Optimising administration of MSC exosomes for cartilage repair in the clinic

Abstract

Background & Aim We previously reported that 12 weekly injections of human mesenchymal stem cell (MSC) exosomes were efficacious in repairing critical-size osteochondral defects in an immunocompetent rat model. However, this injection frequency of MSC exosomes may be too onerous for clinical use and patient compliance. We therefore investigated the feasibility of reducing injection frequency from 12 to 3 intra-articular injections of MSC exosomes in combination with hyaluronic acid (HA). As HA has some chondroprotective properties, we rationalized that MSC exosomes and HA may synergise to reduce the number of injections needed to promote functional cartilage repair. Methods, Results & Conclusion Bilateral osteochondral defects were surgically created on 17 rabbits. Immediately after surgery and at 7 and 14 days after surgery, each of both knees in 9 rabbits received 1-ml injections of 200µg exosomes and HA, and each of both knees in 8 rabbits received 1-ml injections of HA. At 6 and 12 weeks, macroscopic evaluation, histological scoring and compressive testing at different points on the repaired cartilage were performed. Relative to HA alone, exosome/HA combination treatment promoted significant improvements with time in macroscopic and histological scores and mechanical properties of the repaired cartilage. In contrast, HA alone only promoted some repair at 6 weeks, but this was not sustained, as evidenced by significant deterioration of histological scores and a plateau in mechanical properties from 6 to 12 weeks. By 12 weeks, the exosome/HA repaired cartilage demonstrated significantly better macroscopic score (10.33 vs 7.5; P Our results show that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of three intra-articular injections can promote sustained and functional cartilage repair in a rabbit osteochondral defect model, when compared to HA alone. This study provides the basis for developing the use of MSC exosomes towards a clinical protocol for cartilage repair in patients.