Table 1.
Systematic reviews and meta-analyses on the effectiveness of intraarticular injections of MSCs in OA of the knee joint.
| Authors [Reference] |
Year | Methods and Results | Participants | Level of Evidence |
Conclusions |
|---|---|---|---|---|---|
| Xia et al. [34] | 2015 | MSCs injection had no substantial impact on pain. | 314 patients (7 RCTs) | I | The results of this review should be validated utilizing methodologically precise trials. |
| Cui et al. [35] | 2016 | MSC therapy in subjects with knee OA demonstrated continual effectiveness for 2 years. | 565 patients (18 clinical trials) | I | MSC utilization improved the overall results. |
| Xing et al. [19] | 2018 | This study demonstrated that modest reliance could be placed on safety of MSCs treatment for knee OA. | 23 animal studies | I | More high-quality research with high internal and external validity is still needed. |
| Ha et al. [36] | 2019 | All reports except two found significantly superior clinical results in the MSCs group. | 17 studies in patients with knee OA (6 RCTs, 8 prospective observational studies, 3 retrospective case-control studies). | III | Intraarticular MSCs render ameliorations in pain and function in knee OA at short-run follow-up (<28 months) in many cases. |
| Kim et al. [37] | 2019 | This study found significant improvements after treatment. | 220 patients (5 RCTs) | II | Intraarticular MSCs have limited evidence in pain alleviation and functional betterment in knee OA. |
| Di Matteo et al. [38] | 2019 | Twenty-three manuscripts were included in the final analysis. | 23 manuscripts about patients with knee OA (only 4 were RCTs) | NA | The poor quality of the reported studies averted any recommendation on the utilization of either product in a clinical practice. |
| D’Arrigo et al. [39] | 2019 | Encouraging in vitro outcomes were obtained in terms of enhanced cell proliferation, decrease of swelling. | Twenty in vivo and in vitro studies were analyzed. | NA | The different effects of EVs and secretome, and the identification of subjects who may benefit more from intraarticular injections of MSCs must be clarified. |
| Álvarez Hernández et al. [40] | 2020 | Data demonstrated clinical amelioration in 60% of subjects. Structural benefit was found in 50% of subjects. | 169 patients (3 RCTs, 6 QCTs) | NA | Intraarticular implants of MSCs appeared to be safe with no serious complications. Low-quality evidence averts conclusions regarding efficacy. |
| Song et al. [41] | 2020 | MSC therapy could substantially reduce VAS in a 1-year follow-up study compared with controls. | 58 patients (15 RCTs, two retrospective studies and two cohort studies) | NA | These authors suggested that MSC treatment could be efficacious and safe therapy for the treatment of OA. |
| Dai et al. [42] | 2021 | Compared with placebo, there was no significant difference in VAS for pain, WOMAC pain score, WOMAC function score, or WOMAC stiffness score for MSCs. | 13 RCTs (patients) |
I | Intraarticular MSC injection was not encountered to be superior to placebo in pain alleviation and functional betterment for subjects with knee OA. |
| Maheshwer et al. [43] | 2021 | There was no substantial difference in pain alleviation between MSC treatment and controls. | 439 patients (25 studies) | II | MSCs rendered functional benefit only in subjects who experienced concurrent surgery. |
| Qu et al. [44] | 2021 | MSC treatment substantially diminished VAS, WOMAC pain, WOMAC stiffness, and WOMAC function scores at a long-run follow-up (1 or 2 years). | 476 patients (9 RCTs) | NA | The results of this study suggested that MSCs were a promising alternative for the management of subjects with knee OA. |
| Tan et al. [45] | 2021 | All studies reported amelioration in the results after MSC therapy. | 440 knees (19 studies) | NA | Intraarticular injections of MSCs without any adjuvant therapies improved pain and function for OA. |
| Naja et al. [46] | 2021 | This study assessed 7 approaches with WOMAC at 1 year: injection of PRP, corticosteroids, MSCs, hyaluronic acid, ozone, administration of NSAIDs with or without the association of physiotherapy. | 13 trials (patients) |
NA | The results of treatments utilizing MSCs and PRP for the management of knee OA were associated with long-run improvements in pain and function. |
| Muthu et al. [47] | 2021 | At 6 months, culture expanded MSCs demonstrated pain alleviation. | 767 patients (17 studies) | NA | Culture expansion of autologous MSCs was not a necessary factor to attain better results in the treatment of knee OA. |
| Zhao et al. [48] | 2021 | This meta-analysis compared AD-MSCs, LP-PRP, and placebo. At 6 months, VAS scores and WOMAC pain subscores demonstrated that AD-MSCs were the best treatment alternative. | 43 studies (patients) |
II | During 6 months of follow-up, AD-MSCs alleviated pain the best; LP-PRP was most efficacious for functional amelioration. |
| Jeyaraman et al. [49] | 2021 | At 6 months, 1 year and 2 years, AD-MSCs demonstrated substantially better VAS and WOMAC amelioration than BM-MSCs, respectively, compared to controls. | 811 patients (9 studies) | NA | This study established the effectiveness, safety, and superiority of AD-MSC transplantation, compared to BM-MSC, in the treatment of OA. |
| Muthu et al. [50] | 2021 | These authors categorized the studies based on the MSC count used in them into four cohorts, namely <1 × 107 MSCs (Cohort I), 1–5 × 107 MSCs (Cohort II), 5–10 × 107 MSCs (Cohort III), and >10 × 107 MSCs (Cohort IV). | 564 patients (14 studies) | NA | Cohort III demonstrated consistent substantial amelioration in pain and functional result analyzed compared to the other cohorts. Therefore, these authors advised a cell volume of 5–10 × 107 cells. |
| Wei et al. [51] | 2021 | The MSCs were deemed superior over placebo for pain alleviation and ameliorated function in KOA, but demonstrated no substantial differences for cartilage regeneration. Among all the MSCs, the AD-MSCs most effectively alleviated pain. | 203 patients (8 studies) | NA | The findings of this study suggested that MSCs were effective in the treatment of knee OA. However, the evidence did not support the utilization of MSCs for ameliorating cartilage repair in subjects with knee OA. |
| Wiggers et al. [52] | 2021 | After 1 year, 19 of 26 (73%) clinical outcome parameters ameliorated with MSCs compared with control. | 408 patients (14 RCTs) | NA | These authors encountered a positive impact of autologous MSC therapy compared with control treatments on PROMs, and illness severity. The quality of this evidence was low. |
| Álvarez Hernández et al. [40] | 2022 | Clinical improvement was found in 60% of subjects. Structural benefit was seen in 50% of subjects. | 169 patients (252 articles) | NA | Intraarticular implants of MSCs appeared to be safe, with no serious complications. Low-quality evidence precludes conclusions regarding effectiveness in this review. |
| Dhillon et al. [53] | 2022 | After a follow-up 23.4 months, weighted averages of the WOMAC, macroscopic ICRS, subjective IKDC, and VAS scores all demonstrated amelioration from before to after treatment. | 385 patients (7 studies) | NA | Subjects experiencing management of knee OA with hUC-MSCs might be expected to improve. |
| Jeyaraman et al. [54] | 2022 | At 6 months, both direct and vehicle-based delivery of MSCs demonstrated substantially better VAS amelioration. |
963 patients (21 studies) | NA | Employed methods of vehicle-based delivery of MSCs, such as PRP and hyaluronic acid, did not show better outcomes compared to direct delivery. |
| Shoukrie et al. [55] | 2022 | Substantial ameliorations were seen in the MSCs cohorts regarding KOOS, VAS, WOMAC, and MRI. Moreover, no serious complications were found. | 10 studies (723 patients) |
NA | Intraarticular injections of MSCs were efficacious and safe in alleviating pain and ameliorating motor function in subjects with knee OA in the short run. |
MSCs = vesicles; QCTs = Qualifying Clinical Trials; VAS = Visual analog scale; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index; PRP = platelet-rich plasma; NSAIDs = nonsteroidal anti-inflammatory drugs; AD-MSCs = Adipose tissue-derived MSCs; LR-PRP = Leukocyte-rich platelet-rich plasma; BM-MSCs = Bone marrow-derived MSCs; PROMs = Mesenchymal stem cells; OA = Osteoarthritis; n = Number of patients; LoE = Level of evidence; RCTs = Randomized controlled trials; EVs = Extracellular Patient-related outcomes; ICRS = International Cartilage Regeneration and Joint Preservation Society; IKDC = International Knee Documentation Committee; hUC-MSCs = human umbilical cord-derived MSCs; KOOS = Knee injury and Osteoarthritis Outcome Score; MRI = Magnetic resonance imaging; NA = Not available.