Mesenchymal Stem Cell Extracellular Vesicles as Adjuvant to Bone Marrow Stimulation in Chondral Defect Repair in a Minipig Model
Kris Chadwick Hede, Bjørn Borsøe Christensen, Morten Lykke Olesen, Jesper Skovhus Thomsen, Casper Bindzus Foldager, Wei Seong Toh, Sai Kiang Lim, Martin Lind
Abstract
Objective This study evaluated the effects of mesenchymal stem cell-extracellular vesicles (MSC-EVs) on chondrocyte proliferation in vitro and on cartilage repair in vivo following bone marrow stimulation (BMS) of focal chondral defects of the knee. Methods Six adult Göttingen minipigs received 2 chondral defects in each knee. The pigs were randomized to treatment with either BMS combined with MSC-EVs or BMS combined with phosphate-buffered saline (PBS). Intraarticular injections MSC-EVs or PBS were performed immediately after closure of the surgical incisions, and at 2 and 4 weeks postoperatively. Repair was evaluated after 6 months with gross examination, histology, histomorphometry, immunohistochemistry, and micro-computed tomography (µCT) analysis of the trabecular bone beneath the defect. Results Defects treated with MSC-EVs had more bone in the cartilage defect area than the PBS-treated defects (7.9% vs. 1.5%, P = 0.02). Less than 1% of the repair tissue in both groups was hyaline cartilage. International Cartilage and Joint Preservation Society II histological scoring showed that defects treated with MSC-EVs scored lower on “matrix staining” (20.8 vs. 50.0, P = 0.03), “cell morphology” (35.4 vs. 53.8, P = 0.04), and “overall assessment” (30.8 vs. 52.9, P = 0.03). Consistently, defects treated with MSC-EVs had lower collagen II and higher collagen I areal deposition. Defects treated with MSC-EVs had subchondral bone with significantly higher tissue mineral densities than PBS-treated defects (860 mg HA/cm 3 vs. 838 mg HA/cm 3 , P = 0.02). Conclusion Intraarticular injections of MSC-EVs in conjunction with BMS led to osseous ingrowth that impaired optimal cartilage repair, while enhancing subchondral bone healing.