Now, Nick Puizzi, coming up with new emerging blood-based formulations beyond typical formulations of PRP. Perfect. Good morning to everybody. First of all, thank you for the invitation. It's a pleasure to be here tonight, today. I think you made a mistake inviting an arthroplasty surgeon to an arthroscopy, but thanks for the business you give us. So the conflict of interest are listed in the webpage. So I was tasked to talk about the new emerging blood-derived, right? The thing is, I think that in order for us to know what's new, I think we have to see where we're coming from. So when we look at where we are today, PRP is still growing, right? So if you go to Google Trends, if you look at the publications, if you look at the usage, it's still increasing, right? But this is not something new, right? If we go back in history, the first time we used PRP in medicine dates 70 years ago. And what we've done and where we've came along during all these years is surprisingly slow. And I'll guide you through that and what I see. So the first thing is that when we see, well, who is using PRP now in orthopedics, the vast majority is in the general orthopedic field. And then it's divided among all the different subspecialties. But again, the way we were preparing PRP 50 years ago and how we're preparing it today is not that different. When we go into the basics and we can say, and we might have our disagreements perhaps on how we see where we are now, but PRP 1.0, looking at density separation with centrifuges that has been the traditional way of preparing PRP, is the way we still do it. I mean, we can discuss about different centrifuges and what's available and different processes and slight variances in the centrifuges that we have. But if you put it all together, it's like the full increase that you get on the plate. It's relatively within the same range. The challenge that the only thing that we have to compare one PRP with the other one is what it's been presented by the companies that we use the PRP from or the final volume that we inject with each patient. And the thing is that there are plenty of available commercial PRP devices. And if we go into the details of how they classify and how they present it to us, that still remains a little bit challenging. And we're still looking just at the surface because we're still looking at the broad description of how many platelets or leukocytes are there, but we're not going into the in-depth analysis of what's going on. So the challenges remain the same. We still don't know the composition. We still have fixed protocols. We have a fixed PRP output. And more so, we still don't have a quality control to know if we have a release criteria to define if we use it or not in different patients. We've published on how poor the literature is, and this has not changed over the past years, although there might be some improvement coming based on journals becoming a little bit more detailed in requesting for these things. But still, there's inconsistencies. So why am I, if I was tasked to talk about the future, why I'm looking at this is because it's very hard to move the ball forward if we don't know where we're coming from and we don't quite understand or are measuring what we're doing today. So when we talked about mechanism of action, I think this is a major topic. Why? Because most of the things that we've seen on mechanism of action, it's been shown in vitro. But today, we don't have a good idea of how this works in vivo. We have thoughts and we translate observations that we see in the lab into clinical practice, but we still don't know what drives the mechanism of action. We've made associations, we've looked at different links and things, but we still don't have a true understanding of what's happening. We can discuss about the pro-inflammatory and the anti-inflammatory factors within PRP, but still, it's in gray area and we don't have good ideas. So when we look at the broad picture, the main thing that we have to classify different PRPs, aside from the number of platelets, is the concentration of leukocytes. And the data, although it aligns depending on the diagnosis, it's still a little bit uncertain. And we don't have a good idea of which PRP to use in which case scenario. And even so, when we look at leukocytes, it is a big group on itself. So there's more to come on that area. The application, and we've gone through this through multiple great presentations so far, it's still based mainly on consensus. We need to find consensus among ourselves of what to use and when to use. And the cost remains a big elephant in the room. This is not covered by insurance. So when we look at what we're spending and how much our patients are paying for this, and we translate that to efficacy, it's a challenge. We try to mark off this and do a cost-effectiveness assessment, and of course, I'm promoting my business of total joints. We've still seen that in a patient with a kelogren sonority of three that has failed conservative treatments, total knee still is preferred. Only it was in those patients that had high risk of complications with a total joint was that PRP was cost-effective. An interesting thing is that the cost-effectiveness, the reason why the models didn't favor PRP in the broad picture was not because of the cost. It was mainly because of the lack of efficacy proven in our data so far. So where are we? So PRP 1.0 is still challenging because we have multiple aspects of it, going from the source, the preparation, anticoagulation, the dosing that we use that still needs to be defined. And I think Bert presented a great case example. We can look at the data and we look at the activation, and that might or might not present an effect. Well, collagen is one of the main activators of platelets. So how to use it and which patients will benefit from activation or just with the natural activation, it's still to be defined. The challenge is that sometimes we're rolling our dices and we don't know exactly what we're doing with this. So what would be a PRP 2.0 or 3.0, or what's the future? So what we see is that there's still room for us to understand what's driving this effect, right? There are microparticles, right? There are microvesicles like exosomes that have been shown to have some potential role as therapeutic agents. Why? Because exosomes, the way cells connect with each other, does play a role, and we have some early evidence, on mechanisms of disease that we still don't understand. But if we are able to create data and understand how exosomes actually connect in a cell-to-cell basis, then when we are to use them as therapeutic agents, we'll be able to extract them and be able to use them and use the growth factors or cytokines that we want to use. And I think the most interesting things for us to absorb out of all this data, basic science that I'll present now, is that the methods of separation of exosomes or this is what's going to be the future. So once industry and once our academic and our research is able to find ultracentrifugation or size-based or immunoaffinity filtration ways of isolating these factors, and we can link them to mechanism of disease, we'll be able to talk about a PRP 2.0 or different mechanism of disease and treatments to use them. Or even so, we might use them as a way of looking at which patient will be a responder and which one will not, things that are still to be defined. Where are we now? We're very early. If you look into the data, and I was trying to find things to present, there's not that much. There is some ways of and multiple studies looking at extraction of exosomes from synovium, from plasma, which is interesting because you could use them to screen, even some from urine and OA, or you can go into cell cultures, MSCs, and extraction of those, but still it's to be defined. So we can use them as biomarkers or as therapy. In the lab, with some of the exosomes have shown that even extracting them from PRP might facilitate the recovery even in OA, in muscle, and in different treatments as shown in this study here. But again, take this as a very early view of what might be coming because still this is early and this is only on the lab so far. Now the therapeutic effects of these PRP exosomes extracted do and will play a role in how we treat disease in the future. The thing is that when we'll see all this translated into our clinical practice, that's probably going to take a long time. And probably the way this will happen might not necessarily be with autologous use. We could then use plated lysate, the way it's been used traditionally, where you can extract PRP from multiple patients and you can extract the growth factors, and then with different methods of ultrafiltration or different methodologies that will be developed, then we can use that to be able to tailor to the individual treatment of different disease and create specific formulations for indications that will actually be driven and target specific mechanisms of disease. Now all this sounds good, but still way, way ahead of us, sadly. Plated lysate, as how we have it used today, has potential. It might allow for standardization, but still we don't have it available in a way that we can use it and it will be mainstream yet. And I think that going back to, and just to conclude, I think that we also need to be aware that we need to continue and reinvest on going back into identifying the targets that we want to treat. We have two moving targets. One is on developing the best treatment, and another one is to understanding where and what we're treating and getting. And the other thing, and this is something that we are working now as part of the Biologic Association, something that, with the data we have now, we can actually do, is trying to phenotype and find ways of actually detecting those responders. We do have ways of preparing PRP, we do have some acknowledgment, and we have ideas of how we can actually start looking at this and identify patients, disease phenotypes, and candidates that will have a higher chance of responding to current treatments. So perhaps if you're looking at novel treatments, it is not necessarily looking at what's coming or what other new treatment, but how to optimize or how to better select patients with what we have now, and hopefully that will be what we'll have in the very near future. So at the end, going back to the Garner Hype cycle, I think we're still low in where we are, and I hope, I don't like to put this gray forecast ahead of us, but I think it's going to take us time in this slope of alignment to really find the right place for PRP, but we'll get there. Thank you very much. Thank you.

platelet-rich plasma

PRP therapy

orthopedics

leukocytes concentration

cost-effectiveness