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.

中文翻译：

---

第 7 至 14 天可能代表在前交叉韧带横断诱导的创伤后骨关节炎大鼠模型中进行基于干细胞治疗的最佳窗口


背景： 在适当的时候进行早期干预的概念已被认可用于治疗创伤后骨关节炎 （PTOA）。然而，实现卓越治疗效果的最佳干预时机仍不清楚。此外，缺乏关于在不同时间点实现的治疗效果的直接证据。假设：干细胞/基质细胞的给药方案可以显着影响它们改善功能和减缓 PTOA 进展的能力。可能存在实现卓越治疗效果的适当时间窗口。研究设计： 对照实验室研究。方法： 本研究共纳入 72 只 Sprague Dawley 大鼠。进行前交叉韧带横断术 （ACLT） 以诱导 PTOA。对照组动物单独接受 ACLT，而假手术组动物单独接受膝关节囊切开术。在 ACLT 后第 3 、 7 、 14 和 28 天关节内给予骨髓间充质干细胞/基质细胞或磷酸盐缓冲盐水 （PBS） （n = 6）。生物发光成像用于检测在不同时间点施用的干细胞的保留 （n = 3）。实验结束时 （8 周），使用 CatWalk 进行步态分析，比较 2 组膝关节功能的恢复情况。进行显微计算机断层扫描 （CT） 以评估一般外观并量化软骨下骨的微观结构。组织学染色用于评估全关节病变。使用 Osteoarthritis Research Society International 和 Mankin 评分进行半定量评估。结果： 不同时间点 PBS 给药对下肢功能或 PTOA 进展无治疗作用。 步态分析表明，与对照组相比，干细胞给药在所有时间点均显著改善了膝关节的一般功能。然而，ACLT 后第 7 天和第 14 天的占空比显着更高。膝关节样本的 Micro-CT 和组织病理学染色表明，虽然干细胞给药显着改善了 PTOA 的进展，但第 7 天和第 14 天的治疗效果明显更好。干细胞给药后，关节表面相当光滑，散在的骨赘很少，软骨细胞外基质的沉积更加丰富，软骨下骨重塑明显减轻，滑膜增生较少，炎性细胞浸润减少。干细胞的一般保留时间在不同给药时间点无显著差异。结论： 本研究表明，干预方案与干细胞对 PTOA 的治疗效果显著相关，在 ACLT 后第 7 天和第 14 天观察到最佳效果。临床相关性： 创伤后第 7 至 14 天可能是临床预防和治疗 PTOA 的适当干预时间。