Table 3.
Scaffold/Matrix and hydrogel biomaterials for EV/exosome delivery for cartilage tissue engineering or treatment of OA
| EV Source + Isolation Method | Biomaterials | In vivo EV dose/volume | In vivo model/ Species | In vivo timepoints | In vivo outcomes | Ref. |
|---|---|---|---|---|---|---|
| Scaffold/Matrix Biomaterials (Implanted) | ||||||
| Bone marrow derived MSCs + tissue culture plastic (TCP) 50-60% confluence + 1hr 100k xg ultracentrifugation (UC) | 3D printed decellularized porcine cartilage/GelMA scaffold | 200 µg in 200 µL (PBS Control); 200 µg/mL hydrogel | Osteochondral defect in patellar groove; 4mm diameter x 4mm deep; Rabbit | 6 and 12 weeks | EV/hydrogel significantly increased ICRS macroscopic scores, COL2A1 expression, and decreased MMP13 expression after the 6 and 12 weeks compared to all controls. | 214 |
| Passage (p) 3-5 human umbilical cord Wharton's Jelly MSCs + TCP (60% confluence) + 2hr, 100k xg UC | Freeze-dried decellularized porcine cartilage ECM | 25 μg/mL, supplementary EV-only injection once every 7 days for a total of 5 injections | Osteochondral defect in femoral trochlea; 3.5 mm diameter x 1.5 mm deep; Rabbit | 12 and 24 weeks | EVs enhanced the effect of the scaffold and promoted osteochondral regeneration; EVs promoted the polarization of macrophages toward the M2 phenotype and inhibited the inflammatory response in vivo. | 212 |
| Hydrogel Biomaterials (Injected) | ||||||
| Immortalized E1-MYC 16.3 human embryonic stem cell-derived MSCs Size-fractionated, concentrated 50× by tangential flow filtration (100kDa MWCO) |
Hyaluronic acid hydrogel solution | 200 µg of EVs in 1 mL intra-articular injection days 7 and 14 after wound closure | Osteochondral defect in femoral trochlear grooves; 4.5 mm diameter x 1.5 mm depth; Rabbit | 6 and 12 weeks | The combination of MSC-EVs and HA via intra-articular injections (immediately post-surgery and after 7 and 14 days) promoted enhanced functional cartilage repair compared with HA alone. | 230 |
| Human articular chondrocytes + TCP + 2hr, 100k xg UC | Chitosan-hyaluronic acid hydrogel | 30 µg EV + 1.56MSCs + 100 µl hydrogel | Osteochondral defect in patellar groove; 4 mm diameter x 3 mm depth; Rabbit | 4 and 24 weeks | EDC/NHS cross-linked CS-HA/EV/MSC, and CS-HA/MSC hydrogel enhanced cartilage repair compared to EV/MSC or CS-HA controls via MRI and histological analysis. | 213 |
| P4 human iPSC-MSCs + TCP (80% confluency) + 2hr, 100k xg UC | o-nitrobenzyl alcohol-modified hyaluronic acid and gelatin | 111 EVs/ml, 20 uL | Osteochondral defect in patellar groove; 4 mm diameter x 3 mm depth; Rabbit | 12 weeks | Increased defect regeneration and well-organized articular cartilage structure in the EV/hydrogel group compared to gel alone and EVs alone. | 216 |
| Human umbilical cord MSCs + TCP + 70min, 100k xg UC | GelMA and nanoclay composite | 19 EVs/mL, volume not specified | Osteochondral defect; 2.5 mm diameter x 1.5 mm depth; Rat | 12 weeks | EV delivery increased collagen II stainings compared to controls in vivo. | 215 |
| p5-10 human iPSC-line C1P33 + TCP + 70min, 100k xg UC | Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel | 110 EVs/mL (100 uL), supplemental intra-articular treatment; Multi-treatment group received injections on 7, 14, 21, 28 days or a single injection at 7 days after surgery | OA model; transection of the anterior cruciate ligament in combination with partial medial meniscectomy; Rat | 35 days | DAHP hydrogel improved the bioavailability and therapeutic efficacy of MSC-EVs for OA - with the lowest OARSI score following in vivo study. | 217 |
| Human synovial membrane stem cells + TCP (50-60% confluency) + 30% sucrose/D2O cushion + UC, 1hr 100k xg | Thermoresponsive triblock PDLLA-PEG-PDLLA hydrogel (PLEL) | 111 EV/mL (200 µL) + 800 µL of hydrogel solution; Intra-articular injection performed every four weeks after surgery | OA model; transection of the medial collateral ligament, medial meniscus, and anterior cruciate ligament; Rat | 24 weeks | PLEL@circRNA3503-OE-sEVs limited OA progression; Through multiple pathways, circRNA3503-OE-EVs alleviated inflammation-induced apoptosis and the imbalance between ECM synthesis and ECM degradation by acting as a sponge of hsa-miR-181c-3p and hsa-let-7b-3p. | 218 |