4.
    1. Lai LP, Stitik TP, Foye PM, Georgy JS, Patibanda V, Chen B, et al. Use of platelet-rich plasma in intra-articular knee injections for osteoarthritis: a systematic review. PM R. 2015;7(6):637–48. doi: 10.1016/j.pmrj.2015.02.003.
    1. Pourcho AM, Smith J, Wisniewski SJ, Sellon JL. Intraarticular platelet-rich plasma injection in the treatment of knee osteoarthritis: review and recommendations. Am J Phys Med Rehabil. 2014;93(11 Suppl 3):S108–21. doi: 10.1097/PHM.0000000000000115.
    1. Tietze DC, Geissler K, Borchers J, Tietze DC, Geissler K, Borchers J. The effects of platelet-rich plasma in the treatment of large-joint osteoarthritis: a systematic review. Phys Sportsmed. 2014;42(2):27–37. doi: 10.3810/psm.2014.05.2055.
    1. Patel S, Dhillon MS, Aggarwal S, Marwaha N, Jain A. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, double-blind, randomized trial. Am J Sports Med. 2013;41(2):356–64. doi: 10.1177/0363546512471299.
    1. Filardo G, Kon E, DI Matteo B, DI Marino A, Sessa A, Merli ML, et al. Leukocyte-poor PRP application for the treatment of knee osteoarthritis. Joints. 2013;1(3):112–20.

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