Intra-Articular Injection of Adipose-Derived-MSC Exosomes and Hyaluronic Acid in Sheep Knee Osteoarthritic Models Enhances Hyaline Cartilage Regeneration

<b>Background</b>: Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage damage. The limited regenerative capability of articular cartilage poses a therapeutic challenge. Adipose mesenchymal stem cell (MSC) exosomes have shown potential in regenerating cartilage structure in previous in vivo studies on small animals. This study aims to compare the effectiveness of intra-articular injections of adipose-derived MSC exosomes and hyaluronic acid (HA) on cartilage regeneration in a sheep osteoarthritis model. <b>Methods</b>: This in vivo study involved 18 male sheep that were induced to develop OA via meniscectomy. The sheep were randomized and divided into three groups: Group 1 (adipose MSC exosomes + HA), Group 2 (adipose MSC exosomes), and Group 3 (HA). Microscopic evaluation using histological scoring with the Pineda score, cartilage regeneration assessment through histochemical and immunohistochemical examinations, and microtopographic examination using a scanning electron microscope (SEM) were performed 6 weeks post-intervention. <b>Results</b>: Cartilage regeneration in the combination group (Group 1) exhibited a larger area of hyaline cartilage (Group 1 vs. Group 2 [40.38 ± 9.35% vs. 34.93 ± 2.32% vs. 31.08 ± 3.47%; <i>p</i> = 0.034]) and a smaller area of fibrocartilage compared to adipose MSC exosomes (Group 2) or HA alone (Group 3) (13.06 ± 2.21% vs. 18.67 ± 3.13% vs. 28.14 ± 3.67%; <i>p</i> = 0.037). Microtopographic examination also showed a more homogeneous and smoother cartilage surface in the combination group (Group 1) of adipose MSC exosomes and HA. <b>Conclusions</b>: In a sheep knee osteoarthritis model, intra-articular injection of a combination of adipose-derived MSC exosomes and HA significantly enhances cartilage regeneration compared to injections of adipose-derived MSC exosomes or HA alone.