I'd like to thank the organizers for this opportunity to discuss orthobiologics for the treatment of Neo-A in the athlete. I did take the liberty to place a question mark after the phrase extended warranty in my assigned title. My talk will highlight why I think this characterization is problematic. I have no relevant commercial conflicts. Extended warranty is a phrase that carries implicit and explicit promises. One is a promise to fix a problem. The second is that the fix being offered is so good that persistent or recurrent issues just aren't expected. If we are talking about Neo-A, I am not aware of such a fix. There is also insufficient supporting evidence that orthobiologics in its current form can extend the ability of someone's knee to hold up to athletic demands. Orthobiologics took off in 2009 after Heinz Ward came back just two weeks after a knee injury to help the Pittsburgh Steelers win the Super Bowl. His PRP treatment received widespread coverage. In subsequent years, increased marketing of allergenic products also ensued. These new products were largely brought to market through pathways that did not require clinical trials to demonstrate safety and efficacy. In the past five years, the regulatory environment has evolved to better clarify the status of these products. The bottom line is that most of the cell and tissue therapies that had been offered to patients without supporting clinical trials now need to follow FDA procedures to demonstrate safety and efficacy. Aside from autologous minimally manipulated blood and bone marrow, this guidance applies to most of the cell and tissue products previously marketed for orthopedic indications. This is not saying that papers have not been published. The PRP and stem cell literature shows an exponential increase in Neo-A treatment papers since 2009. The FDA guidance clarified that extracting cell fractions for therapeutic use is considered more than minimally manipulated in most cases. Furthermore, minimally manipulated bone marrow aspirate contains few stem cells and should not be referred to as a stem cell therapy. Clinical data on the use of bone marrow aspirate concentrate for the treatment of Neo-A is scarce. Of 115 papers recently reviewed by Keeling et al., there was only one level one study. This study by Shapiro et al. was limited to 25 patients with bilateral Neo-A. Here, one knee was treated with bone marrow aspirate concentrate and the other knee was treated with saline. There were no differences in patient reported outcomes related to whether bone marrow aspirate or saline was used. No regenerative effects were observed by MRI T2 map. While there are more PRP trials, study and product variability are major concerns. If you read the study selected for just this one review by Belk et al., you will find a mishmash of OA disease states, how the PRP was prepared, the number of injections, what else was added to the injections, outcome measures, and pretty much every parameter that might be considered important in a clinical trial. Thus, it is not surprising that there are conflicting data and opinions concerning every aspect of PRP treatment to include whether to remove the leukocytes. The Academy did their own evaluation of the existing literature and concluded that the available evidence to support PRP treatment of symptomatic Neo-A is limited. Now you might say, I have many super happy patients who swear the PRP treatment fixed their Neo-A and allowed them to get back to sports. I do too. I have an ongoing clinical trial where I give patients with early to moderate Neo-A three injections of leukocyte-poor PRP. I then follow them with PRO, gait analysis, and quantitative MRI. We also measure the platelet counts and the cytokine and proteomic profiles of the injected PRP. Overall, these patients show main improvements in pain, stiffness, and function through six months and now two years follow up. Our gait studies do show that the people who said they felt better walked better. However, not everyone improved. About 40% improved. These are our happy patients. Most were about the same and a small percentage were worse off. When less than half of patients improved, it becomes important to understand who responds. We have not yet determined any consistent predictors of improved outcomes after PRP treatment. The mechanisms of action also remain poorly understood. If one thinks that PRP is helpful for Neo-A because it reduces inflammation, it is important to know that we found that the PRP from older males with Neo-A could actually depress chondrocyte metabolism and upregulate inflammation. For example, macrophages are immune cells important for tissue repair. This cartoon demonstrates our findings that the addition of PRP from young healthy males stimulated the development of the M2 anti-inflammatory macrophage. In contrast, PRP from older males with Neo-A incited production of the pro-inflammatory M1 macrophage. Aging itself alters blood composition. Studies connecting the circulation of old mice to young mice show that the older mice healed better and became healthier. However, the young mice worsened. This means that older individuals may have negative factors in their blood. PRP is a blood product. This study and the previous study highlight that the properties of minimally manipulated autologous blood and tissue products depend on the age and the health of the donor. In conclusion, use of minimally manipulated autologous blood or tissues are generally considered low risk, but we don't really know what we're giving and whether it will be helpful or not. The regulatory environment has changed. It is now critically important to understand the FDA requirements for any cell or tissue-based therapy. Finally, there is insufficient evidence to support claims of a regenerative effect or to support suggestion of an extended warranty, particularly in regards to the treatment of osteoarthritis. Thank you for your attention.

orthobiologics

Neo-A

athletes

extended warranty

clinical trials