## 4 Discussion
Recently, regenerative medicine has found widespread use in the therapy of KOA, with the use of platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Their action is related to the inhibition of matrix metalloproteinases, inflammatory cytokines (TNF-\(\alpha\) and IL-1), and immune cell maturation, with consequent prevention of cartilage damage and disease progression [31]. Although these treatments are safer and more effective than conventional conservative treatments in terms of pain reduction, functional capacity restoration, and tissue repreparation, the evidence on their efficacy is limited [31]. HA's powerful anti-inflammatory and analgesic potential has proven effective in several disease states including knee OA, in both normal and overweight patients. Although the intra-articular injection of HA is included in the OA management guidelines, to date, there is conflicting evidence on its effectiveness, especially in the long term, and there is a lack of agreement regarding its use [6]. In clinical practice, there are different types of hyaluronic acid that are not equivalent, whose characteristics depend on the origin, dose, and molecular weight [32]. In recent years, several studies and literature reviews have been carried out to assess the long-term effectiveness of intra-articular AI in KOA, but the evidence is always limited [6; 30; 31; 32; 33]. Viscosupplementation improves pain, stiffness, and function, in addition to improving the strength of the flexed knee muscles. Unlike intra-articular corticosteroids, intra-articular AI restores the ideal rheological properties of the synovial fluid, but does not produce an immediate analgesic effect. Some studies agree that the clinical efficacy of intra-articular AI is maintained up to 6 months after treatment before undergoing involution [33]. A control-case study showed a significant improvement in knee pain and function 5 weeks after treatment in patients treated with HA infiltration compared to placebo, with these effects being maintained only up to the 25 th week [33]. [PERSON] et al. [34] conducted a study to evaluate the effectiveness of single intra-articular injections of cross-linked hyaluronic acid (HYA-JOINT Plus) compared to the single injections of Synvisc in patients with KOA. Compared to the endpoints examined, the authors noted that the group treated with HYA-JOINT Plus showed significant improvements in pain and stiffness, which remained up to 6 months after the end of treatment. No statistically significant improvement was observed in scores of the WOMAC and Lequesne scale or with respect to the consumption of analgesics. In a retrospective study carried out by [PERSON] et al. [6], it was observed that the administration of two doses of Hypovis at a distance of 1 week resulted in a reduction in pain both at rest and on the move for about 1 year. This also led to a lower consumption of analgesics (e.g., NSAIDs and paracetamol), emphasizing the importance of treating those patients with K-L stage KOA I who are at risk of pharmacological interference or gastropathy from NSAIDs. [PERSON] et al. evaluated the effectiveness of single in-articular injections of HYLAN GF20 compared to placebo in patients with KOA. In addition to reducing the number of intra-articular injections required, the proposed treatment showed efficiency in terms of pain and improved functional mobility for about 26 weeks [32]. A further study showed that repeated intra-articular AI cycles in KOA resulted in greater improvements in pain and functionality compared to a single treatment cycle. The authors also showed a continuous improvement after further treatment cycles up to the fourth treatment cycle, after which a plateau effect was established [35]. The results of our study agree with the literature. In this study, we observed that overweight and obese patients who underwent intra-articular hybrid HA injection experienced a statistically significant five-point reduction in pain severity on the VAS scale.