So good afternoon, everyone. This is great to be here, because it's such a great topic, right, of where do we really go from here. And I don't know if any of us has the answers, but we at least have a point of view as we've gone through some of these chapters before. And I think we can learn a lot about what's happened in sports medicine, maybe some of the mistakes that we've made as a profession to set the stage for a springboard of going forward in a good direction. Let's go back a little bit and think about how we would design some innovation. Let's just use a drug, for example, to solve a problem. And I'm going to deliberately talk about an example that we, if we wanted to cure a problem with the pancreas, I'm going to argue that we wouldn't design something for the pancreas, that we'd have to go all the way back to a pancreas cell and say, what does that cell do? And can we tell the difference between that cell and one that's diseased? And if we don't know that, we're never going to get anywhere with the pancreas, let alone a clinical trial and a drug to treat something. And I say that because I think we've made mistakes and not done that in the past. And so basic science can provide the baseline understanding to build innovation from the very beginning. And I'm going to argue that same sort of thing, that whatever we're going to talk about in orthopedics, we've got to go back to the most basic unit of everything, whether that's the tissue level or more likely the cell level, understand that. And then we can understand how our treatments can affect the normal versus diseased state. And then finally, we can go to the clinical trials. I say that because in sports medicine, something happened that we've all experienced, right? We had problems. We have tendinopathy. We have lots of issues in sports medicine. And what we started with was clinical trials. Hey, we have something called peer P. Let's use it. Let's use it for everything, because it's got to be good. It's a biologic. But we had no baseline understanding. And instead, as a whole, then we came to the conclusion it was a sham. This doesn't work. That's not true either. We just didn't have any basic understanding from the beginning. We started with number three rather than starting with number one. We've got to go back to the basics. So let's talk about how we can maybe approach something that we all deal with in sports medicine every day and how maybe we can think differently to innovate in the future. What about muscle injury? There's two ways this can go, right? When the cells are injured, they can either A, differentiate and make new muscle fibers, or B, they can proliferate, make additional cells, which often lead to scar tissue formation. And the question is, we don't want the scar tissue formation in our athletes. We want regenerative muscle. How are we going to do it? Well, we can start with what the literature did. Let's just use PRP. Oh, gosh, yeah, that didn't work. We had no idea what we were doing. OK, well, if PRP doesn't work, how are we going to figure it out? Let's go back to number one. Let's go back to the laboratory. And let's take these muscle progenitor cells and figure out what makes them tick. How do we actually make muscle? And what are the cues that they need to accomplish this? So we did this, and what we found was it's exactly opposite of PRP. Matter of fact, we made a mistake in the laboratory. There's a lot of good innovation. That's how it comes about. We made a mistake and took the platelets out of the PRP by spinning it down too much. And guess what? Muscle in the culture dish, right? So it was actually platelet-poor plasma was the thing that changed the cells to muscle rather than PRP, which just made more cells. And for all the basic scientists in the group, if any of you are out there, it kind of makes sense. Because if you ask a basic scientist, how do you make muscle in the culture disk, you know what they're going to say? Horse serum, right? Well, FDA is not so good on that for the use of humans, right? But at the same time, what about our own serum? It kind of makes sense, right? And then we can build on that. If we can make it in the culture dish, then we can then give it to animals. And you see the difference between the disordered scar tissue that occurs with PRP versus the platelet-poor plasma with the then platelets removed, and you could see the regenerative muscle going across the area of the injury. And finally, which is our level of clinical trials. And now it makes sense, one, two, three, and we're using this on our athletes and professional athletes now with really good results. And stay tuned for the actual data because this is brand new discovery, but maybe we're going in a better direction than we were before because we went back to basics to set the table for our discovery. Well, what about tendinopathy, a similar problem? And here's a article by David Flanagan saying all the stuff we do is not very good. I think PRP, again, just as a classic example, just to beat home the point here, also not very good, right? When's the last time 55% of flipping a coin is okay to use with our patients, right? So we went back in a very similar strategy. We're all surgeons, or most of us here are surgeons. We can actually get tissue from our patients. We got normal tissue from bone patella bone harvest of ACL. We took tendinopathy tissue of the patients that we're trying to treat, and we went back to the laboratory because we had to answer, number one, how are these cells different? And we use a technology called single cell sequencing here, which gives the signature of the genes. And we see, at number one, we had this huge new understanding of tendinopathy. Tendinopathy cells lost their ability to respond to their environment. They lost their ability, believe it or not, to become tenocytes or tendon cells. They were going down other pathways, such as fibroblast or cartilage pathways, but they couldn't make tendon. And they had inflammatory mediators that were associated with it. That's also different than we thought, right? We were all taught that tendinopathy, you don't give anti-inflammatories because it's not an inflammatory condition, and that's not all true either. So we learned, again, the building blocks, and we learned a lot along the way, such as the discovery of these mechanically responsive stem cells that are in the niche within our tendons there. And we can activate those, but when those become deactivated, somehow we need to reactivate them. Here's what we saw initially, and you can see under the normal, you see the cells line up. They're due to stress. Maybe? And then on the right side, you see the disorder. They've lost their ability to do it. So proof positive, even the culture that we were seeing with our assays were correct. And so then we tried the low-hanging fruit, right? And we tried what about PRP with the different formulations of PRP? None of them worked. None of them changed that cell machinery to make them tenosynovitis. To make them tenosytes again, or have the ability to make tendon. Now, please don't misunderstand me. I wanted to give you guys a little fresh look at the data here. So far, the only thing that we've used that's been able to take these cells and change them back to normal has been bone marrow aspirate concentrate. I say that with a warning, please don't go out and use it, because the problem is, is we also don't know what we're doing with regards to bone marrow. Depending on the different type of machine that you use, the bone marrow concentrate is so different that we only got this to work in certain patients. So we have a lot of work to do as far as the science, but you see the potential that this unlocks because of going back to number one, the basic science, and how then maybe we can come up with a better answer for tendinopathy. We have some ability now with modern day science to edit things. And if we find a problem and we can't find a solution, we can make a solution because we could then understand the genes that are right and the genes that are wrong, and we can paste in the good genes using CRISPR technology. And this is something that's right around the corner, so again, big promise for the future. The same thing goes with cells. We can't just go and use stem cells for everything, right? That's also been shown not to work. But instead, maybe this approach is to having a newly described adipose-derived cell and actually look at what does it take for these cells to become the different types of tissues that we want them to be. And then we should be able to do that in the culture. We should be able to make them respond. And if we can make them respond, then we can grow new tissues here in the animal model, and then we can go to the clinical trials where we are today. And then if we have all of the boxes checked, we're gonna have a better chance of making this successful. And just for the surgeons in the room, this is how the technology works. The understanding is that the calcified cartilage layer below the cartilage always has to be removed with a biologic procedure. Here we have our cells that are harvested from the fat tissue along with a matrix that has no cells within it. And you can see how that's patched into place and held into position using fiber and glue. So it's a technique that's usable and doable with a little bit of practice, but certainly you can see that there's potential. And then we have to, again, look through the clinical trials and I wished that I can give you even more in-depth information than this, but our MRI is coming back from Europe. This is a very controlled trial, so we don't ever get to see the patient's MRI. They're immediately shipped to Europe for independent analysis, but you can see how this cartilage is incorporated. And this was their old matrix system, so we're anticipating even better results coming forward. So stay tuned for the new ways of cartilage regeneration. Part of basic science also will require new ways for us to gather data. And this is the Biologic Association National Biorepository Network, which is just beginning. And this is happening in the other room over there where we're having discussions about really how is the future going to be for us to collect data. But all these centers, what they do is for every surgical patient that goes into the OR, they collect tissue. Some of that tissue is normal, some of it's diseased, but through that we can examine the difference between the diseased data normal and then we can create scientific approaches to change that over time. Just a few words on devices. That's different, but the question is do we need some sort of basic science strategy for our devices that we develop? Well, the model that we're currently operating on is a typically driven MD, or one of us has an idea about how we can do something better with surgery. And we work with one of the engineers typically associated with a company. Then we undergo production, testing with a company, and we've had a lot of great devices and great successes. But my question is, is that how we're gonna truly achieve innovation? So here's one of our projects, and again, I wanted just to talk through it because we went through a lot of mistakes. So maybe as we go forward, we could just talk about the mistakes which will decrease the mistakes going forward. So our question here is how can we design a brace that's not the old generation, but this is a bioactive interventional brace, right? So then when we move as athletes, it will detect the forces and our movement patterns and it can immediately not only note in the computer system about our abnormal forces, but it can immediately then give us feedback as athletes that we're using risky behaviors that can lead to issues such as ACL tears. So we had all these grand plans, we had the app device that was correlated with this so we could see real time the athlete's performance when we're doing this, and then, so then we had all of the systems, we had the microprocessors installed in the braces, and we had some problems. We had software and the processors that were not fast enough to keep up with the athletes. We didn't have real time. And so although we purchased these microprocessor, et cetera, we needed additional help. We needed the computer engineers to design these circuits so they would keep up with the real speed of human movement. We had wireless systems and our Bluetooth systems and circuits were, again, not fast enough, and so we had to use electronic engineers to figure out the circuit so we can decrease the time in between decision making of the brace to get it back to the player. And then we had the interaction user, so we put on the athletes and that was fine, but then the wires that were holding our little IMUs became broken and the tactile users were, units were uncomfortable, so we had to add an orthotist to the team and a biomechanical engineer to measure our movement. But you see, this created an entirely different perspective. We actually had experts in each of the areas of the basic science to really add to this and to troubleshoot. And this took us years, right? But what if we had this team from the beginning? Would it really have taken us that long to produce a brace that would work and be able to be given to the athletes? And I'm just going to argue that we could have saved ourself a lot of time and a lot of headaches if we designed the team correctly. Another example of going back to the basics. So in summary, new generation innovation will likely require a different approach than we've had and that's what this whole session is about. It will sometimes require basic science, sometimes the basics of engineering and mathematics, but taking a step back before we take a step forward and then we use new thinking to create then the solutions to old problems rather than using the old thinking to go in a circle and have the same old results time and time again. So thank you very much. Like I said, I'm really sorry. I'd love to stay for this, but we do have that Biologic Association, of course. If any of you are interested in biologics, I welcome you to that anytime. Any questions that, it's a small enough group, we can probably hear without microphones. Any questions on basic science as a gateway to innovation? Jason, I would just ask, is this on? Can you hear me? I would just ask, in your own practice when you're thinking about biologics, how much are you utilizing them in either professional or elite collegiate athletes versus your high school and recreational athletes? Do you have a different treatment, different recommendations for those groups? How do you incorporate that into your practice? Well, not much of a difference if we've gone one, two, three. So then if we feel comfortable that we have researched it, we understand that it's safe, and that we have gone through the trials for it to be appropriate, I have no problem of using biologics within, let's just say, our professional players. Matter of fact, we have been using this in the NFL, the collegiate, the Olympic teams. And it's just, I don't know. It's met with such good success that I think that we have no problems of doing that. But it's only because we took those steps back. And if somebody handed me a biologic, or I'll give you another example, and maybe it's not the best example, but if somebody asked me, well, what about using amniotic fluid? Now, FDA has taken that off the market, just to be clear. But if somebody asked that, I would ask the athlete, or I'd ask their family member, or the coach who's ever asking to give it, have we gone through this? Do we know this is OK to give to your athlete? Have we gone through all of this process, these processes, to ensure that? The answer for me for that would be no, because we haven't. But the platelet-poor-plasma, as an example, the answer would be yes. I don't know if we need to wait for level one evidence to give it to our players, but we have to establish some sort of science and some sort of safety before doing so. So there is a line, and it's a comfort level that we'll all have different levels of comfort doing that. All right. That was great. Thank you so much. We appreciate it. Thank you.

basic science

innovation

sports medicine

muscle injury

tendinopathy