| Musculoskeletal and articular diseases affect tens of millions of people. Articular cartilage is a smooth, white tissue covering the ends of bones in joints. It can maintain smooth, frictionless movement, and dissipates stresses in the joints. Articular cartilage is a no blood vessel and no nerve tissue, and once damaged, it has no spontaneous healing capacity. Articular cartilage defects are very common in clinic, and one of the most challenging diseases of orthopedics and sport medicine. Since articular cartilage has no vessel and nerve, as well as poor nutritional supply, it has long been recognized that chondral defects do not heal spontaneously. If untreated, they will further worn and finally progress into OA. On the other hand, although osteochondral defects possess certain reparative capacity, the reapir of osteochondral defects are often accompanied with chondrocyte terminal differentiation. It would produce irreversible damage to the structure and function of the joint and affect the life and work of patients. Our study developed specific bioactive materials to treat the hard-to-heal cartilage defects.First, the self-healing capacities of partial-thickness, fullthickness and osteochondral defects were evaluated using New Zealand white rabbit model. Spontaneous repair with MSCs migration into the defect area was observed in full-thickness defects, but not in partial-thickness defects in rabbit model. Osteochondral defects had certain reparative capacity, while the repaird tissue showed signs of cartilage hypertrophy.Second, for partial-thickness defects, the adhesion and morphology of MSCs were evaluated on the surface of partial-or full-thickness cartilage defects ex vivo as well as scaffold made of collagen type Ⅰ (col Ⅰ) or collagen type Ⅱ (col Ⅱ). The chemotaxis effect of SDF-1was determined using Transwell assay. Ex vivo and in vitro studies showed that subchondral bone or col I scaffold was more permissive for MSCs adhesion than cartilage or col Ⅱ scaffold and induced robust SDF-1dependent migration of MSCs. Furthermore, creating a matrix environment with col I scaffold containing SDF-1enhanced in situ self-repair of partial-thickness defects in rabbit6weeks post-injury.Finally, for osteochondral defects, in vitro studies showed that PTHrP treatment significantly reduced Alizarin Red staining and expression of terminal differentiation-related markers. This is achieved in part through blocking activation of the canonical Wnt/β-catenin signaling pathway. For the in vivo repair study, intra-articular injection of PTHrP was carried out at three different time windows (4-6,7-9and10-12weeks) together with implantation of a bi-layer collagen-silk scaffold to treat rabbit knee joint osteochondral defect. Defects treated with PTHrP at the4-6weeks time window exhibited better regeneration (reconstitution of cartilage and subchondral bone) with minimal terminal differentiation (hypertrophy, ossification and matrix degradation), as well as enhanced chondrogenesis (cell shape, Col II and GAG accumulation) compared with treatment at other time windows. Furthermore, the timing of PTHrP administration also influenced PTHrP receptor expression, thus affecting the treatment outcome.In summary, for partial-thickness cartilage defects, we developed a col I scaffold containing SDF-1conducive to C-MSCs and SM-MSCs migration and adhesion to initiate the self-repair capacity of cartilage. For osteochondral cartilage defects, we adopted bi-layer collagen-silk scaffold together with PTHrP injection to inhibit terminal differentiation and enhance chondrogenesis, thereby improving the quality of spontaneous repair. Our study is not only helpful for understanding the mechanisms involved in cartilage defect repair, but also provides valuable insight for future clinical translation of treatment for cartilage repair. |
PDF Full Text Request