Table I.
Studies evaluating the use of exogenous extracellular vesicles (EVs) to alter bone or cartilage repair in vivo
| First author | EV fractions studied | Cell source of EVs | Experiment model | Delivery method | Outcome measures | Key findings |
|---|---|---|---|---|---|---|
| Furuta et al (2016)53 | Multiple* | Human BM-MSCs | Murine femoral fracture | Injection (×2) | X-ray, µCT, histology/IHC | Injections of MSC-EVs rescued delayed fracture healing in CD9-/- mice and enhanced normal healing in wild type mice |
| Li et al (2017)77 | Exosomes | Rabbit BM-MSCs (+/- HIF-1α overexpression) | Rabbit steroid-induced avascular necrosis of femoral head | Injection | MRI, histology/IF | Exosomes from HIF-1α-overexpressing MSCs promoted increased trabecular bone generation and neo-vascularization in femoral heads compared with unmodified MSC-EVs and saline-treated groups |
| Qi et al (2016)63 | Exosomes | Human iPSC-derived MSCs | Rat critical-sized cranial defects (×2) | TCP scaffold | µCT, histology/histomorphometry/IHC | EVs from iPSC-derived MSCs dose-dependently enhanced bone formation and vasculogenesis compared with TCP controls |
| Qin et al (2016)54 | Multiple | Human BM-MSCs | Rat critical-sized cranial defects (×2) | Hydrogel scaffold | µCT, histology | MSC-EVs stimulate bone formation compared with hydrogel controls |
| Xie et al (2017)79 | Multiple | Rat BM-MSCs | Subcutaneous implantation in nude mice | Bovine DBM scaffold | µCT, histology/IHC | EVs from rat MSCs enhanced vessel formation within DBMs implanted subcutaneously, although they did not independently enhance bone formation compared with scaffold-only controls |
| J. Zhang et al (2016)64† | Exosomes | Human iPSC-derived MSCs | Rat critical-sized cranial defects (×2) | TCP scaffold | µCT, histology/IHC | EVs from iPSC-derived MSCs dose-dependently enhanced bone formation compared with TCP controls |
| S. Zhang et al (2016)57 | Exosomes | Human ESC-derived MSCs | Rat osteochondral defects | Weekly injections | Histology/IHC | EVs from ESC cell-line-derived MSCs enhanced cartilage repair score (O’Driscoll) and cartilage marker deposition by six weeks |
| S. Zhang et al (2018)58‡ | Exosomes | Human ESC-derived MSCs | Rat osteochondral defects | Weekly injections | Histology/IHC | EVs from ESC cell-line-derived MSCs enhanced cartilage repair score (Wakitani) as early as two weeks |
Based on the described isolation method, the specification of exosomes does not seem consistent with criteria established by a position paper from the International Society of Extracellular Vesicles7
Follow-up study to Qi et al (2016)63
Follow-up study to S. Zhang et al (2016)57
BM-MSC, bone-marrow-derived mesenchymal stem cells; µCT, micro-computed tomography; IHC, immunohistochemistry; MSC-EVs, mesenchymal stem cell extracellular vesicles; HIF-1α, hypoxia-inducible factor 1-alpha; MRI, magnetic resonance imaging; IF, immunofluorescence; iPSC, induced pluripotent stem cell; TCP, tricalcium phosphate; DBM, demineralized bone matrix; ESC, embryonic stem cell