PURPOSE: Damage of the knee cartilage is a common condition manifesting itself mainly by pain and/or swelling that may substantially reduce the quality of life while ultimately leading to osteoarthritis in affected patients. Here, we aimed to evaluate the safety and efficacy of cultured autologous bone marrow mesenchymal stem cells (BM-MSCs) attached to the 3D Chondrotissue® scaffold by autologous blood plasma coagulation (BiCure® ortho MSCp) in the treatment of knee cartilage defects. METHODS: The primary endpoint of this phase I/IIa clinical trial was to evaluate the safety of the treatment. The secondary objective was to determine the short-to-medium-term therapeutic outcomes by standardized scoring questionnaires including Lysholm Knee Scoring Scale (Lysholm score), Knee Injury and Osteoarthritis Outcome Score (KOOS), and pain Visual Analogue Scale (VAS) systems and imaging (X-ray and magnetic resonance imaging, MRI). A total of six patients were included and followed for 12 months after the surgery. RESULTS: BiCure® ortho MSCp was well tolerated with no adverse events associated with the investigational medicinal product. Significant improvements were observed in Lysholm scores and KOOS while X-ray showed no deterioration of the arthritis and MRI revealed a persistent filling of the chondral defects by the implant. CONCLUSION: Overall, our data demonstrate the safety of the tested investigational medicinal product. The function of the treated knee improved within one year after surgery in all enrolled patients. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: EudraCT No.: 2018-004,067-31; October 18 2018.

Bioinova a s Prague Czech Republic

Department of Orthopaedics 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Orthopaedics and Traumatology University Hospital Pilsen Pilsen Czech Republic

Department of Orthopaedics University of J E Purkyne in Usti Nad Labem Masaryk Hospital Krajska zdravotni Usti nad Labem Czech Republic

Department of Sports Medicine Masaryk Hospital Krajska zdravotni Usti nad Labem Czech Republic

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Hjelle K, Solheim E, Strand T, Muri R, Brittberg M (2002) Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy 18:730–734. https://doi.org/10.1053/jars.2002.32839 PubMed DOI

Mankin HJ (1982) The response of articular cartilage to mechanical injury. J Bone Joint Surg Am 64:460–466 PubMed DOI

Siclari A, Mascaro G, Kaps C, Boux E (2014) A 5-year follow-up after cartilage repair in the knee using a platelet-rich plasma-immersed polymer-based implant. Open Orthop J 8:346–354. https://doi.org/10.2174/1874325001408010346 PubMed DOI PMC

Hunziker EB (2002) Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthr Cartil 10:432–463. https://doi.org/10.1053/joca.2002.0801 DOI

Neckar P, Havlas V, Lykova D, Branis J, Kvizova J, Bauer PO (2020) Comparison of bone marrow stromal cells from different anatomical locations for evaluation of their suitability for potential clinical applications. Acta Chir Orthop Traumatol Cech 87:183–190 PubMed DOI

Garvin K, Feschuk C, Sharp JG, Berger A (2007) Does the number or quality of pluripotent bone marrow stem cells decrease with age? Clin Orthop Relat Res 465:202–207. https://doi.org/10.1097/BLO.0b013e318159a9b8 PubMed DOI

Sittinger M, Hutmacher DW, Risbud MV (2004) Current strategies for cell delivery in cartilage and bone regeneration. Curr Opin Biotechnol 15:411–418. https://doi.org/10.1016/j.copbio.2004.08.010 PubMed DOI

Lee WY, Wang B (2017) Cartilage repair by mesenchymal stem cells: clinical trial update and perspectives. J Orthop Translat 9:76–88. https://doi.org/10.1016/j.jot.2017.03.005 PubMed DOI PMC

Becher C, Ettinger M, Ezechieli M, Kaps C, Ewig M, Smith T (2015) Repair of retropatellar cartilage defects in the knee with microfracture and a cell-free polymer-based implant. Arch Orthop Trauma Surg 135:1003–1010. https://doi.org/10.1007/s00402-015-2235-5 PubMed DOI

Glasbrenner J, Petersen W, Raschke MJ, Steiger M, Verdong R, Castelli CC, Zappala G, Fritschy D, Herbort M (2020) Matrix-augmented bone marrow stimulation with a polyglycolic acid membrane with hyaluronan vs microfracture in local cartilage defects of the femoral condyles. Orthop J Sports Med 8:2325967120922938. https://doi.org/10.1177/2325967120922938 PubMed DOI PMC

Dhollander A, Verdonk P, Lambrecht S, Verdonk R, Elewaut D, Verbruggen AKF (2012) Midterm results of the treatment of cartilage defects in the knee using alginate beads containing human mature allogenic chondrocytes. Am J Sports Med 40:75–82. https://doi.org/10.1177/0363546511423013 PubMed DOI

Erggelet C, Neuman K, Endres M, Haberstroh K, Sittinger M, Kaps C (2007) Regeneration of ovine articular cartilage defects by cell-free polymer-based implants. Biomaterials 28:5570–5580. https://doi.org/10.1016/j.biomaterials.2007.09.005 PubMed DOI

Kellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16:494–502. https://doi.org/10.1136/ard.16.4.494 PubMed DOI PMC

Schreiner MM, Raudner M, Marlovits S, Bohndorf K, Weber M, Zalaudek M, Röhrich S, Szomolanyi P, Filardo G, Windhager R, Trattnig S (2021) The MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) 2.0 Knee Score and Atlas. Cartilage 13:571S-587S. https://doi.org/10.1177/1947603519865308 PubMed DOI

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317. https://doi.org/10.1080/14653240600855905 PubMed DOI

Outerbridge RE (1961) The etiology of chondromalacia patellae. J Bone Joint Surg Br 43-B:752–757. https://doi.org/10.1302/0301-620X.43B4.752 PubMed DOI

Pridie KH (1959) A method of resurfacing osteoarthritic knee joints. J Bone Joint Surg 41:618–619

Tegner Y, Lysholm J (1985) Rating systems in the evaluation of knee ligament injuries. Clin Orthop Relat Res 198:43–49 DOI

Collins NJ, Misra D, Felson DT, Crossley KM, Roos EM (2011) 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) 63:208–228. https://doi.org/10.1002/acr.20632 DOI

Zamborsky R, Danisovic L (2020) Surgical techniques for knee cartilage repair: an updated large-scale systematic review and network meta-analysis of randomized controlled trials. Arthroscopy 36:845–858. https://doi.org/10.1016/j.arthro.2019.11.096 PubMed DOI

Słynarski K, de Jong W, Snow M, Hendriks JAA, Wilson CE, Verdonk P (2020) Single-stage autologous chondrocyte-based treatment for the repair of knee cartilage lesions: two-year follow-up of a prospective single-arm multicenter study. Am J Sports Med 48:1327–1337. https://doi.org/10.1177/0363546520912444 PubMed DOI

Maheshwer B, Polce E, Paul K, Williams BT, Wolfson TS, Yanke A, Verma NN, Cole BJ, Chachla J (2021) Regenerative potential of mesenchymal stem cells for the treatment of knee osteoarthritis and chondral defects: a systematic review and meta-analysis. Arthroscopy 37:362–378. https://doi.org/10.1016/j.arthro.2020.05.037 PubMed DOI

Steinwachs MR, Gille J, Volz M, Anders S, Jakob R, De Girolamo L, Volpi P, Schiavone-Panni A, Scheffler S, Reiss E, Wittmann U (2019) Systematic review and meta-analysis of the clinical evidence on the use of autologous matrix-induced chondrogenesis in the knee. Cartilage 13:42S-56S. https://doi.org/10.1177/1947603519870846 PubMed DOI PMC

Migliorini F, Berton A, Salvatore G, Candela V, Khan W, Longo UG, Denaro V (2020) Autologous chondrocyte implantation and mesenchymal stem cells for the treatments of chondral defects of the knee - a systematic review. Curr Stem Cell Res Ther 15:547–556. https://doi.org/10.2174/1574888X15666200221122834 PubMed DOI

Peterson L, Vasiliadis HS, Brittberg M, Lindahl A (2010) Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med 38:1117–1124. https://doi.org/10.1177/0363546509357915 PubMed DOI

Ogura T, Mosier BA, Bryant T, Minas T (2017) A 20-year follow-up after first-generation autologous chondrocyte implantation. Am J Sports Med 45:2751–2761. https://doi.org/10.1177/0363546517716631 PubMed DOI

Teo AQA, Wong KL, Shen L, Lim JY, Toh WS, Lee EH, Hui JHP (2019) Equivalent 10-year outcomes after implantation of autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation for chondral defects of the knee. Am J Sports Med 47:2881–2887. https://doi.org/10.1177/0363546519867933 PubMed DOI

Akgun I, Unlu MC, Erdal OA, Ogut T, Erturk M, Ovali E, Kantarci F, Caliskan G, Akgun Y (2015) Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg 135:251–263. https://doi.org/10.1007/s00402-014-2136-z PubMed DOI

Røsland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lønning PE, Bjerkvig R, Schichor C (2009) Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 69(13):5331–5339. https://doi.org/10.1158/0008-5472.CAN-08-4630 PubMed DOI

Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M, Koyama T, Nawata M, Tensho K, Kato H, Uematsu K, Kuroda R, Kurosaka M, Yoshiya S, Hattori K, Ohgushi H (2011) Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med 5:146–150. https://doi.org/10.1002/term.299 PubMed DOI

Fahy N, Alini M, Stoddart MJ (2018) Mechanical stimulation of mesenchymal stem cells: implications for cartilage tissue engineering. J Orthop Res 36:52–63. https://doi.org/10.1002/jor.23670 PubMed DOI

Martin JA, Buckwalter JA (2003) The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg Am 85:106–110. https://doi.org/10.2106/00004623-200300002-00014 PubMed DOI

Martin JA, Buckwalter JA (2001) Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis. Iowa Orthop J 21:1–7 PubMed PMC

Dozin B, Malpeli M, Camardella L, Cancedda R, Pietrangelo A (2002) Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: molecular and cellular aspects. Matrix Biol 21:449–459. https://doi.org/10.1016/s0945-053x(02)00028-8 PubMed DOI

Autologous Mesenchymal Stromal Cells Immobilized in Plasma-Based Hydrogel for the Repair of Articular Cartilage Defects in a Large Animal Model