Autologous bone marrow expanded mesenchymal stem cells in patellar tendinopathy: protocol for a phase I/II, single-centre, randomized with active control PRP, double-blinded clinical trial

Gil Rodas, Robert Soler, Ramón Balius, Xavier Alomar, Xavier Peirau, Mercedes Alberca, Ana Sánchez, Javier García Sancho, Clementina Rodellar, Antonio Romero, Lorenzo Masci, Lluís Orozco, Nicola Maffulli, Gil Rodas, Robert Soler, Ramón Balius, Xavier Alomar, Xavier Peirau, Mercedes Alberca, Ana Sánchez, Javier García Sancho, Clementina Rodellar, Antonio Romero, Lorenzo Masci, Lluís Orozco, Nicola Maffulli

Abstract

Introduction: Patellar tendon overuse injuries are common in athletes. Imaging may show a change in tissue structure with tendon thickening and disruption of the intratendinous substance. We wish to test the hypothesis that both autologous bone marrow expanded mesenchymal stem cells and autologous leukocyte-poor platelet-rich plasma (LP-PRP) implanted into the area of the disrupted tendinopathic patellar tendon will restore function, but tendon regeneration tissue will only be observed in the subjects treated with autologous bone marrow expanded mesenchymal stem cells.

Methods and analysis: This is a single-centre, pilot phase I/II, double-blinded clinical trial with randomisation with active control. Twenty patients with a diagnosis of patellar tendinopathy with imaging changes (tendon thickening and disruption of the intratendinous substance at the proximal portion of the patellar tendon) will be randomised in a 1:1 ratio to receive a local injection of either bone-marrow autologous mesenchymal stem cells (MSC), isolated and cultured under GMP at The Institute of Biology and Molecular Genetics (IBGM) (Spain) or P-PRP. The study will have two aims: first, to ascertain whether a clinically relevant improvement after 3, 6 and 12 months according to the visual analogue scale (VAS), Victorian Institute of Sport Assessment for patellar tendons (VISA-P) and dynamometry scales (DYN) will be achieved; and second, to ascertain whether the proposed intervention will restore tendon structure as determined by ultrasonography (US), Doppler ultrasonography (DUS), and innovative MRI and ultrasound techniques: Magnetic Resonance T2 FAT SAT (UTE, Ultrashort Echo TE) sequence and Ultrasound Tissue Characterization (UTC). Patients who are randomised to the P-PRP treatment group but do not achieve a satisfactory primary endpoint after 6 months will be offered treatment with MSC.

Trial registration: NCT03454737.

Keywords: Tendinopathy; Mesenchymal stem cells; Platelet-rich plasma.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study flow chart

References

    1. Magnusson SP, Hansen M, Langberg H, Miller B, Haraldsson B, Westh EK, Koskinen S, Aagaard P, Kjaer M. The adaptability of tendon to loading differs in men and women. Int J Exp Pathol. 2007;88:237–240. doi: 10.1111/j.1365-2613.2007.00551.x.
    1. Kaux JF, Forthomme B, Goff CL, Crielaard JM, Croisier JL. Current opinions on tendinopathy. J Sports Sci Med. 2011;10:238–253.
    1. Øystein B, Engebretsen L, Bahr R. Prevalence of jumper’s knee among elite athletes from different sports: a cross-sectional study. Am. J Sports Med. 2005;33:561–567. doi: 10.1177/0363546504270454.
    1. Pruna R, Medina D, Rodas G, Artells R. Patellar tendinopathy. Therapeutic model in sport. Med Clin (Bar) 2013;141(3):119–124. doi: 10.1016/j.medcli.2012.12.006.
    1. Kettunen JA, Kvist M, Alanen E, Kujala UM. Long-term prognosis for jumper’s knee in male athletes. A prospective follow-up study. Am J Sports Med. 2002;30:689–692. doi: 10.1177/03635465020300051001.
    1. Magnusson SP, Langberg H, Kjaer M. The pathogenesis of tendinopathy: balancing the response to loading. Nat. Rev. Rheumatol. 2010;6:262–268.
    1. Del Buono A, Battery L, Denaro V, Maccauro G, Maffulli N. Tendinopathy and inflammation: some truths. Int J Immunopathol Pharmacol. 2011;24(1 Suppl 2):45–50. doi: 10.1177/03946320110241S209.
    1. D'Addona A, Maffulli N, Formisano S, Rosa D. Inflammation in tendinopathy. Surgeon. 2017;15(5):297–302. doi: 10.1016/j.surge.2017.04.004.
    1. Battery L, Maffulli N. Inflammation in overuse tendon injuries. Sports Med Arthrosc Rev. 2011;19(3):213–217. doi: 10.1097/JSA.0b013e31820e6a92.
    1. Tol JL, Spiezia F, Maffulli N. Neovascularization in Achilles tendinopathy: have we been chasing a red herring? Knee Surg Sports Traumatol Arthrosc. 2012;20(10):1891–1894. doi: 10.1007/s00167-012-2172-6.
    1. Khan KM, Cook JL, Maffulli N, Kannus P. Where is the pain coming from in tendinopathy? It may be biochemical, not only structural, in origin. Br J Sports Med. 2000;34(2):81–83. doi: 10.1136/bjsm.34.2.81.
    1. Cook JL, Khan KM, Purdam C. Achilles tendinopathy. Manual Therapy. 2002;7:121–130. doi: 10.1054/math.2002.0458.
    1. Rees JD, Wilson AM, Wolman RL. Current concepts in the management of tendon disorders. Rheumatology (Oxford) 2006;45:508–521. doi: 10.1093/rheumatology/kel046.
    1. Riley G. Tendinopathy from basic science to treatment. Nature Clinical Practice Rheumatology. 2008;4:82–89. doi: 10.1038/ncprheum0700.
    1. Malliaras P, Cook J, Purdam C, Rio E. Patellar tendinopathy: clinical diagnosis, load management, and advice for challenging case presentations. J Orthop Sports Phys Ther. 2015;45(11):887–898. doi: 10.2519/jospt.2015.5987.
    1. Maffulli N, Giai Via A, Oliva F. Revision surgery for failed patellar tendinopathy exploration. Sports Med Arthrosc Rev. 2017;25(1):36–34. doi: 10.1097/JSA.0000000000000141.
    1. Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RKW. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44:25–32. doi: 10.1111/j.2042-3306.2011.00363.x.
    1. Romero A, Barrachina L, Ranera B, Remacha AR, Moreno B, de Blas I, Sanz A, Vázquez FJ, Vitoria A, Junquera C, Zaragoza P, Rodellar C. Comparison of autologous bone marrow and adipose tissue derived mesenchymal stem cells, and platelet rich plasma, for treating surgically induced lesions of the equine superficial digital flexor tendon. Vet J. 2017;224:76–84. doi: 10.1016/j.tvjl.2017.04.005.
    1. Le Blanc K, Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med. 2007;262:509–525. doi: 10.1111/j.1365-2796.2007.01844.x.
    1. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75:389–397. doi: 10.1097/01.TP.0000045055.63901.A9.
    1. Frank MH, Sayegh MH. Immunomodulatory functions of mesenchymal stem cells. Lancet. 2004;363(9419):1411–1412. doi: 10.1016/S0140-6736(04)16134-5.
    1. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822. doi: 10.1182/blood-2004-04-1559.
    1. Rasmusson I. Immunemodulation by mesenchymal stem cells. Exp Cell Res. 2006;312(Issue 12, 15):2169–2179. doi: 10.1016/j.yexcr.2006.03.019.
    1. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499–3506. doi: 10.1182/blood-2007-02-069716.
    1. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Review Immunobiology of mesenchymal stem cells. Cell Death Diff. 2014;21:216–225. doi: 10.1038/cdd.2013.158.
    1. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, ProckopDj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905.
    1. Andia Isabel, Maffulli Nicola. New biotechnologies for musculoskeletal injuries. The Surgeon. 2019;17(4):244–255. doi: 10.1016/j.surge.2018.08.004.
    1. Orozco L, Soler Rich R, Morera C, Alberca M, Sánchez A, García Sancho J. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplant J. 2011;92(Issue 7):822–828. doi: 10.1097/TP.0b013e3182298a15.
    1. Orozco L, Munar A, Soler R, Alberca M, Huguet MJ, Sánchez A, García-Sancho J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplant J. 2013;95(12):1535–1541. doi: 10.1097/TP.0b013e318291a2da.
    1. Soler F, Soler R, Peirau X, Orozco L. Rapid Isolation of Human Stem Cells. Arthroscopy. 2012;28:895–896. doi: 10.1016/j.arthro.2012.05.004.
    1. Soler R, Munar A, Soler Romagosa F, Peirau X, Huguet M, Alberca M, Sánchez A, García Sancho J, Orozco L. Treatment of Knee Osteoarthritis with Autologous Expanded Bone Marrow Mesenchymal Stem Cells: 50 Cases Clinical and MRI Results at One YearFollow-Up. J Stem Cell Res Ther. 2015;5:285.
    1. Soler R, Ll O, Munar A, Huguet M, López R, Vives J, Coll R, Codinach M, García-López J. 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. The Knee. 2016;23:647–654. doi: 10.1016/j.knee.2015.08.013.
    1. Vega A, Martín-Ferrero A, Del Canto F, Alberca M, García V, Munar A, Orozco L, SolerR FJJ, Huguet M, Sánchez A, García-Sancho J. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681–1690. doi: 10.1097/TP.0000000000000678.
    1. Barrachina L, Remacha AR, Romero A, Vázquez FJ, Albareda J, Prades M, Ranera B, Zaragoza P, Martín-Burriel I, Rodellar C. Inflammation affects the viability and plasticity of equine mesenchymal stem cells: possible implications in intra-articular treatments. J Vet Sci. 2017;18(1):39–49. doi: 10.4142/jvs.2017.18.1.39.
    1. Barrachina L, Remacha AR, Romero A, Vázquez FJ, Albareda J, Prades M, Gosálvez J, Roy R, Zaragoza P, Martín-Burriel I, Rodellar C. Priming Equine Bone Marrow-Derived Mesenchymal Stem Cells with Proinflammatory Cytokines: Implications in Immunomodulation-Immunogenicity Balance, Cell Viability, and Differentiation Potential. Stem Cells Dev. 2017;26(1):15–24. doi: 10.1089/scd.2016.0209.
    1. Barrachina L, Remacha AR, Romero A, Zaragoza P, Vázquez FJ, Rodellar C. Differentiation of equine bone marrow derived mesenchymal stem cells increases the expression of immunogenic genes. Vet Immunol Immunopathol. 2018;200:1–6. doi: 10.1016/j.vetimm.2018.04.004.
    1. Andia I, Maffulli N. Muscle and tendon injuries: the role of biological interventions to promote and assist healing and recovery. Arthroscopy. 2015;31(5):999–1015. doi: 10.1016/j.arthro.2014.11.024.
    1. Kon E, Filardo G, Delcogliano M, Kon E, Presti ML, Russo A, Bondi A, Di Martino A, Cenacchi A, Fornasari PM, Marcacci M. Platelet-rich plasma: New clinical application: A pilot study for treatment of jumper’s knee. Injury. 2009;40:598–603. doi: 10.1016/j.injury.2008.11.026.
    1. Andia I, Maffulli N. Use of platelet-rich plasma for patellar tendon and medial collateral ligament injuries: best current clinical practice. J Knee Surg. 2015;28(1):11–18. doi: 10.1055/s-0034-1384671.
    1. Soler R, Soler F, Peirau X, Anglés F, Buló J, Rodas G, Orozco L. My experience with PRP. ICRS Newsletter. 2011. pp. 31–32.
    1. Martinez-Zapata MJ, Orozco L, Balius R, Soler R, Bosch A, Rodas G, Til LL, Peirau X, UrrutiaG GI, Bonfill X on behalf of the PRP-RICE group Efficacy of autologous Platelet rich plasma for treatment of muscle rupture with haematoma: a multicentre, randomized, double-blind, placebo-controlled clinical trial. Blood Transfusion. 2016;14(3):245–254.
    1. Fitzpatrick J, Bulsara M, Zheng MH. The effectiveness of platelet-rich plasma in the treatment of tendinopathy: a meta-analysis of randomized controlled clinical trials. Am J Sports Med. 2017;45(1):226–233. doi: 10.1177/0363546516643716.
    1. van Schie HT, de Vos RJ, de Jonge S, Bakker EM, Heijboer MP, Verhaar JA, Tol JL, Weinans H. Ultrasonographic tissue characterization of human Achilles tendons: quantification of tendon structure through a novel non-invasive approach. Br J Sports Med. 2010;44:1153–1159. doi: 10.1136/bjsm.2009.061010.
    1. Warden SJ, Kiss ZS, Malara FA, Ooi ABT, Cook JL, Crossley KM. Comparative Accuracy of Magnetic Resonance Imaging and Ultrasonography in Confirming, Clinically Diagnosed Patellar Tendinopathy. Am J Sports Med. 2007;35:427–436. doi: 10.1177/0363546506294858.
    1. Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost. 2004;91(1):4–15. doi: 10.1160/TH03-07-0440.
    1. Maffulli N, Oliva F, Loppini M, Aicale R, Spiezia F, King J. The Royal London Hospital test for the clinical diagnosis of patellar tendinopathy. Muscles Ligaments Tendons J. 2017;7(2):315–322. doi: 10.11138/mltj/2017.7.2.315.
    1. Mascaró A, Cos MA, Morral A, Roig A, Purdam C, Cook J. Load management in tendinopathy: Clinical progression for Achilles and patellar tendinopathy. Apunts Med Sport. 2018;53(197):19–27.
    1. Budny AM, Ley AN. Fluoroquinolone-mediated Achilles rupture: a case report and review of the literature. J Foot Ankle Surg. 2015;54(3):494–496. doi: 10.1053/j.jfas.2014.09.037.
    1. Bisaccia DR, Aicale R, Tarantino D, Peretti GM, Maffulli N. Biological and chemical changes in fluoroquinolone-associated tendinopathies: a systematic review. Br Med Bull. 2019;130:39–49. doi: 10.1093/bmb/ldz006.
    1. Hernandez-Sánchez S, Hidalgo MD, Gomez A. Responsiveness of the VISA-P scale for patellar tendinopathy in athletes. Br J Sports Med. 2014;48:453–457. doi: 10.1136/bjsports-2012-091163.
    1. Hoksrud A, Ohberg L, Alfredson H, Bahr R. Ultrasound-guided sclerosis of neovessels in painful chronic patellar tendinopathy: a randomized controlled trial. Am J Sports Med. 2006;34(11):1738–1746. doi: 10.1177/0363546506289168.
    1. de Groot R, Malliaras P, Munteanu S, Payne C, Morrissey D, Maffulli N. Foot posture and patellar tendon pain among adult volleyball players. Clin J Sport Med. 2012;22(2):157–159. doi: 10.1097/JSM.0b013e31824714eb.
    1. Longo UG, Berton A, Stelitano G, Madaudo C, Perna M, Ciuffreda M, Guarnieri A, Papalia R, Maffulli N, Denaro V. 2017 Marathon of Rome: Anthropometry and Sport Profile in 350 Runners and Association With Achilles and Patellar Tendinopathy. Clin J Sport Med. 2018. 10.1097/JSM.0000000000000695.
    1. Oliva F, Piccirilli E, Berardi AC, Frizziero A, Tarantino U, Maffulli N. Hormones and tendinopathies: the current evidence. Br Med Bull. 2016;117(1):39–58. doi: 10.1093/bmb/ldv054.
    1. Oliva F, Piccirilli E, Berardi AC, Tarantino U, Maffulli N. Influence of Thyroid Hormones on Tendon Homeostasis. Adv Exp Med Biol. 2016;920:133–138. doi: 10.1007/978-3-319-33943-6_12.
    1. Denaro V, Ruzzini L, Longo UG, Franceschi F, De Paola B, Cittadini A, Maffulli N, Sgambato A. Effect of dihydrotestosterone on cultured human tenocytes from intact supraspinatus tendon. Knee Surg Sports Traumatol Arthrosc. 2010;18(7):971–976. doi: 10.1007/s00167-009-0953-3.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe