# Intra-Articular Bone Marrow Aspirate Concentrate Injection in Patients with Knee Osteoarthritis
## 4 Discussion
### Potential Biomechanical Factors of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis  
The molecular and cellular mechanisms involved in the development and progression of OA are well known. First, immunogenic cells, such as macrophages, initiate or aggravate OA, resulting in the early inflammatory phase of OA [8]. Next, pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-\(\alpha\) and interleukin (IL)-18, shift tissue homeostasis toward catabolism by degradation, resulting in cartilage resorption [19]. Biomolecular mechanisms, such as an increased level of proinflammatory cytokines (e.g., IL-1 or TNF-\(\alpha\)), decreased levels of growth factors, such as TGF-\(\beta\), activation of matrix metalloproteinase, and ultimately chondrocyte senescence can be observed at the molecular level [20; 21]. Considering the biomechanical aspects of OA, BMAC can be an effective therapeutic agent for managing OA [22; 23]. BMAC contains MSCs, hematopoietic stem cells, growth factors, and cytokines [6; 7; 15]. Particularly, several studies have proven that BMAC contains several anti-inflammatory growth factors, such as PDGF, TGF-\(\beta\), and VEGF, within \(\alpha\)-granules of the platelets and MSCs that possess high chondrogenic ability. Moreover, PDGF, TGF-\(\beta\), and other factors, such as IGF-I, also serve as chemoattractants. Further, MSCs have the potential for local tissue regeneration, as well as paracrine and anti-inflammatory actions through their interaction with several growth factors and cytokines [8; 24; 25; 26; 27]. In addition, by modulating the activation of immune cells, such as natural killer cells, macrophages, and T and B lymphocytes, MSCs also exert an immunosuppressive effect [28; 29]. The pathological mechanism of OA can be attributed to both degenerative changes and inflammatory responses. Therefore, MSCs could improve the intra-articular environment secondary to their potential role as a disease-modifying biological tool [8; 29]. On the basis of the positive outcomes observed in previous studies with the use of MSCs for OA, a few studies have investigated the outcomes of an intra-articular MSC injection to treat knee OA [1; 30; 31]. A study using high-dose \begin{table}
\begin{tabular}{c c c c c} \hline \hline  & **Secondary Operation \({}^{*}\)** & **Medication \({}^{*}\)** & **Total** & \(p\) \\ \hline K-L grade 1 (1 knee) & 0 & 0 & 0 (0\%) & \\ K-L grade 2 (33 knees) & 6 & 2 & 8 (24\%) & \\ K-L grade 3 (20 knees) & 8 & 6 & 14 (70\%) & \\ K-L grade 4 (16 knees) & 9 & 6 & 15 (94\%) & \\ \hline Total (70 knees) & 23 & 14 & 37 (53\%) & Failure rate = 53\% \\ \hline \hline \end{tabular} Note: Values are presented as the mean \(\pm\) standard deviation. K-L grade, Kellgren–Lawrence grade. \({}^{*}\) Patients who underwent a secondary operation during the follow-up. \({}^{*}\) Patients with intolerable pain that could not be managed with the usual medication.  
\end{table} 
Table 4: Treatment failure rate of the BMAC injection (5-year follow-up). autologous BM-MSCs injections reported significant improvement in clinical outcomes and cartilage quality over 24 months after administrating the injection [32]. However, the number of cells was increased by 1-2 weeks of laboratory culture. Additionally, the sample size was too small to investigate the statistical significance of the results. Although the expansion procedure to culture MSCs can provide a sufficient number of cells, the process is usually time consuming and expensive and requires specialized facilities [33; 34]. Moreover, during culture, the cells may lose their ability to differentiate or may transform into malignant cells [17]. Another study reported the outcomes of injection of allogeneic BM-MSCs in patients with OA of K-L Grade II to IV, which showed a significant improvement in pain and cartilage quality [26]. Although the study reported no major adverse events, the risk of host immune rejection, tumorigenesis, and disease transmission with the use of allogeneic MSCs cannot be excluded [35].