Purpose

We had previously reported the efficacy of human mesenchymal stem cell (MSC) exosomes in repair of critical-size osteochondral defects in rats and rabbits. To enable clinical translation of MSC exosomes, we proposed a validation of the efficacy of MSC exosomes in a large animal model.

Materials & Methods: Bilateral osteochondral defects (6mm diameter and 1mm depth) were surgically created on the medial femoral condyles of 24 knees in 12 micropigs. Immediately after surgery and at days 8 and 15 post-surgery, 6 micropigs in exosome/HA group received sequential administration of 1mg exosomes in 1ml phosphate-buffered saline (PBS) followed by 1ml hyaluronic acid (HA; Synvisc®) in both knees, whereas the other 6 micropigs in the HA group received 1ml of PBS followed by 1ml HA in both knees. Except for MRI performed on day 15, 2 and 4 months, macroscopic, histological, biomechanical, and micro-CT assessments were performed at 4 months.

Results

At 4 months, exosome/HA-treated defects had significantly higher MRI scores than that for HA-treated defects at day 15 (4.46 vs 3.63; P=0.017), 2 months (7.83 vs 5.79; P=0.023) and 4 months (9.25 vs 6.71; P=0.024). Exosome/HA-treated defects also had significantly better ICRS macroscopic score (9.22 vs 7.25; P=0.008) and ICRS II histological score (79.71 vs 65.10; P=0.032) than HA-treated defects. The mean Young’s moduli of exosome/HA-treated defects were higher than that of HA-treated defects in the defect periphery (19.92 vs 5.50MPa; P=0.003) but modestly in the defect centre (15.17 vs 3.53MPa; P=0.119). Micro-CT analysis revealed structural improvements in the subchondral bone with significantly higher BV/TV and Tb.Th in exosome/HA-treated defects than in HA-treated defects. Importantly, no adverse responses or systemic alterations were observed.

Conclusion

MSC exosomes and HA combination administered at a clinically acceptable frequency of three intra-articular injections promote osteochondral repair with significantly improved morphological, histological, and biomechanical outcomes in a clinically relevant porcine model.