Cartilage regeneration and inflammation modulation in knee osteoarthritis following injection of allogeneic adipose-derived mesenchymal stromal cells: a phase II, triple-blinded, placebo controlled, randomized trial

Abstract

Background Intra-articular injection of mesenchymal stromal cells (MSCs) with immunomodulatory features and their paracrine secretion of regenerative factors proposed a noninvasive therapeutic modality for cartilage regeneration in knee osteoarthritis (KOA). Methods Total number of 40 patients with KOA enrolled in two groups. Twenty patients received intra-articular injection of 100 × 106 allogeneic adipose-derived mesenchymal stromal cells (AD-MSCs), and 20 patients as control group received placebo (normal saline). Questionnaire-based measurements, certain serum biomarkers, and some cell surface markers were evaluated for 1 year. Magnetic resonance imaging (MRI) before and 1 year after injection was performed to measure possible changes in the articular cartilage. Results Forty patients allocated including 4 men (10%) and 36 women (90%) with average age of 56.1 ± 7.2 years in control group and 52.8 ± 7.5 years in AD-MSCs group. Four patients (two patients from AD-MSCs group and two patients from the control group) excluded during the study. Clinical outcome measures showed improvement in AD-MSCs group. Hyaluronic acid and cartilage oligomeric matrix protein levels in blood serum decreased significantly in patients who received AD-MSCs (P < 0.05). Although IL-10 level significantly increased after 1 week (P < 0.05), the serum level of inflammatory markers dramatically decreased after 3 months (P < 0.001). Expressions of CD3, CD4, and CD8 have a decreasing trend during 6-month follow-up (P < 0.05), (P < 0.001), and (P < 0.001), respectively. However, the number of CD25+ cells increased remarkably in the treatment group 3 months after intervention (P < 0.005). MRI findings showed a slight increase in the thickness of tibial and femoral articular cartilages in AD-MSCs group. The changes were significant in the medial posterior and medial anterior areas of ​​the tibia with P < 0.01 and P < 0.05, respectively. Conclusion Inter-articular injection of AD-MSCs in patients with KOA is safe. Laboratory data, MRI findings, and clinical examination of patients at different time points showed notable articular cartilage regeneration and significant improvement in the treatment group. Trial registration: Iranian registry of clinical trials (IRCT, https://en.irct.ir/trial/46), IRCT20080728001031N23. Registered 24 April 2018.

Transplantation of three mesenchymal stem cells for knee osteoarthritis, which cell and type are more beneficial? a systematic review and network meta-analysis

“…Notably, adipose tissue yields an MSC volume approximately 500 times greater than bone marrow [ 42 , 43 ]. While some researchers assert that BM-MSC exhibits superior cartilage generation capabilities compared to AD-MSC, others propose that augmenting the stromal vascular fraction derived from AD-MSC with growth factors and cytokines can also enhance cartilage growth [ 44 , 45 ]. Synovium-derived MSCs have been explored for assessing efficacy and functional outcomes in osteoarthritic knees, with several studies suggesting their superior chondrogenesis potential [ 46 , 47 ].…”

Autologous and Allogeneic Cytotherapies for Large Knee (Osteo)Chondral Defects: Manufacturing Process Benchmarking and Parallel Functional Qualification

“…However, the various advantages presented hereabove in favor of the implementation of allogeneic cell-based protocols are counterbalanced by the time- and resource-consuming process of obtaining the ad hoc regulatory approvals [ 50 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ]. Specifically, extensive risk-based approaches to the transition from autologous to allogeneic investigational medicinal products (IMP) must be followed, along with appropriate (i.e., specific and general) risk analyses (for product quality, purity, efficacy, safety, and stability; see Tables S4–S7 ) [ 48 ].…”

Hyaluronic acid, platelet-rich plasma, bone marrow aspirate concentrate, the stromal vascular fraction, or mesenchymal stem cells: which is the best candidate for treating knee osteoarthritis?

“…In another review, 12 articles comprising 539 patients and 576 knees treated with a single intraarticular injection of MSCs for knee OA were analyzed by Kyriakidis et al (2023) 28 , who reported that MSC injection is a safe and effective treatment for K-L grade I-III knee OA. Interestingly, a triple-blinded, placebo-controlled, randomized trial compared the treatment efficacy of allogeneic MSCs (from adipose tissue) to that of normal saline (control group) and confirmed that allogeneic MSC injection is safe and significantly improves treatment efficacy 29 . The efficacy of this therapy depends on various factors, including the dose of cells, the kind of MSCs, and the grade of knee OA.…”

“…Matas et al (2019) reported that two doses of UC-MSCs (on day 0 and after 6 months, 20.10 6 cells per dose) were better than a single dose of 20.10 6 UC-MSCs 55 . In a recent publication, Sadri et al (2023) used a high dose of 100.10 6 allogeneic AT-MSCs to treat knee OA patients. At this high dose, the authors found that intra-articular injection is safe, as indicated by significant improvements in laboratory data, MRI findings, and clinical examination at the 12-month follow-up 29 .…”

“…In a recent publication, Sadri et al (2023) used a high dose of 100.10 6 allogeneic AT-MSCs to treat knee OA patients. At this high dose, the authors found that intra-articular injection is safe, as indicated by significant improvements in laboratory data, MRI findings, and clinical examination at the 12-month follow-up 29 . Based on 14 studies with 564 patients, categorized the treatments into four doses, namely < 10.10 6 MSCs, 10-50.10 6 MSCs, 50-100.10 6 MSCs, and > 100.10 6 MSCs, and recommended that a dose of 50-100.10 6 MSCs confers superior benefits 56 .…”