The clinical and radiographic results of the patients in this study improved in both the low-dose and high-dose groups from baseline to 12 months postoperatively. However, there was no significant difference in the clinical or imaging results between the groups, which does not support our hypothesis.
Favorable clinical outcomes of ADSC cell therapy for knee OA have been reported [10, 28, 29]. ADSCs have properties similar to those of BMSCs but require several weeks to isolate, culture, and amplify in specialized laboratories. In contrast, SVF cells are not cultured and can be harvested, prepared, and re-injected in a single procedure. Similar to BMSCs, SVF cells include cells with multilineage potential, can be easily isolated in large quantities from autologous adipose tissues, and can be used without culturing [18, 19]. Several studies have reported the use of autologous SVF cells alone for the treatment of knee OA [23, 30, 31]. Michialek et al. have reported that the intra-articular injection of SVF cells is a safe and clinically effective strategy for improving the quality of life; however, detailed clinical evaluations were not conducted in their clinical trial . Fodor et al. reported that autologous SVF cells are safe and present a new potential treatment to reduce pain in patients with knee OA; however, their sample size was small . In our previous report, we found that the short-term clinical effects of intra-articular injection of 2.5×107 SVF cells for knee OA were excellent, and our study included an effective sample size . The effects of intra-articular injection treatment with different doses of ADSCs have been investigated [9, 10]. Pers et al. reported significant improvements in terms of pain, function, and mobility only in patients treated with the even lowest dose of ADSCs at the 6-month follow-up . Jo et al. also reported that a high-dose, intra-articular injection of ADSCs improves knee function and pain and reduces cartilage defects in patients with knee OA more effectively than a low-dose injection . However, to the best of our knowledge, the present study is the first study to evaluate the effect of different doses of SVF cells for the treatment of knee OA.
While no significant difference in clinical evaluations was observed between the high- and low-dose groups in this study, the high-dose group tended to have better clinical evaluation scores than the low-dose group. The mean extension angle from baseline to 12 months in both groups was significantly improved as the muscle force of knee extension gradually improved postoperatively. However, the mean flexion angle did not significantly improve from baseline in either group. The mean total VAS scores at 1, 3, 6, and 12 months postoperatively were significantly better than the preoperative VAS score. Although Luc-Harkey et al. reported that greater quadriceps and hamstring muscle strength was associated with less pain , the improvement in knee pain may influence extension muscle strength more than flexion muscle strength.
In this study, the mean total WOMAC scores in both groups at 6 and 12 months postoperatively were significantly better than the preoperative scores. The mean 5-subscale KOOS scores from baseline to 6 months postoperatively were also significantly improved in both groups. There was no significant difference between the groups in the mean total WOMAC and average 5-subscale KOOS scores at 12 months postoperatively, indicating no significant difference in postoperative functional activity between the groups. Furthermore, no significant improvement in clinical scores was observed from 6 months to 12 months in either group, suggesting that there is an option to re-inject SVF cells into the knee joint about 12 months around the first intra-articular injection. Minonzio et al. reported that freeze adipose-derived SVF cells maintained their growth and differential potential . Kaita et al. also reported that frozen SVF cells comprised a heterogeneous cell population, including stem cells and leukocytes, and expressed high levels of mesenchymal stem cell markers, similar to fresh SFV cells . These results indicate that treatment options for knee OA can include initial doses of 2.5×107 SVF cells, with cryopreservation of the remaining cells for subsequent re-injection.
A larger baseline BML size is associated with greater baseline knee pain and structural damage as well as disease progression, and baseline BML size may be particularly important when assessing the associations between changes in BML size and disease progression [35, 36]. In the present study, approximately 30% of BMLs located in the medial TF joint improved at 12 months postoperatively compared to baseline in both the low-dose and high-dose groups. Wojdasiewicz et al. reported that mediating cytokines and their signaling pathways are upregulated in OA joints and most often have catabolic effects; these cytokines include interleukin-1 beta and tumor necrosis factor-alpha, and their levels are elevated in the synovial fluid, synovium, cartilage, and subchondral bone of OA patients. The synergistic effects of these cytokines on signaling pathways result in an increase in inflammation and cartilage degradation during the OA process . Approximately 30-40% of Hoffa’s synovitis and effusion synovitis improved at 12 months postoperatively compared to baseline in both the low-dose and high-dose groups in this study. SVF cells obtained from adipose tissue also contain a significant proportion of cells that are involved in the immunoregulatory function and cells of hematopoietic origin that are involved in vascular remodeling . Macrophages present in rodent adipose tissue constitute 20% of the cells in SVF cells, 70% of which are positive for the anti-inflammatory M2 macrophage marker CD301 [39, 40]. The anti-inflammatory effect of M2 macrophages is thought to contribute to the improvement of BMLs, Hoffa’s synovitis, and effusion synovitis in knee OA, thereby resulting in postoperative functional and pain improvements.
The patients followed a standardized rehabilitation protocol after the procedure which required them to perform daily exercises at home by themselves in addition to being treated by a physical therapist. Sun et al. reported that moderate physical exercise is effective for a decreased risk of severe osteoarthritis of the knee and suggested that exercise has a protective effect against cartilage degradation . Hawker et al. also reported that an exercise program that combined endurance and strength training in patients with osteoarthritis increased functional capacity and reduced pain . Rehabilitation is recommended in addition to regenerative medicine , and it is considered that rehabilitation contributed to the improvement in the clinical score in addition to the effect of SVF cell treatment in the current study.
The present study has some limitations. First, the study compared only two groups and did not include a control group that underwent other intra-articular interventions. The association between SVF cells and other intra-articular interventions should be investigated in the future. Second, the clinical and imaging evaluations were only performed preoperatively and at 1, 3, 6, and 12 months after the intra-articular injection of SVF cells. A long-term investigation of the clinical and structural changes is warranted. Third, we did not evaluate the relationship between the clinical and imaging results. Fourth, although the high-dose group tended to have better clinical evaluation scores than the low-dose group, there was no significant difference between the two groups. This may be due to an insufficient number of cases. However, it is the preoperative clinical score of the high-dose group was better than that of the low-dose group and this could have contributed to the bias in the results. Finally, this study focused on patients who underwent a single injection of SVF cells. In order to determine the optimal treatment for OA, multiple injections should be evaluated in these patients.