Table 1.
Characteristics of the studies included in the comparisons
| Study | Year | Country | Experimental subject | Sex n | Intervention arms & subjects | Age | Weight | Model | Source of exosomes | Isolation method | Treatment group (method/dose of Exos) | Treatment cycle | Duration of follow-up (weeks) | Sample area | Outcome index | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Zhu et al | 2017 | China | C57B/L10 mice | Female n = 35 | Normal (n = 5), iMSC-Exos treatment (n = 10), SMMSC-Exos treatment (n = 10), OA (n = 10) | 6 week-old | – | CIOA | iMSC/ SMSC | Ultracentrifugation | Intra-articular injection/8 μl | On days 7, 14, and 21 after OA induction | 4 | knee joints | 1. Macroscopic (ICRS score) 2. Histology (OARSI score) 3. IHC (Collagen I and II) 4. Chondrocyte migration and proliferation assays | [23] |
| Tao et al | 2017 | China | SD rats | Male n = 30 | Normal (n = 10), OA (n = 10), OA + SMSC-Exos group (n = 10) | Approximately 12 weeks old | 300–350 g | Complete transection of the medial collateral ligament, ACLT and DMM | SMSC | Unknown | Intra-articular injection/100 μl | Weekly on weeks 8, 9 and 10 after OA induction | 12 | knee joints | 1. Histology (OARSI score) 2. IHC (Collagen II, ACAN) 3. Chondrocyte counts | [24] |
| Wang et al | 2017 | China | C57BL/6 J mice | Unknown n = 32 | Sham group (n = 12), OA (n = 10), Exo group (n = 10) | 2 month-old | – | DMM | ESC-MSCs | Ultracentrifugation | Intra-articular injection/5 μl | Twice a week at week 4 after OA induction | 8 | knee joints | 1. Histology (OARSI score) 2. IHC (Collagen II and ADAMTS5) | [25] |
| Cosenza et al | 2017 | France | C57BL/6 mice | Unknown n = 45 | Normal group (n = 15), OA (n = 15), Exo group (n = 15) | 3 days old | – | CIOA | BMSC | Ultracentrifugation | Intra-articular injection/5 μl |
Weekly at week 1 after OA induction |
6 | knee joints |
1. Bone parameter 2. Confocal laser scanning microscopy 3. Histology (OARSI score, osteophyte score) 4. qPCR (ACAN, COL2B, COL1, MMP-13, ADAMTS5 and iNOS) |
[26] |
| Wu et al | 2019 | China | C57BL/6 mice | Male n = 39 | Unknown | 9 week-old | – | DMM | IPFP-MSC | ExoQuick ™ reagent kit and ultrafiltration | Intra-articular injection/10 μl |
Twice a week at week 4 after OA induction |
8 | knee joints |
1. Histology (OARSI score) 2. IHC (Collagen II, MMP13 and ADAMTS5) 3. Gait analysis 4. Apoptosis |
[27] |
| Zavatti et al | 2019 | Italy | CD® rats | Unknown n = 12 | OA (n = 4), Exo group (n = 8) | 8 week-old | – | MIA-OA | AFSC | Ultracentrifugation | Intra-articular injection/100 μg | twice(10 days of distance) after OA induction | 3 | knee joints | 1. Histology (OARSI score) 2. IHC (Collagen II, HMIT and Sox9) 3. pain level | [28] |
| Zhou et al | 2020 | China | C57BL/6 J mice | Male n = 23 | Control (n = 5), OA (n = 6), BMSC-EXOs treatment (n = 6), pBMSC-EXOs treatment (n = 6) | 6 week-old | – | CIOA | BMSC | total exosome isolation kit | Intra-articular injection | On days 7, 14, and 21 after OA induction | 4 | knee joints | 1. Histology (OARSI score) 2.Chondrocyte counts 3. Wound-healing assays | [29] |
| Li et al | 2020 | China | C57BL/6 mice | Unknown n = 60 | Control (n = 20), OA (n = 20),BMSCs-exosomes treatment group (n = 20) | – | 25–30 g | Surgically induce instability in the lumbar spine | BMSC | Ultracentrifugation | Tail vein injection/200 μl | weekly for 4 weeks after surgery | 8 | Lumbar facet joint |
1. Pain assessment (vocalization threshold) 2. Bone parameter 3. Histology (OARSI score) 4.Immunofluorescence (MMP13 and ACAN) |
[30] |
| Zhang et al | 2020 | China | SD rats | Male n = 36 | Sham group (n = 12), OA group (n = 12), BMSC-derived exosomes group (n = 12) | Adult | 200 − 250 g | ACLT and DMM | BMSC | Ultracentrifugation | Intra-articular injection/10 μl |
Once every three days at 4 weeks after OA induction |
8 | knee joints |
1. Bone parameters 2. Histology (OARSI score, Osteophyte score) 3. IHC (Collagen II and X) 4. Cytokine determination in synovial fluid |
[31] |
| He et al | 2020 | China | SD rats | Male n = 24 | Normal group (n = 8), OA (n = 8), Exo group (n = 8) | 10 week-old | – | MIA-OA | BMSC | Ultracentrifugation | Intra-articular injection/100 μ | Weekly at week 1 after OA induction | 6 | knee joints |
1. Histology (OARSI score) 2. IHC (Collagen II and MMP13) 3. Pain assessment 4. Chondrocyte migration 5. qPCR (TGFβ1, PCNA, Casp3, COL2A1, ACAN, MMP13 and ADAMTS5) 6. ELISA(IL-1β, IL-6, IL-10 and TNF-α) |
[32] |
| Xu et al | 2020 | China | SD rats | Male n = 40 | Normal group (n = 5), OA (n = 5), Exo group (n = 5) | – | 200–220 g | DMM | SF-MSCs | Ultracentrifugation | Intra-articular injection/100 μl | Weekly at week 1 after OA induction | 5 | knee joints |
1. Histology (OARSI score) 2. IHC (Collagen I, II and ACAN) |
[33] |
| Wang et al | 2020 | China | Specific pathogen-free (SPF) BALB/C mice | Unknown n = 30 | Normal group (n = 10), OA (n = 10), Exo group (n = 10) | – | – |
Low-temperature induction |
SMSC | Unknown | Intra-articular injection/30 μl |
20 days later; continuous injection for 2 weeks, once a day |
7 | knee joints |
1. Histology (OARSI score) 2. IHC (Collagen II and Caspase-3) 3. Chondrocyte counts 4. Chondrocyte migration |
[34] |
| Rong et al | 2020 | China | SD rats | Female n = 60 | Normal group (n = 10), OA (n = 10), Exo group (n = 10) | 7–8 weeks | 200–250 g | ACLT and DMM | BMSC | Ultracentrifugation | Intra-articular injection/200 μl | In the 4th week after operation | 8 | knee joints |
1. Histology (OARSI score and osteophyte score) 2. Bone parameters 3. IHC (Collagen II and PCNA) |
[35] |
| Woo et al | 2020 | Korea | SD rats | Male n = 50 | Four treatment groups (n = 6) | 7 weeks | 200–250 g | MIA-OA(subacute arthritis model) | AD-MSC | TFF | Intra-articular injection/30 μl | Weekly at week 1 after OA induction | 4 | knee joints | 1. Histology (OARSI and Mankin score) 2. IHC (MMP13) 3. chondrocyte proliferation 4. qPCR (MMP-1, MMP-3, MMP-13, COL2A1 and ADAMTS-5) | [36] |
| SD rats | Male n = 50 | Four treatment groups (n = 6) | 7 weeks | 200–250 g | MIA-OA(chronic arthritis model) | AD-MSC | TFF | Intra-articular injection/30 μl |
Twice a week for 40 days at week 2 after OA induction |
8 | ||||||
| C57BL/6 mice | Male n = 18 | Unknown | 9 weeks | 20–25 g | DMM | AD-MSC | TFF | Intra-articular injection/6 μl | Weekly at week 5 after OA induction | 11 | ||||||
| Wang et al | 2020 | China | C57 mice | Male n = 20 | Sham group (n = 5), OA (n = 5), OA + SMSC-EV group (n = 5) | 8 weeks old | 25–30 g | Complete transection of the medial collateral ligament, ACLT and DMM | SMSC | Ultracentrifugation | Intra-articular injection/5 μl | every 3 days for 4 weeks after OA induction | 12 | knee joints |
1. Histology (OARSI score) 2. Cytokine determination in synovial fluid 3. Chondrocyte counts |
[37] |
| Tang et al | 2021 | China | SD rats | male n = 24 | Normal group (n = 6), treatment with hUC-MSCs (n = 6), treatment with hUC-MSC-sEVs (n = 6), control (n = 6) | 8 weeks old | – | ACLT | hUC-MSCs | commercial kit | intra-articular injection/200 μL | once a week for 4 weeks | 9 | Knee joint | 1. Histology (OARSI) 2. IHC (Collagen II, ADAMTS5 and MMP13) 3. Chondrocyte migration | [38] |
| Hoda Fazaeli et al | 2021.9 | Qom, Iran | BALB/C mice | Female n = 40 | normal (n = 5), OA (n = 5), AD-Exo (n = 10), BMM-Exo (n = 10), sham (n = 10) | 3 weeks | – | Ciprofloxacin | BM-MSC/AD-MSC | Exocib exosome extraction kit | Intra-articular injection/25 μl | On the 15th, 22nd, and 29th day after OA induction | 9 | tibia | 1. Histology (OARSI score) 2. IHC (Collagen I and II) 3.qPCR (collagen type I, Sox9, collagen type II, and aggrecan) | [39] |
| Jin et al | 2021.1 | China | SD rats | male n = 20 | Control (n = 5), OA (n = 5),EXOs treatment group (n = 5) | – | 358 ± 5 g | ACLT and DMM | BM-MSC | Ultracentrifugation | Intra-articular injection/100 μl | Weekly after OA induction | 8 | knee joints | 1. Histology (OARSI score, Mankin score) 2.Bone parameter analyses 3. qPCR (ADAMTS5, MMP‐13 and COL2A1) | [40] |
| Liu et al | 2022 | China | SD rats | Female n = 40 | Sham (n = 10), PBS (n = 10), hUSC-Exos (n = 10) | 12 week-old | 250 ± 20 g | ACLT and DMM | hUSCs | Ultracentrifugation | Intra-articular injection/100 mL | 30 days after OA surgery, once a week | 4 | knee joints | 1.Behavioral and Macroscopic Evaluation 2. Histology (OARSI score) 3. IHC (Collagen I and II, VEGFA) | [41] |
| Li et al | 2022 | China | SD rats | Unknown n = 15 | Normal group (n = 5), OA (n = 5), Exo group (n = 5) | – | 230–280 g | MIA-OA | AD-MSC | Ultracentrifugation | Intra-articular injection/250 μl | Once after 2 weeks of MIA injection | 2 | knee joints | 1.Histology (OARSI score) 2.IHC (Collagen II) 3.Chondrocyte counts | [42] |
AD-MSC, adipose tissue-derived mesenchymal stem cell; BMSC, bone marrow-derived mesenchymal stem cell; CIOA, collagenase-induced osteoarthritis; DMM, destabilization of the medial meniscus; ESC-MSC, embryonic stem cell-derived mesenchymal stem cell; ICRS, international cartilage repair society; IHC, immunohistochemistry; iMSC, induced pluripotent stem cell-derived mesenchymal stem cell; MIA-OA, monosodium iodoacetate induces osteoarthritis; MSC, mesenchymal stem cell; OA, osteoarthritis; OARSI, osteoarthritis research society international; SF-MSC, synovial fluid-derived mesenchymal stem cell; SMSC, synovium-derived mesenchymal stem cell; TFF, T angential flow filtratio; hUSC, human urine–derived stem cells; ACLT, anterior cruciate ligament transection; IPFP-MSC, infrapatellar fat pad mesenchymal stem cell; AFSC, amniotic fluid stem cell; hUC-MSCs, human umbilical cord-derived mesenchymal stem cells