Cross-Linked Versus Linear Hyaluronic Acid for Cartilage Repair in Rat Post-Traumatic Osteoarthritis

Post-traumatic knee osteoarthritis develops following acute joint injuries and can progress rapidly, causing significant morbidity. Intra-articular hyaluronic acid injections are a common treatment, but efficacy varies between formulations. We hypothesized that cross-linked hyaluronic acid would provide superior chondroprotective and anti-inflammatory effects compared to linear hyaluronic acid in a standardized post-traumatic osteoarthritis model. Post-traumatic osteoarthritis was induced via anterior cruciate ligament transection in 84 male Sprague-Dawley rats assigned to four groups: Sham (n = 12), untreated osteoarthritis (n = 24), linear hyaluronic acid-Jetknee (n = 24), or cross-linked hyaluronic acid-HYAJOINT Plus (n = 24). At each of four time points (Day 7, Week 4, Week 8, and Week 12 post-surgery), three Sham and six rats per treatment group were sacrificed. Functional recovery was assessed by weight-bearing distribution. Cartilage integrity was evaluated histologically using hematoxylin and eosin and Safranin O staining, scored with the Osteoarthritis Research Society International histopathological grading system. Immunohistochemical expression of type II collagen, type X collagen, matrix metalloproteinase-13, and tumor necrosis factor-alpha was analyzed. Both hyaluronic acid formulations significantly improved weight-bearing compared to untreated controls. Cross-linked hyaluronic acid demonstrated more sustained functional recovery and superior cartilage preservation with lower histological scores. Immunohistochemistry revealed reduced catabolic and inflammatory marker expression with higher type II collagen in the cross-linked hyaluronic acid group. High molecular weight cross-linked hyaluronic acid conferred stronger and longer-lasting chondroprotective effects than linear hyaluronic acid, suggesting that structural optimization of hyaluronic acid formulations may confer more sustained chondroprotective effects in this preclinical model of post-traumatic osteoarthritis.