# Potential New Treatments for Knee OA: A Prospective Review of Registered Trials
## 4 Discussion
### Intraarticular Injections  
IA were very well represented among the future trials. There are several benefits of IA administration: decreased systemic effects, high local concentrations, ease of access to the knee, proven placebo effect and very rare adverse events [29]. We found that most trials were for cell therapies, using MSCs. Orthobiologic products already in clinical practice include bone marrow aspirates, adipose derived stem cells and PRP (platelet rich plasma). Ideal candidates should have normal lower limb alignment and no major mechanical disturbances [30]. Nevertheless, current evidence suggests that progenitor cells relieve pain by activating mu-opioid receptors and that they have anti inflammatory properties. It is less likely that they can rebuild tissue [31]. Bone marrow aspirate is harvested from the iliac crest and concentrated by centrifugation. It contains hematopoietic stem cells which stimulate the regeneration process and promote wound healing, MSCs and endothelial progenitor cells which support vascularization. It has higher concentration of interleukin 1 receptor antagonist (IL-1 ra) compared to PRP [29; 30; 31; 32; 33; 34]. In the USA, bone marrow aspirate concentrate is preferred as opposed to culture-expanded MSCs because it meets the FDA (Food and drug administration) standards as a minimally manipulated autologous source MSCs [29; 31]. MSCs injection obtained from bone marrow concentrate may also improve posttraumatic shoulder osteonecrosis compared to simple core decompression [31]. Adipose derived products use micro fragmented adipose tissue, stromal vascular fraction, and cultured adipose derived stem cells. The rationale for using adipose tissue is mainly that it contains up to 500 MSCs per milliliter than bone marrow concentrate [29; 31]. Adipose autograft is harvested in the operating room or less commonly in the office from the abdomen using a large syringe. Micronized fat only minimally manipulates the tissues and thus does not separate cells from clusters [29; 32]. It is currently the only FDA approved adipose tissue therapy. A step further is syringe emulsification which uses pressure and a dense mesh filter. Adipose tissue derived MSCs and stromal vascular fraction improve WOMAC (Western Ontario and McMaster Universities Arthritis Index) scores, reduce pain and improve function in old adults with symptomatic knee OA [33]. [PERSON] et al. administered a single injection of autologous microfragmented adipose tissue to 120 knees (75 patients) with a mean age of 69.6 years, BMI 28.4 and Kellgren Lawrence grades 2 to 4. They found grade 2 disease had the best results in KOOS--Pain up to 24 months. Functional and quality of life success was seen in 88.3%, (66 patients) at all follow-up time points [34]. Umbilical cord products are harvested at birth and saved as potential adjuvants for future disease such as cancer. It is a highly valuable source of stem cells in general, also known as Wharton Jelly MSCs [3, 7, 10, 11, 29]. There is currently very little data available, but many clinical trials are under way. Umbilical cord MSCs have shown WOMAC improvements up to 1 year in patients with diffuse knee pain due to OA. The effect was superior to HA [35]. For patients receiving high tibial osteotomy, the intraarticular addition of bone marrow aspirate concentrate or human umbilical cord blood-derived MSCs provided similar, outcomes in terms of pain relief, functional scores, and quality of life at a mean follow-up of 33 months [36]. PRP is obtained by collecting peripheral blood and processing it by centrifugation (usually 5 min at 1500 rpm). It contains platelets, growth factors, white blood cells, and red blood cells [3, 7, 10, 11, 29, 37]. Growth factors which promote cartilage healing are transforming growth factor (TGFB-1), insulin like growth factor (IGF-1), fibroblast growth factor (bFGF), and bone morphogenic proteins (BMP-2).