Intra-articular injections of mesenchymal stem cell exosomes and hyaluronic acid improve structural and mechanical properties of repaired cartilage in a rabbit model.

Wong McI, Keng Lin; Zhang, Shipin; Wang, Ming; Ren, Xiafei; Hassan, Afizah; Lai, Ruenn Chai; Lim, Sai Kiang; Lee, Eng Hin; Po Hui, James Hoi; Toh, Wei Seong

PURPOSE The aim of this study is to compare the efficacy of MSC exosomes with hyaluronic acid (HA) against HA alone for functional cartilage regeneration in a rabbit osteochondral defect model. METHODS Critical-size osteochondral defects (4.5-mm diameter and 1.5-mm depth) were created on the trochlear grooves in the knees of eighteen rabbits and were randomly allocated to two treatment groups: (1) Exosomes and HA combination and (2) HA alone. Three 1-ml injections of either exosomes and HA or HA alone were administered intra-articularly immediately after surgery and thereafter at 7 and 14 days after surgery. At 6 and 12 weeks, gross evaluation, histological and immunohistochemical analysis, and scorings were performed. The functional biomechanical competence of the repaired cartilage was also evaluated. RESULTS Compared to defects treated with HA, defects treated with exosomes and HA showed significant improvements in macroscopic scores (P=0.032; P=0.001) and histological scores (P=0.005; P<0.001) at 6 and 12 weeks, respectively. Defects treated with exosomes and HA also demonstrated improvements in mechanical properties compared to HA-treated defects, with significantly higher Young's moduli (P<0.05) and stiffness (P<0.05) at 6 and 12 weeks. By 12 weeks, the newly-repaired tissues in defects treated with exosomes and HA composed mainly of hyaline cartilage that are mechanically and structurally superior to that of HA-treated defects and demonstrated mechanical properties that approximated that of adjacent native cartilage (P>0.05). In contrast, HA-treated defects showed some repair at 6 weeks, but this was not sustained, as evidenced by significant deterioration of histological scores (P=0.002) and a plateau in mechanical properties from 6 to 12 weeks. CONCLUSIONS This study shows 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 post-traumatic cartilage defect model, when compared to HA alone. CLINICAL RELEVANCE Human MSC exosomes and HA administered in combination promote functional cartilage repair, and may represent a promising cell-free therapy for cartilage repair in patients.