Table 3.
Summary of animal studies and treatment parameters.
| Author | Year | Group/treatment | Concentration | Volume | Delivery route | Frequency | Euthanasia |
|---|---|---|---|---|---|---|---|
| Chen [41] | 2019 | 1. HA/HAp/HP hydrogel loaded with exosomes isolated from miR-375-overexpressing human adipose MSCs | 50 μg/mL | 20 μL + 250 μL hydrogel | Implantation | At day 0 | 3 days, 2, 4 and 8 weeks |
| 2. HA/HAp/HP hydrogel loaded with exosomes isolated from human adipose MSCs expressing the control vector | 50 μg/mL | 20 μL + 250 μL hydrogel | Implantation | At day 0 | 3 days, 2, 4 and 8 weeks | ||
| 3. HA/HAp/HP hydrogel | NA | 250 μL | Implantation | At day 0 | 3 days, 2, 4 and 8 weeks | ||
| 4. No treatment | NA | NA | NA | NA | 3 days, 2, 4 and 8 weeks | ||
| Furuta [42] | 2016 | 1. Injection of human BM-MSC exosomes into CD9−/− mice | NR | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks |
| 2. Injection of human BM-MSC exosomes into WT mice | NR | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 3. Injection of human BM-MSC CM into CD9−/− mice | NR | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 4. Injection of human BM-MSC CM into WT mice | NR | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 5. Injection of human BM-MSC CM (exosome-depleted) into CD9−/− mice | NA | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 6. Injection of human BM-MSC CM (exosome-depleted) into WT mice | NA | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 7. Injection of PBS into CD9−/− mice | NA | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 8. Injection of PBS into WT mice | NA | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| 9. Injection of exosomes derived from the human osteosarcoma cell line into CD9−/− mice | NR | 100 μL | Injection into fracture site | At day 1 and 8 | 6 weeks | ||
| Guo [43] | 2016 | 1. Exosomes from human synovial MSCs | 1 × 1011 particles | 200 μL | Intravenous injection | At day 0 | 3 days, 6 weeks |
| 2. PBS | NA | 200 μL | Intravenous injection | At day 0 | 3 days, 6 weeks | ||
| 3. Normal group | NA | NA | NA | NA | 3 days, 6 weeks | ||
| Jia [44] | 2020 | 1. Exosomes from rat BM-MSCs | 1 × 1010 particles | 100 μL | Injection into distraction gap | Weekly | 7 weeks |
| 2. PBS | NA | 100 μL | Injection into distraction gap | Weekly | 7 weeks | ||
| Kuang [45] | 2019 | 1. Exosomes from human Wharton's jelly UC-MSCs | NR | 100 μg | Intramuscular injection | Daily for 5 weeks | 10 weeks |
| 2. Exosomes from human Wharton's jelly UC-MSCs and miR-21 antagomir | NR | 100 μg | Intramuscular injection | Daily for 5 weeks Weekly for miR-21 |
10 weeks | ||
| 3. miR-21 agomir | NR | 10 μM | Intramuscular injection | Weekly | 10 weeks | ||
| 4. No treatment | NA | NA | NA | NA | 10 weeks | ||
| 5. Normal group | NA | NR | Intramuscular injection | Daily for 5 weeks | 10 weeks | ||
| Li [46] | 2017 | 1. Exosomes from rabbit BM-MSCs transfected with WT HIF-1α adenovirus | 80 μg/mL | 0.5 mL | Injection into femoral head | At day 0 | 6 weeks |
| 2. Exosomes from rabbit BM-MSCs transfected with mutant HIF-1α adenovirus | 80 μg/mL | 0.5 mL | Injection into femoral head | At day 0 | 6 weeks | ||
| 3. PBS | NA | NR | Injection into femoral head | At day 0 | 6 weeks | ||
| Li [47] | 2018 | 1. PLGA/pDA scaffold immobilised with exosomes from human adipose stem cells | 1 μg/μL | 250 μL | Implantation | At day 0 | 6 weeks |
| 2. PLGA/pDA scaffold | NA | NA | Implantation | At day 0 | 6 weeks | ||
| 3. PLGA scaffold | NA | NA | Implantation | At day 0 | 6 weeks | ||
| Li [48] | 2019 | 1. HyStem-HP hydrogel with exosomes from human UC-MSCs | 100 μg/150 μL | 150 μL | Injection into femoral head | At day 0 | 3 weeks |
| 2. No treatment | NA | NA | NA | NA | 3 weeks | ||
| Li [49] | 2020 | 1. PLGA scaffold loaded with human BM-MSCs from ilium cultured with exosomes from human BM-MSCs from ilium | NR | NR | Implantation | At day 0 | 12 weeks |
| 2. PLGA scaffold loaded with human BM-MSCs from ilium cultured with exosomes from human BM-MSCs from jawbone | NR | NR | Implantation | At day 0 | 12 weeks | ||
| 3. PLGA scaffold loaded with exosomes from human BM-MSCs from ilium | NR | NR | Implantation | At day 0 | 12 weeks | ||
| 4. PLGA scaffold loaded with exosomes from human BM-MSCs from jawbone | NR | NR | Implantation | At day 0 | 12 weeks | ||
| 5. PLGA scaffold | NA | NA | Implantation | At day 0 | 12 weeks | ||
| Liang [50] | 2019 | 1. HAp scaffold with exosomes from human BM-MSCs | 0.5 μg/μL | 200 μL | Implantation | At day 0 | 8 weeks |
| 2. HAp scaffold with exosomes from human BM-MSCs preconditioned with DMOG | 0.5 μg/μL | 200 μL | Implantation | At day 0 | 8 weeks | ||
| 3. HAp scaffold with PBS | NA | 200 μL | Implantation | At day 0 | 8 weeks | ||
| Liao [51] | 2019 | 1. Exosomes from rabbit BM-MSCs transfected with miR-122-5p negative control | NR | NR | Intravenous injection | At day 0 | 8 weeks |
| 2. Exosomes from rabbit BM-MSCs transfected with miR-122-5p agomir | NR | NR | Intravenous injection | At day 0 | 8 weeks | ||
| Liu [52] | 2017 | 1. Exosomes from human iPSC-MSCs | 1 × 1010 or 1011 particles/mL | 100 μL | Intravenous injection | At day 0 | 3 weeks |
| 2. Control medium | NA | 100 μL | Intravenous injection | At day 0 | 3 weeks | ||
| 3. No treatment | NA | NA | NA | NA | 3 weeks | ||
| 4. Normal group | NA | NA | NA | NA | 3 weeks | ||
| Liu [53] | 2020 | 1. Exosomes from human UC-MSCs cultured in normoxic condition | 1 μg/μL | 200 μL | Injection near fracture site | At day 0 | 7 days |
| 2. Exosomes from human UC-MSCs cultured in hypoxic condition | 1 μg/μL | 200 μL | Injection near fracture site | At day 0 | 7 days | ||
| 3. PBS | NA | 200 μL | Injection near fracture site | At day 0 | 7 days | ||
| Qi [54] | 2016 | 1. β-TCP scaffold with exosomes from human iPSC-MSCs | 100 μg/scaffold | NA | Implantation | At day 0 | 8 weeks |
| 2. β-TCP scaffold with exosomes from human iPSC-MSCs | 200 μg/scaffold | NA | Implantation | At day 0 | 8 weeks | ||
| 3. β-TCP scaffold | NA | NA | Implantation | At day 0 | 8 weeks | ||
| Takeuchi [55] | 2019 | 1. Atelocollagen sponge with exosomes from human BM-MSC CM | NR | 30 μg | Implantation | At day 0 | 2, 4 weeks |
| 2. Atelocollagen sponge with exosomes from human BM-MSC CM and anti-VEGFA antibody | NR | 30 μg | Implantation | At day 0 | 2, 4 weeks | ||
| 3. Atelocollagen sponge with human BM-MSC CM | NR | NR | Implantation | At day 0 | 2, 4 weeks | ||
| 4. Atelocollagen sponge with PBS | NA | NR | Implantation | At day 0 | 2, 4 weeks | ||
| 5. No treatment | NA | NA | NA | NA | 2, 4 weeks | ||
| Xu [56] | 2019 | 1. Exosomes from human BM-MSCs | NR | 400 μg | Intramuscular injection | At day 1 | 6 weeks |
| 2. Exosomes from human BM-MSCs with negative control | NR | 400 μg | Intramuscular injection | At day 1 | 6 weeks | ||
| 3. Exosomes from human BM-MSCs with miR-224-3p mimic | NR | 400 μg | Intramuscular injection | At day 1 | 6 weeks | ||
| 4. Exosomes from human BM-MSCs with inhibitor negative control | NR | 400 μg | Intramuscular injection | At day 1 | 6 weeks | ||
| 5. Exosomes from human BM-MSCs with miR-224-3p inhibitor | NR | 400 μg | Intramuscular injection | At day 1 | 6 weeks | ||
| 6. No treatment | NA | NA | NA | NA | 6 weeks | ||
| 7. Normal group | NA | NA | NA | NA | 6 weeks | ||
| Xu [57] | 2020 | 1. Exosomes from 4-week old rat BM-MSCs | 1 μg/μL | 200 μL | Injection near fracture site | At day 0 | 2, 3, 4 weeks |
| 2. Exosomes from 72-week old rat BM-MSCs | 1 μg/μL | 200 μL | Injection near fracture site | At day 0 | 2, 3, 4 weeks | ||
| 3. PBS | NA | 200 μL | Injection near fracture site | At day 0 | 2, 3, 4 weeks | ||
| Yang [58] | 2020 | 1. Exosomes from human UC-MSCs | NR | NR | Intramuscular injection | NR | 8 weeks |
| 2. Exosomes from human UC-MSCs and miR-1263 inhibitor | NR | NR | Intramuscular injection | NR | 8 weeks | ||
| 3. miR-1263 mimics | NR | NR | Intramuscular injection | NR | 8 weeks | ||
| 4. PBS | NA | NR | Intramuscular injection | NR | 8 weeks | ||
| 5. Normal control | NA | NA | Intramuscular injection | NA | 8 weeks | ||
| Zhang [59] | 2016 | 1. β-TCP scaffold with exosomes from human iPSC-MSCs | 5 × 1011 particles/mL | 100 μL | Implantation | At day 0 | 8 weeks |
| 2. β-TCP scaffold with exosomes from human iPSC-MSCs | 1 × 1012 particles/mL | 100 μL | Implantation | At day 0 | 8 weeks | ||
| 3. β-TCP scaffold with PBS | NA | 100 μL | Implantation | At day 0 | 8 weeks | ||
| Zhang [60] | 2019 | 1. HyStem-HP hydrogel with exosomes from human UC-MSCs | 100 μg/mL | NR | Injection near fracture site | At day 0 | 2 weeks |
| 2. HyStem-HP hydrogel with exosomes from HEK293 cells | 100 μg/mL | NR | Injection near fracture site | At day 0 | 2 weeks | ||
| 3. HyStem-HP hydrogel with PBS | NA | NR | Injection near fracture site | At day 0 | 2 weeks | ||
| Zhang [61] | 2020 | 1. Exosomes from rat BM-MSCs | 1 × 1010 particles in 100 μL | 100 μL | Injection into fracture site | At day 0 | 8, 14, 20 weeks |
| 2. Exosome-depleted CM from rat BM-MSCs | NA | 100 μL | Injection into fracture site | At day 0 | 8, 14, 20 weeks | ||
| 3. PBS | NA | 100 μL | Injection into fracture site | At day 0 | 8, 14, 20 weeks | ||
| Zhou [62] | 2019 | 1. HyStem-HP hydrogel with exosomes from human UC-MSCs | 1 μg/μL | 100 μL | Injection into fracture site | At day 0 | 2, 3 weeks |
| 2. HyStem-HP hydrogel with PBS | NA | 100 μL | Injection into fracture site | At day 0 | 2, 3 weeks | ||
| 3. No treatment | NA | NA | NA | NA | 2, 3 weeks | ||
| Zuo [63] | 2019 | 1. Irradiation and treatment with exosomes from rat BM-MSCs | 1.6 mg/kg | 400 μL | Intravenous injection | At day 0 | 4 weeks |
| 2. Irradiation and treatment with rat BM-MSCs | 1 × 106 cells | 400 μL | Intravenous injection | At day 0 | 4 weeks | ||
| 3. Irradiation and no treatment | NA | NA | NA | NA | 4 weeks | ||
| 4. No irradiation and no treatment (4 weeks) | NA | NA | NA | NA | 4 weeks | ||
| 5. No irradiation and no treatment (day 0) | NA | NA | NA | NA | day 0 |
NR, not reported; NA, not applicable; MSCs, mesenchymal stem cells; BM-MSC, bone marrow mesenchymal stem cell; UC-MSCs, umbilical cord mesenchymal stem cells; iPSC-MSCs, induced pluripotent stem cell-derived mesenchymal stem cells; HEK293, human embryonic kidney 293; SD, Sprague Dawley; WT, wild type; PLGA, poly-lactic-co-glycolic acid; pDA, poly-dopamine; PLGA/pDA, PLGA scaffold coated with poly-dopamine; HAp, Hydroxyapatite; HA/HAp/HP, hydrogel based on thiol-modified hyaluronan, hydroxyapatite and thiol-modified heparin; HyStem-HP, hydrogel based on thiol-modified hyaluronan, gelatin and heparin; β-TCP, Beta-tricalcium phosphate; PBS, phosphate-buffered saline; CM, conditioned medium; DMOG, dimethyloxaloylglycine; HIF-1α, hypoxia inducible factor-1α; VEGFA, vascular endothelial growth factor A.