Days 7 to 14 May Represent an Optimal Window for Stem Cell–Based Treatment in a Rat Model of Anterior Cruciate Ligament Transection–Induced Posttraumatic Osteoarthritis

Abstract

Background: The concept of early intervention at the appropriate time has been recognized for treating posttraumatic osteoarthritis (PTOA). However, the optimal intervention timing to achieve superior therapeutic efficacy remains unclear. In addition, there is a lack of direct evidence regarding therapeutic efficacies achieved at different time points. Hypothesis: The administration schedule of stem/stromal cells can significantly influence their ability to improve function and slow progression of PTOA. There may exist an appropriate time window for achieving superior therapeutic efficacy. Study Design: Controlled laboratory study. Methods: A total of 72 Sprague Dawley rats were included in this study. Anterior cruciate ligament transection (ACLT) was performed to induce PTOA. Animals in the control group underwent ACLT alone, whereas those in the sham group underwent knee articular capsulotomy alone. Bone marrow mesenchymal stem/stromal cells or phosphate-buffered saline (PBS) was intra-articularly administered on days 3, 7, 14, and 28 after ACLT (n = 6). Bioluminescence imaging was used to detect the retention of stem cells administered at different time points (n = 3). At the end of the experiment (8 weeks), gait analysis was conducted using CatWalk to compare the recovery of knee function between the 2 groups. Micro–computed tomography (CT) was performed to assess general appearance and quantify the microstructure of subchondral bone. Histological staining was used to evaluate the whole-joint pathology. Semiquantitative evaluations were conducted using Osteoarthritis Research Society International and Mankin scores. Results: PBS administration at different time points had no therapeutic effects on lower limb function or PTOA progression. Gait analysis suggested that stem cell administration significantly improved the general function of knee joints compared with the control group at all time points. However, the duty cycle was significantly higher on days 7 and 14 after ACLT. Micro-CT and histopathological staining of the knee samples suggested that although stem cell administration significantly ameliorated the progression of PTOA, the therapeutic efficacy was significantly better on days 7 and 14. After stem cell administration, the articular surface was considerably smoother with few scattered osteophytes, the deposition of cartilage extracellular matrix was more abundant, subchondral bone remodeling was significantly alleviated, and the synovium was less hyperplastic with reduced inflammatory cell infiltration. The general retention time of stem cells did not differ significantly at different administration time points. Conclusion: This study suggests that the intervention schedule is significantly correlated with the therapeutic efficacy of stem cells for PTOA, with the best effects observed on days 7 and 14 after ACLT. Clinical Relevance: Days 7 to 14 after trauma may be the appropriate intervention timing for clinical prevention and treatment of PTOA.