Additional Table 1.
Characteristics of the included studies
| Studies | Country | The sample size of each group | Animal | Sex | Weight | TBI and SCI model | MSC source | Immunocompatibilit y | EV isolation and size/morphology analysis | EV positive markers | EV negative markers | Dosage regimen (time, dosage, the number of doses, and route) | Outcomes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Zhang et al., 2015 | USA | 1.TBI + exosomes (n=8) 2.TBI + PBS (n=8) 3.sham (n=8) |
Adult Wistar rats | Male | 325 ± 11g (2-3 months old) | CCI: a 6-mm-diameter tip at a rate of 4 m/s and 2.5 mm of compression |
Rat bone marrow | Allogeneic | ExoQuick exosome isolation kit; 40-120 nm (TEM); 116 ± 49 nm (NTA) (small EVs) | Alix | Not described | 24 h after TBI; 100ug; 1 dose; Intravenous | mNSS, Foot Fault Test |
| Zhang et al., 2017 | USA | 1.TBI+ exosomes from hMSCs in 3D culture (Exo-3D) (n=8) 2.TBI + exosomes from hMSCs in 2D culture (Exo-2D) (n=8) 3.TBI + liposomes (Lipo) (n=8) 4.Sham (n=8) |
Adult Wistar rats | Male | 317 ± 10 g (2-3 months old) | CCI: a 6-mm-diameter tip at a rate of 4 m/s and 2.5 mm of compression |
Human bone marrow | Xenogeneic | ExoQuick exosome isolation kit; Not described | CD9, CD63, and CD81 | Not described | 24 h after TBI; 100ug; 1 dose; Intravenous | mNSS, Foot Fault Test |
| Ni et al., 2019 | China | 1.TBI + Exosomes (n=7) 2.TBI + PBS (n=7) 3.Sham (n=7) |
C57BL/6J mice | Male | 12-14 weeks old | CCI: a velocity of 4 m/s and a dwell time of 150 ms and a deformation depth of 1.0 mm using a 3-mm-diameter impactor tip | Rat bone marrow | Allogeneic | Ultracentrifugation; 30-100 nm (TEM); 110.4 nm (NTA) (small EVs) | CD63 and TSG101 | Cytochrome c | 15 min after TBI; 30ug; 1 dose; Retro-orbital injection | mNSS |
| Yang et al., 2019 | China | 1.TBI + MiR-124 Enriched Exosomes (n=6) 2.TBI (n=6) 3.Sham + MiR-124 Enriched Exosomes (n=6) 4.Sham (n=6) |
SD rats | Male | 250–300 g (8– 10 weeks old) | CCI: a velocity of 3 m/s and a dwell time of 100 ms and a deformation depth of 1.5 mm using a 3-mm-diameter impactor tip | Rat bone marrow | Allogeneic | ExoQuick exosome isolation kit; 40-100 nm (TEM); 77.1 ± 19.5 nm (NTA) (small EVs) | CD9, CD63, and CD81 | Not described | 24 h after TBI; 100ug; 1 dose; Intravenous | mNSS |
| Chen et al., 2020 | China | 1.TBI + hADSC (n=8) 2.TBI + exosomes (n=8) 3.TBI + PBS (n=8) 4.Sham (n=8) |
Adult SD rats | Male | 300 ± 11 g (6-8 weeks) | CCI: a 25-g weight fall from a height of 20 cm | Human adipose tissue | Xenogeneic | Ultracentrifugation; 40-100 nm (TEM) (small EVs) | CD63 and HSP70 | Not described | 24 h after TBI; 20ug; 1 dose; Contralateral intracerebroventricular | mNSS, Foot Fault Test |
| Xu et al., 2020 | China | 1.TBI + BDNF-induced MSCs-Exo (n=6) 2.TBI + MSCs-Exo (n=6) 3.TBI + PBS (n=6) 4.Sham (n=6) |
Adult SD rats | Male | 220–250 g | CCI: a velocity of 4.0 m/s and a dwell time of 200 ms and a deformation depth of 2.5 mm |
Rat bone marrow | Allogeneic | Ultracentrifugation; 30-150 nm (TEM); 110 nm (NTA) (small EVs) | CD9 and CD63 | Not described | 24 h after TBI; 100ug; 1 dose; Intravenous | mNSS |
| Zhang et al., 2020b | China | 1.TBI + 200 μg exosomes (n=8) 2.TBI + 100 μg exosomes (n=8) 3.TBI + 50 μg exosomes (n=8) 4.TBI + PBS (n=8) 5.Sham (n=8) |
Adult Wistar rats | Male | 339.2 ± 13.6 g (3 months) | CCI: a 6-mm-diameter tip at a rate of 4 m/s and 2.5 mm of compression |
Human bone marrow | Xenogeneic | Ultracentrifugation; 200 nm (TEM); 122 nm (NTA) (small EVs) | Alix and Hsp70 | β-actin | 1,4, or 7 days after TBI; 50,100, or 200 ug; 3 doses; Intravenous | mNSS, Foot Fault Test |
| Zhang et al., 2021c | China | 1.TBI + MiR-17-92 enriched exosomes (n=8) 2.TBI + exosomes (n=8) 3.TBI + PBS (n=8) 4.Sham (n=8) |
Young Wistar rats | Male | 2–3 months | CCI: a 6-mm-diameter tip at a rate of 4 m/s and 2.5 mm of compression |
Human bone marrow | Xenogeneic | Ultracentrifugation; 200 nm (TEM,NTA) (small EVs) | Alix and Hsp70 | β-actin | 24 h after TBI; 100ug; 1 dose; Intravenous | mNSS, Foot Fault Test |
| Huang et al., 2017 | China | 1.SCI + MSC-exosomes (n=5) 2.SCI + PBS (n=5) |
Adult SD rats | Male | 180–220 g | T10, moderate contusion injury: a modified Allen’s weight drop apparatus (8 g weight at a vertical height of 40 mm, 8 g×40 mm) | Rat bone marrow | Allogeneic | Ultracentrifugation; 20-130 nm (TEM,NTA) (small EVs) | CD9, CD63, and CD81 | Not described | 1.5 h after SCI; 100 μg (1 × 10^10 particles); 1 dose; Intravenous | BBB |
| Kim et al., 2018 | Korea | 1.SCI + iron oxide nanoparticle (IONP)– incorporated exosome in the presence of a magnet (n=10) 2.SCI + iron oxide nanoparticle (IONP)– incorporated exosome in the absence of a magnet (n=10) 3.SCI + exosome (n=10) 4.SCI + PBS (n=10) 5.Sham (n=10) |
C57BL/6 mice | Not described | 20-25 g (8 weeks) | T10-T11, compression injury: a 20 G metal impounder was then gently placed on T10-T11 dura for 1 min | Human bone marrow | Xenogeneic | Serial extrusion, density-gradient ultracentrifugation, and magnetic sorting; TEM,NTA; 151.4 ± 32.5 nm (NV) and 158.7 ± 40.7 nm (NV-IONP) (small EVs) | CD9 and CD63 | Not described | 1 h after SCI; 40 μg; 1 dose; Intravenous | BMS |
| Li et al., 2018 | China | 1.SCI + miR-133b exosomes (n=6) 2.SCI + miR-con exosomes (n=6) 3.SCI + PBS (n=6) 4.Sham (n=6) |
Adult SD rats | Male | 250-300 g | T10, compression injury: an aneurysm clip of 35 g closing force for 60 s | Rat bone marrow | Allogeneic | ExoQuick exosome isolation kit; Not described | CD9, CD63, and CD81 | Not described | 24 h after SCI; 100 μg; 1 dose; Intravenous | BBB |
| Ruppert et al., 2018 | United States | 1.SCI + MSC-EVs (n=16) 2.SCI + vehicle (n=6) 3.Sham (n=6) |
Adult SD rats | Male | 225-250 g | T10, moderate contusion injury: Infinite Horizon Impactor (150 kdynes of force with 1 s dwell) | Human bone marrow | Xenogeneic | Sequential filtration; 75-165 nm (TEM,NTA) (small EVs) | CD9, CD63, CD81, HSP70, and LAMP-1 | Not described | 3 h after SCI; 1 × 10^9 particles; 1 dose; Intravenous | BBB |
| Sun et al., 2018 | China | 1.SCI + 200μg exosomes (n=8) 2.SCI + 20μg exosomes (n=8) 3.SCI + PBS (n=8) |
C57BL/6 mice 4 Sham (n=8) |
Female | 17–22 g (7-8 weeks) | T11, contusion injury: a 10 g rod dropped at a height of 6.25 mm | Human umbilical cord | Xenogeneic | Ultrafiltration centrifugation combined with ultracentrifugation; 70 nm (TEM,NTA) (small EVs) | CD9 and CD63 | β-tubulin and LaminA | 30 min after SCI; 20 μg or 200 μ g respectively; 1 dose; Intravenous | BMS |
| Wang et al., 2018 | China | 1.SCI + MSC-exosomes (n=10) 2.SCI + MSC (n=10) 3.SCI + PBS (n=10) 4 Sham (n=10) |
Adult SD rats | Male | 200-250 g | T10, contusion injury: Infinite Horizon Impactor (200 kilodyne) | Rat bone marrow | Allogeneic | Ultracentrifugation; 30-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and CD81 | Not described | 30 min after SCI; 40 μg; 1 dose; Intravenous | BBB |
| Guo et al., 2019 | United States | 1.SCI + ExoPTEN (IN) (n=7) 2.SCI + Exosome (IN) (n=10) 3.SCI + ExoPTEN (IL) (n=4) 4.SCI + PTEN-siRNA (IL) (n=3) 5.SCI + PBS (n=15) IL: intralesional; IN: intranasal. |
Adult SD rats | Female | 200-250 g | T10, complete transection injury: microscissor | Human bone marrow | Xenogeneic | Ultracentrifugation; 111±64 nm (TEM,NTA) (small EVs) | CD9 and CD81 | Calnexin | Intranasal treatment: 40 μl(40.43 ×10^8 particles/ml); 2-3 h after SCI, and every 24 h, for 5 days; 5 doses Intralesional treatment: 40 μ l(40.43×10^8 particles/ml); immediately after SCI; 1 dose | BBB |
| Kang et al., 2019 | China | 1.SCI + exosomes isolated from MSCs transfected with PTEN siRNA (n=3) 2.SCI + exosomes isolated from MSCs transfected with miR-21 (n=3) 3.SCI + exosomes isolated from MSCs transfected with a scramble control (n=3) 4.Sham (n=3) |
Adult SD rats | Not described | 200 ± 20 g | T9/10, contusion injury: a 2-mm impactor (with a 10 g weight) was quickly dropped from a 25 mm height | Rat bone marrow | Ultracentrifugation; 40-110 nm (TEM,NTA) (small EVs) | Yes | CD9 and CD81 | Not described | immediately after SCI; not described; intravenous injection; Allogeneic | BBB |
| Li et al., 2019 | China | 1.SCI + BMSCs-Exos (n=10) 2.SCI + PBS (n=10) 3.Sham (n=10) |
Adult Wistar rats | Male | 150-200 g | T10, contusion injury: a 10 g metal weight was dropped from a height of 5 cm | Rat bone marrow | Allogeneic | Ultracentrifugation; TEM | CD9, CD63, and CD81 | Not described | Immediately after SCI; 200 μ g/dose, 1 dose every 3 days until the 27th day after SCI; Intravenous | BBB |
| Liu et al., 2019 | China | 1.SCI + Exosomes (n=10) 2.SCI + PBS (n=10) |
SD rats | Female | 170-220 g | T10, contusion injury: a 10 g rod (2.5 mm in diameter) dropped from a height of 12.5 mm. | Rat bone marrow | Allogeneic | Density-gradient ultracentrifugation; 20-150 nm (TEM,DLS) (small EVs) | CD9, CD63, and CD81 | Not described | Immediately after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Lu et al., 2019 | China | 1.SCI + BMSC-EV (n=10) 2.SCI + EV-free CM (n=10) 3.SCI + PBS (n=10) 4.Sham (n=10) |
Adult SD rats | Male | 200-250 g | T10, contusion injury: Infinite Horizon Impactor (200 kilodyne) | Rat bone marrow | Allogeneic | Ultracentrifugation; TEM (EVs) | CD9, CD63, and CD81 | Not described | 30 min after SCI; 40 μg; 1 dose; Intravenous | BBB |
| Yu et al., 2019 | China | 1.SCI + miRNA-29b exosomes (n=20) 2.SCI + miR NC BMSCs (n=20) 3.SCI + miRNA-29b BMSCs |
Adult SD rats | Female | 230-250 g | T10, contusion injury: a striking force of 2 N | Rat bone marrow | Allogeneic | ExoQuick exosome isolation kit; Not described | CD9, CD63, and CD81 | Not described | 1 h after SCI; 100 μg; 1 dose; Intravenous | BBB |
| (n=20) | |||||||||||||
| 4.SCI + exosomes (n=20) | |||||||||||||
| 5.SCI (n=20) | |||||||||||||
| Zhao et al., 2019 | China | 1.SCI + BMSCs-Exo (n=5) 2.SCI + PBS (n=5) 3.Sham (n=5) |
Adult Wistar rats | Male | 200-250 g | T10, hemisection injury: an iris knife | Rat bone marrow | Allogeneic | QEV kit; 20-130 nm (TEM) (small EVs) | CD9 and TSG101 | Calnexin | 1 h after SCI; 100 μg; 1 dose; Intravenous | BBB |
| Zhou et al., 2019 | China | 1.SCI + MSCs-EVs which were transfected with the miR-21-5p inhibitor (n=6) 2.SCI + MSCs-EVs which were transfected with the miR-21-5p inhibitor-NC (n=6) 3.SCI + MSCs-EVs (n=6) 4.SCI + PBS (n=6) 5.Sham (n=6) |
Adult Wistar rats | Male | 200-250 g | T10, hemisection injury: an iris knife | Rat bone marrow | Allogeneic | EVs isolation kit; 40-160 nm (TEM,NTA) (small EVs) | CD9 and TSG101 | Calnexin | 1 h after SCI; 100 μg(1 × 10^10 particles); 1 dose; Intravenous | BBB |
| Gu et al., 2020 | China | 1.SCI + BMSCs-Exo (n=8) 2.SCI + PBS (n=8) 3.Sham (n=8) |
Adult SD rats | Male | 220-260 g | T10, contusion injury: a 10 g rod (2.5 mm in diameter) dropped from a height of 12.5 mm | Bone marrow | Not described | Ultrafiltration-centrifugation combined with ultracentrifugation; 30-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Calnexin | 1 h after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Huang et al., 2020b | China | 1.SCI + EVs (n=8) 2.SCI + Saline (n=8) 3.SCI (n=8) 4.Sham (n=8) |
Adult SD rats | Male | 180-220 g | T10, moderate contusion injury: a modified Allen’s weight drop apparatus (8 g weight at a vertical height of 40 mm, 8 g×40 mm) | Human epidural fat | Xenogeneic | Ultracentrifugation; 60-130 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Not described | Immediately after SCI; 100 μg; 1 dose; Intravenous | BBB |
| Huang et al., 2020a | China | 1.SCI + miR-126 Ex (n=10) 2.SCI + miR-con Ex (n=10) 3.SCI + PBS (n=10) 4.Sham (n=10) |
Adult SD rats | Male | 180-220 g | T10, moderate contusion injury: a modified Allen’s weight drop apparatus (8 g weight at a vertical height of 40 mm, 8 g×40 mm) | Rat bone marrow | Allogeneic | Ultracentrifugation; 30-120 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Not described | 30 min after SCI; 100 μg; 1 dose; Intravenous | BBB |
| Lee et al., 2020 | Korea | 1.SCI + MF-NV (n=8) 2.SCI + N-NV (n=8) 3.SCI + PBS (n=8) 4.Sham (n=8) |
C57BL/6 mice | Female | 20–25 g (6-8 weeks) | T10, compression injury: a stainless steel impounder (weight: 20 g) was loaded to the T10 spinal cord for 30 sec | Human umbilical cord | Xenogeneic | Serial extrusion; N-NVs: 238.3±82.2 nm, MF-NVs: 233.5±70.3 nm (TEM,NTA) (small and large EVs) | CD9 | Not described | 1 h and 7 days after SCI; 25 μ g/dose; 2 doses; Intravenous | BMS |
| Li et al., 2020a | China | 1.SCI + Exo-pGel (n=8) 2.SCI + Exo-IV (n=8) 3.SCI + pGel (n=8) 4.SCI + PBS (n=8) 5.Sham (n=8) |
Adult SD rats | Female | 220-250 g | T10, transection injury: a long-span lesion of 4.0 ± 0.5 mm | Human placenta | Xenogeneic | Size-exclusion chromatography and ultracentrifugation; 40-150 nm (TEM,NTA) (small EVs) | CD9 and CD63 | Not described | Immediately after SCI; 100 μg; 1 dose; Intravenous | BBB |
| Liu et al., 2020 | China | 1.SCI + HExo (n=8) 2.SCI + Exos (n=8) 3.SCI + PBS (n=8) |
C57BL/6 mice | Male | 6–8 weeks old | T10, contusion injury: a 10 g rod dropped from a height of 6.5 cm | Rat bone marrow | Allogeneic | Ultrafiltration-centrifugation combined with density-gradient ultracentrifugation; 50-150 nm (TEM), normoxic: 121.6 nm, hypoxic: 125.3 nm (NTA) (small EVs) | CD9, CD63, CD81, and TSG101 | Not described | Immediately after SCI; 200 μg; 1 dose; Intravenous | BMS |
| Zhang et al., 2020a | China | 1.SCI + hPMSCs-Exos (n=6) 2.SCI + PBS (n=6) |
C57BL/6 mice | Male | 8 weeks old | T10, contusion injury: a modified Allen’s weight drop apparatus (8 g weight at a vertical height of 40 mm) | Human placenta | Xenogeneic | Ultracentrifugation; 30-200 nm (TEM,NTA) (small EVs) | CD9 and CD63 | Not described | Immediately after SCI; 200 μg; 1 dose; Intrathecheal | BMS |
| Chang et al., 2021 | China | 1.SCI + B-Exo (n=12) 2.SCI + PBS (n=12) 3.Sham (n=12) |
Adult SD rats | Male | 220-260 g | T10, contusion injury: a 10 g rod (2.5 mm in diameter) dropped from a height of 125mm | Rat bone marrow | Allogeneic | Ultrafiltration-centrifugation combined with density-gradient ultracentrifugation; 30-150 nm (TEM,NTA) (small EVs) | TSG101 and CD63 | Calnexin | 1 h after SCI; 4 μg; 1 dose; Intrathecheal | BBB |
| Chen et al., 2021 | China | 1.SCI + miR-26a exosomes (n=6) 2.SCI + exosomes (n=6) 3.SCI + PBS (n=6) |
Adult SD rats | Male | 6–8 weeks old | T10, compression injury: an aneurysm clip of 75 g closing force for 30 s | Rat bone marrow | Allogeneic | Ultracentrifugation; 50-100 nm (TEM,NTA) (small EVs) | CD9, CD63, and Flotillin-1 | Calnexin | Immediately after SCI; 200 μg; 1 dose; Intrathecheal | BBB |
| Cheng et al., 2021 | China | 1.SCI + GelMA-Exos (n=5) 2.SCI + Exos (n=5) 3.SCI + PBS (n=5) 4.Sham (n=5) |
Adult SD rats | Not described | Not described | T10, contusion injury: a 10 g rod dropped from a height of 25 mm | Rat bone marrow | Allogeneic | Ultracentrifugation; 30-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Not described | Not described; Intrathecheal | BBB |
| Fan et al., 2021 | China | 1.SCI + BMSCs-Exo (n=6) 2.SCI + PBS (n=6) 3.Sham (n=6) |
Adult SD rats | Male | 200-250 g | T10, contusion injury: NYU Impactor (10g×25mm) | Bone marrow | Not described | Exosome extraction kit; Not described | CD9, CD63, CD81, Alix, and TSG101 | Not described | 7 consecutive days after SCI; 200 μL/dose; 7 doses; Intrathecheal | BBB |
| Huang et al., 2021b | China | 1.SCI + Exo-miR-494 (n=6) 2.SCI + Exo-miR-con (n=6) 3.SCI + PBS (n=6) 4.Sham (n=6) |
SD rats | Male | 80-100 g (2 weeks) | T10, contusion injury: spinal cord injury percussion apparatus (The weight of the metal rod reached 25 g, and the height was 50 mm) | Rat bone marrow | Allogeneic | Exosome isolation kit; 30-200 nm (TEM), 150 nm (NTA) (small EVs) | CD9 and CD63 | Not described | per 24 h for 7 consecutive days after SCI; 100 μg/dose; 7 doses; Intravenous | BBB |
| Huang et al., 2021a | China | 1.SCI + Exo-siRNA (n=6) 2.SCI + Exo (n=6) 3.SCI + siRNA (n=6) 4.SCI + PBS (n=6) 5 Sham (n=6) |
SD rats | Female | 200–250 g (10 weeks old) | T10, contusion injury: metal rod weight of 30 g and height of 50 mm | Rat bone marrow | Allogeneic | Ultrafiltration-centrifugation combined with ultracentrifugation; 30-200 nm (TEM), 150 nm (NTA) (small EVs) | CD9 and CD63 | Calnexin | per 24 h for 5 consecutive days after SCI; 100 μg/dose; 5 doses; Intravenous | BBB |
| Jia et al., 2021a | China | 1.SCI + MSC-EVs-miR-381 mimic+oe-WNT5A (n=8) 2.SCI + MSC-EVs-miR-381 mimic+oe-BRD4 (n=8) 3.SCI + MSC-EVs-miR-381 mimic+oe NC (n=8) 4.SCI + MSC-EVs-NC mimic+oe-NC (n=8) |
SD rats | Male | 180-205 g (6 -8 weeks) | T9, compression injury: a mosquito clamp for one minute | Rat bone marrow | Allogeneic | Ultracentrifugation; 30-120 nm (TEM,DLS) (small EVs) | CD9, CD63, and CD81 | GM130 | 3 days after SCI; Not described; intravenous injection; Allogeneic | BBB |
| Jia et al., 2021b | China | 1.SCI + Shh-Exo (n=5) 2.SCI + Exo (n=5) 3.SCI + PBS (n=5) 4.Sham (n=5) |
SD rats | Male | 230–250 g | T10, contusion injury: a striking device was then used to apply a 2 N striking | Rat bone marrow | Allogeneic | Exo Quick-TC kit; TEM (Not described) | CD9, CD63, and TSG101 | Not described | 1 h after SCI, one dose every other day; 40 μg/dose; 3 doses; Intravenous | BBB |
| Jia et al., 2021c | China | 1.SCI + Exo/sh-Shh (n=5) 2.SCI + Exo/sh-NC (n=5) 3.SCI + Exo (n=5) 4.SCI + PBS (n=5) 5.Sham (n=5) |
SD rats | Male | 230–250 g | T10, contusion injury: a striking device was then used to apply a 2 N striking | Rat bone marrow | Allogeneic | Exo Quick-TC kit; TEM (Not described) | CD9, CD63, and TSG101 | Not described | 1 h after SCI, one dose every other day; 40 μg/dose; 3 doses; Intravenous | BBB |
| Jiang and Zhang, 2021 | China | 1.SCI + EX-miR-145-5p (n=3) 2.SCI + EX-miR-NC (n=3) 3.SCI + PBS (n=3) 4.SCI (n=3) 5.Sham (n=3) |
Adult SD rats | Male | 200 ± 20 g (7 weeks old) | T9/10, contusion injury: NYU | Rat bone marrow | Allogeneic | Ultracentrifugation; TEM,NTA (Not described) | CD9, CD63, and TSG101 | Not described | 30 min after SCI; 100 μg(1 × 10^10 particles); 1 dose; Intravenous | BBB |
| Li et al., 2021 | China | 1.SCI + EEM (n=5) 2.SCI + MQ (n=5) 3.SCI + PBS (n=5) 4.Sham (n=5) |
C57BL/6 mice | Female | 8 weeks old | T10, contusion injury: Infinite Horizon Impactor (50 kilodyne) | Mouse bone marrow | Allogeneic | Ultracentrifugation; 30-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Actin | Immediately after SCI; Not described; Intrathecheal | BMS |
| Liu et al., 2021a | China | 1.SCI + shUSP29-MEVs (n=8) 2.SCI + shNC-MEVs (n=8) 3.SCI + MEVs (n=8) 4.SCI + EVs (n=8) 5.SCI + PBS (n=8) |
C57BL/6 mice | Not described | 6-8 weeks | T8, contusion injury: a spinal cord impactor (a 5 g rod dropped from a height of 6.5 cm) | Mouse bone marrow | Allogeneic | Ultracentrifugation; 100 nm (TEM,NTA) (small EVs) | CD9, Alix, and TSG101 | Calnexin | Immediately after SCI; 200 μg; 1 dose; Intravenous | BMS |
| Luo et al., 2021 | China | 1.SCI + GIT1-BMSCs-Exos (n=10) 2.SCI + BMSCs-Exos (n=10) 3.SCI + PBS (n=10) |
SD rats | Female | 170-220 g (12 weeks) | T10, contusion injury: a 10 g rod (2.5 mm in diameter) dropped from a height of 12.5 mm | Rat bone marrow | Allogeneic | Ultrafiltration-centrifugation combined with density-gradient ultracentrifugation; 50-150 nm (TEM,DLS) (small EVs) | CD9, CD63, and CD81 | Not described | Immediately after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Mu et al., 2021 | China | 1.SCI + FG-Exo (n=6) 2.SCI + FG (n=6) 3.SCI + PBS (n=6) 4.Sham (n=6) |
SD rats | Female | 230 g | T10, transection injury: leaving a lesion gap of 4– 5 mm | Human umbilical cord | Xenogeneic | Ultrafiltration-centrifugation combined with ultracentrifugation; 100-200 nm (TEM), 150 nm (NTA) (small EVs) | CD9 and CD63 | Not described | Immediately after SCI; 100 μg; 1 dose; Intrathecheal | BBB |
| Nakazaki et al., 2021 | United States | 1.SCI + MSC-derived sEVs delivered in three fractionated doses over 3 days (n=14) 2.SCI + MSC-derived sEVs delivered in a single dose (n=14) 3.SCI + MSCs (n=14) 4.SCI + Vehicle (n=17) |
Adult SD rats | Male | 185-215 g | T9, contusion injury: a delivery of 22.5 Newton impact (equal to 225 kilodynes) with a 2.5 mm tip using the Infinite Horizon (IH) impactor |
Rat bone marrow | Allogeneic | Ultracentrifugation; 30-100 nm (TEM); 83.0 ± 14.1 nm (NTA) (small EVs) | CD63, CD9, and Alix | Not described | 7 days after SCI; 4.6 ± 0.5 μg (2.5 × 10^9 particles)/dose; one-dose or fractioned dose (On 7, 8 and 9 days after SCI); Intravenous | BBB |
| Nie and Jiang, 2021 | China | 1.SCI + EVs (n=24) 2.SCI + GW (n=24) 3.SCI + PBS (n=24) 4.Sham (n=24) |
SD rats | Male | 180–220 g | T10, transection injury: microsurgical scissors | Rat bone marrow | Allogeneic | Ultracentrifugation; 50-150 nm (TEM,qNano) (small EVs) | CD9, CD63, and CD81 | Calnexin | 24 h after SCI; 100 μg; 1 dose; Intravenous | BBB |
| Romanelli et al., 2021 | Austria | 1.SCI + EVs(Intravenous) (n=5) 2.SCI + Evs(Intrathecheal) (n=5) 3.SCI + Vehicle(Intrathecheal) (n=5) 4.Sham (n=5) |
F344-rats | Female | 140–190 g (10 –12 weeks) | T8, contusion injury: Infinite Horizon Impactor (200 kilodyne, 1,000 μm of displacements) | Human umbilical cord | Xenogeneic | Tangential flow filtration (TFF) and ultracentrifugation; 125 nm (NTA) (small EVs) | CD9, CD81, and TSG101 | GM130 | Intrathecheal treatment: immediately after SCI; 2μl (2 × 10^9 particles); 1 dose Intravenous treatment: immediately after SCI; 100μl (2 × 10^9 particles); 1 dose | BBB |
| Sheng et al., 2021 | China | 1.SCI + Exos (n=5) 2.SCI + PBS (n=5) 3.Sham (n=5) |
C57BL/6 mice | Female | 8–10 weeks old | T10, contusion injury: an NYU impactor with a 5-g rod dropped from a height of 6 mm | Mouse bone marrow | Allogeneic | Ultracentrifugation; 50-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Not described | Immediately after SCI; 200 μg; 1 dose; Intrathecheal | BMS |
| Wang et al., 2021a | China | 1.SCI + FE-EVs (n=8) 2.SCI + EVs (n=8) 3.SCI + FE (n=8) 4.SCI + PBS (n=8) 5.Sham (n=8) |
Rats | Female | 230 g | T10, transection injury: a microscissor | Human adipose tissue | Xenogeneic | Ultracentrifugation; 50-200 nm (TEM,NTA) (small EVs) | CD63, CD81, Alix, and TSG101 | Not described | Immediately after SCI; 1 μg; 1 dose; Intrathecheal | BBB |
| Wang et al., 2021b | China | 1.SCI + Exo-K (n=10) 2.SCI + Exo (n=10) 3.SCI + PBS (n=10) 4.Sham (n=10) |
Adult SD rats | Female | 6–7 weeks old | T10, compression injury: an artery clamp (35 g 3 mm depth for 30s) | Human umbilical cord | Xenogeneic | Exosome extraction kit; 30-150 nm (TEM,NTA) (small EVs) | CD9 and CD63 | β-actin | 30 min and 24 h after SCI; 200 μ g/dose; 2 doses; Intravenous | BBB |
| Xiao et al., 2021 | China | 1.SCI + EVs (n=6) 2.SCI + GW (n=6) 3.SCI + PBS (n=6) 4.Sham (n=6) |
Adult SD rats | Male | 150-200 g | T10, compression injury: an aneurysm clip for 60 s | Human umbilical cord | Xenogeneic | Ultracentrifugation; 30-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Grp94 | 24 h after SCI; 100 mg (2 × 10^9 particles/mL); 1 dose; Intravenous | BBB |
| Xin et al., 2021 | China | 1.SCI + siTIMP2-Exos (n=5) 2.SCI + Exos (n=5) 3.SCI + PBS (n=5) 4.Sham (n=5) |
Adult SD rats | Female | 220-250 g | T9, moderate contusion injury: an Infnite Horizon Impact Device(150 kdyn force with no dwell time) | Human bone marrow | Xenogeneic | Ultracentrifugation; 50-150 nm (TEM,NTA) (small EVs) | CD9, CD63, and TSG101 | Not described | Once a day for 1 week after SCI; 100 μg/dose; 7 doses; Intrathecheal | BBB |
| Zhai et al., 2021 | China | 1.SCI + CD73+huc MSC-EVs (n=20) 2.SCI + hucMSC-EVs (n=20) 3.SCI + CD73 (n=20) 4.SCI + PBS (n=20) 5.Sham (n=20) |
ICR mice | Male | 30-35 g (6 weeks old) | T8-T9, contusion injury: a 10 g rod dropped at a height of 6.25 mm | Human umbilical cord | Xenogeneic | Ultracentrifugation, ultrafiltration, and size exclusion chromatography; hucMSC-EVs: 103.41±42.03 nm, CD73+hucMCS-EVs: 106.51±53.99 nm (TEM,NTA) (small EVs) | CD9, CD63, CD81, TSG101, and ALIX | Calnexin | Once a day and for 10 days after SCI; 20 μg/dose; 10 doses; Intrathecheal | BMS |
| Zhang et al., 2021a | China | 1.SCI + LBMP (n=10) 2.SCI + LMP (n=10) 3.SCI + LM (n=10) 4.SCI + LP (n=10) 5.SCI (n=10) |
Adult SD rats | Female | 180-200 g | T10, transection injury: scissors (4 mm in length) | Human umbilical cord | Xenogeneic | Ultracentrifugation; 130.3 ± 3.3 nm (TEM,NTA) (small EVs) |
CD81, TSG101, CD63, and TfR | Not described | Immediately after SCI; 100 μ g/dose; 1 dose; Intrathecheal | BBB |
| Zhang et al., 2021b | China | 1.SCI + Exo(181C)+PTEN (n=6) 2.SCI + Exo(181C) (n=6) 3.SCI + Exo (n=6) 4.SCI + PBS (n=6) 5.Sham (n=6) |
Adult SD rats | Male | 200–280 g (8 weeks) | T10, moderate contusion injury: a NYU-III weight drop apparatus (10 g weight at a vertical height of 12.5 mm, 10 g×12.5 mm) | Rat bone marrow | Allogeneic | Ultracentrifugation; 99.02 nm (TEM,NTA) (small EVs) | CD9 and CD63 | β-actin | 30 min after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Zhou et al., 2021 | China | 1.SCI + Exo (n=6) 2.SCI + PBS (n=6) |
SD rats | Female | 200–220 g (7-8 weeks) | T11, transection injury | Human placenta | Xenogeneic | Polyethylene glycol (PEG) and ultracentrifugation; 100-200 nm (TEM) (small EVs) | TSG101 and CD63 | Not described | 1 h and 2 weeks after SCI; 25 μ g/dose; 2 doses; Intravenous | BBB |
| Han et al., 2022 | China | 1.SCI + BMSC EVs+ SB431542 day3-treated (n=10) 2.SCI + BMSC-EVs+ SB431542 day0-treated (n=10) 3.SCI + BMSC-EVs (n=10) 4.SCI + DMEM/F12 (n=10) |
Adult Wistar rats | Female | 200–250 g (6– 8 weeks old) | T10, contusion injury: Infinite Horizon Impactor | Rat bone marrow | Allogeneic | Ultracentrifugation; TEM,DLS (Not described) | CD9, CD63, and TSG101 | CD90 | Immediately after SCI; 72 μL (The medium in the pump was released at a rate of 1 μL/h, 3 consecutive days after SCI); Intrathecheal | BBB |
| Huang et al., 2022 | China | 1.SCI + Hyp-Evs-miR-511-3p mimic (n=10) 2.SCI + Hyp-EVs (n=10) 3.SCI + PBS (n=10) 4.Sham (n=10) |
SD rats | Not described | 200–220 g (8 weeks) | T10, contusion injury: a 5 g rod dropped at a height of 6.5 cm | Adipose tissue | Not described | Ultrafiltration-centrifugation combined with density-gradient ultracentrifugation; 80-120 nm (TEM) (small EVs) | CD9, CD63, CD81, and TSG101 | Not described | Immediately after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Kang and Guo, 2022 | China | 1.SCI + Exo (n=10) 2.SCI + PBS (n=10) 3.Sham (n=10) |
SD rats | Female | 170-220 g (8 weeks) | T10, contusion injury: a 10 g rod (2.5 mm in diameter) dropped from a height of 12.5 mm | Human umbilical cord | Xenogeneic | Exosome extraction kit; 50-100 nm (TEM),80-100 nm (NTA) (small EVs) | CD9, CD63, and CD81 | GAPDH | Immediately after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Liang et al., 2022 | China | 1.SCI + Hypo-exo (n=6) 2.SCI + Norm-exo (n=6) 3.SCI + PBS (n=6) 4.Sham (n=6) |
Adult SD rats | Female | 180-220 g | T10, contusion injury: a 10 g rod (2 mm in diameter) dropped from a height of 50 mm | Rat adipose tissue | Allogeneic | Ultracentrifugation; normoxia: 127.2 nm, hypoxia: 123.5 nm (TEM,NTA) (small EVs) | CD9, CD63, CD81, and TSG101 | Not described | 24 h after SCI; 200 μg; 1 dose; Intravenous | BBB |
| Zhou et al., 2022 | China | 1.SCI + Exo (n=6) 2.SCI + PBS (n=6) 3.Exo (n=6) 4.Sham (n=6) |
Adult SD rats | Male | 200–250 g (3 months) | T10, contusion injury: Infinite Horizon Impactor (2N, equal to 200 kilodyne) | Rat bone marrow | Allogeneic | Ultracentrifugation; 100 nm (TEM,NTA) (small EVs) | CD9, CD63, and CD81 | Not described | 30 min and 24 h after SCI; 20 μ g/dose; 2 doses; Intravenous | BBB |