Mesenchymal Stromal CellsIntra-articular implantation of autologous bone marrow–derived mesenchymal stromal cells to treat knee osteoarthritis: a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial
Introduction
Osteoarthritis (OA) is the most recurrent type of arthritis and the most common cause of disability in the elderly. The prevalence of OA is increasing in the United States and expected to double by 2020 [1]. OA is diagnosed by structural abnormalities such as cartilage loss and osteophyte development or symptoms associated with these abnormalities that include pain as the major symptom of OA, tenderness, limitations in motion, joint deformity and instability [2].
Current treatment options for the frequently occurring OA in the knee joint aim to reduce the inflammation and relieve the pain without addressing the cause of OA [3], for example, by performing total knee replacement [4]. Recent studies have evaluated the effects of treating focal cartilage defects through autologous chondrocyte implantation (ACI), matrix-induced autologous chondrocyte (MACI) implantation or tissue engineering [5], [6], [7], [8]. However, ACI or MACI cannot treat OA because of its large, non-contained cartilage defect and pathogenesis [9].
An alternative treatment for OA of the knee is the intra-articular implantation of mesenchymal stromal cells (MSCs) [10], [11], [12], [13], [14], [15], [16], [17], [18]. In our previous studies, we demonstrated that implantation of MSCs in different OA-affected joints (knees, ankles or hips) is safe and therapeutically beneficial [19], [20]. Also, it has been demonstrated that intra-articular injection of autologous bone marrow–MSCs in knee OA patients led to significant improvements after 1 year [21]. Accordingly, this group confirmed the beneficial effects of MSC treatment using a long-term follow-up (2 years) and demonstrated both the feasibility and safety of the treatment as the well as clinical improvements [22]. Furthermore, intra-articular infusion of autologous bone marrow–MSCs in patients with OA resulted in cartilage repair, long-lasting amelioration of pain and improvements in quality of life (up to 4 years) [23], [24]. In a systematic review, McIntyre et al. analyzed 14 studies on 227 individuals with OA who were treated with bone marrow– or adipose tissue–derived MSCs [10]. MSCs were administered into the knees (n = 216), ankles (n = 6) or hips (n = 5). The mean follow-up time was 24.4 months after MSC therapy. They concluded that autologous intra-articular MSC therapy is safe, with overall positive clinical outcomes [10]. Two meta-analyses were performed to evaluate the therapeutic efficacy and safety of MSCs used to treat patients with knee OA [11], [12]. One meta-analysis examined 18 clinical trials on knee OA, which included 10 single-arm prospective studies, four quasi-experimental studies and four randomized controlled trials (RCTs) for a total of 565 treated patients [11]. Another meta-analysis assessed 11 RCTs that enrolled 582 patients with knee OA [12]. The results of these two analyses demonstrated that MSC administration improved the overall outcomes for patients with knee OA, including pain relief and functional improvements. These improvements were observed from basal evaluations in at least one clinical outcome measure, particularly at 12 and 24 months after follow-up. No study has reported any major adverse events attributed to MSC therapy. There is sufficient proof supporting the safety of MSC therapy for knee OA [13], [14], [15], [16], [17], [18]; however, the efficacy outcomes are not convincing due to limitations of the current studies [25]. Thus, additional clinical trials are necessary.
MSCs differentiate into chondrocytes [26] and can control immune activity, thereby reducing inflammation and pain [27]. Moreover, it has been demonstrated that allogeneic MSCs produce a greater increase in the peak of inflammation at 24 h compared with autologous MSC groups [28].
Although clinical improvements have been reported in OA trials, the overall quality of the studies is poor. Heterogeneity and lack of study blindness limit the ability to draw firm conclusions regarding the efficacy of MSC treatments. Therefore, larger, blinded, RCTs are needed to support these encouraging preliminary results.
In this triple-blind RCT, we randomly divided patients with OA of the knee into two groups of study and control. The study group received an intra-articular implantation of 40 × 106 autologous bone marrow–derived MSCs, and the control group received saline (placebo). The objectives of this study were to evaluate the safety and efficacy of the implanted MSCs according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC) total score and its subscales of pain and physical function, assessment of walking distance and visual analog scale (VAS).
Section snippets
Study design
This triple-blind RCT study evaluated the safety and efficacy of MSC implantation based on pain level, walking distance and other functional variables in adults with knee OA. We conducted this study in accordance with the Declaration of Helsinki after receiving approval from the Ethics Committee at Royan Institute (approval code: EC/90/1026). This trial was registered at ClinicalTrials.gov (National Institutes of Health number: NCT01504464). Prior to their enrollment in the study, the
Results
Patients enrolled in this study between January 2012 and February 2016. We assessed 250 patients to determine eligibility. Of these patients, 47 were selected and randomly assigned to receive either MSCs (n = 22) or placebo (n = 25). Three patients in the MSC group and one patient in the placebo group dropped out of the study. For the 3-month follow-up, one patient from the study group and one patient from the placebo group did not participate but returned and were assessed for the 6-month
Discussion
This randomized, triple-blind, placebo-controlled phase 1/2 clinical trial assessed the safety and efficacy of intra-articular implantation of 40 × 106 autologous bone marrow–derived MSCs in patients with knee OA. The results indicate that painless walking distance increased in both groups; however, this increase was significantly higher in the MSC group. Reduction in pain scores might explain the improvement in knee flexion angle and increased painless walking distance in these patients.
Acknowledgments
We would like to express our gratitude to Dr. Moininia for the bone marrow aspirations and to the members of the Department of Regenerative Medicine for their critical comments. We would like to thank the patients and their families in particular for participating in this study.
Disclosure of interests: This trial was supported by a grant from the Royan Institute.
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2022, Journal of ArthroplastyCitation Excerpt :Three studies compared BMSC to HA, but no improvement differences were demonstrated [72,75,82]. As compared to NS, BMSC demonstrated higher WOMAC pain scores but equivocal VAS scores [70,78]. As compared to exercise therapy, BMSC provided equivalent range of motion and VAS, Short Form 12-Item, Levels of Emotional Awareness Scale, as well as Knee Society Score at 3-month follow-up [69].
Protecting the regenerative environment: selecting the optimal delivery vehicle for cartilage repair—a narrative review
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These authors contributed equally to this work.