Thanks, Aaron, I appreciate the opportunity. Having heard this, I didn't know what they were going to actually talk about, and they've talked about some of the newer options. So I'm going to go kind of really quickly over the newer options, because I think it's more the thought process, and that's what I'd like to convey. My disclosures are currently available. So if I happen to use a brand name, I apologize. It's not an endorsement of a product or a promotion. It's just for clarity. So you've heard this whole little panel here. In fact, they have gone through every one of these. So that's why I'm going to talk more about the philosophy rather than a specific product. So I think right now, we're being thrown up against this. You have to understand HCTP 351 and 361. So 351, these are the ways that we use allograft. So allograft is not FDA approved. FDA approves the procurement and the processing. They make sure they have good manufacturing processes. But they don't actually say, oh, this osteochondral allograft, you can use it. No. They say it's FDA allowed. So that's where allografts come in. So because they're not really approving it, you don't have to go through this randomized controlled trial and have an IDE and go through this whole process, which is very expensive. And so many of the companies now are trying to use 351. So they're saying it's some type of an allograft. Because they'd certainly like to go, I'm sorry, they're using a 361. Because if it's a 351, if it's manipulated, culturing, additional growth factors are non-homologous. So a lot of these, if you're mincing it up, if you ask a person on the street, is mince cartilage, are you manipulating it? Well, they might say, I think you are. Whoever's making the little minced allograft is saying, no, no, this is just allograft. This is homologous use. So there are some gray areas. And I'm not into pressing the limits on it. I'm going to try to stay certainly within the bounds of what the FDA. So the RCTs for these 351 products are very time-consuming and expensive. Typically to have an adequately powered study, you're going to have to have 200 to 300 subjects. Enrollment is very difficult. I find that in myself. I'm having a patient come in where you usually have to have a control. What's the control arm? Microfracture. You already heard how many of us do microfracture in our normal practice. Very few times. I don't think I've done a microfracture outside of a study in probably five years. So when I'm talking to this patient and they have a lesion, especially if it's over four centimeters square, I'm feeling a little uneasy recommending, let's participate in a study and you might get microfracture and you have a four centimeter area. It takes a minimum of two years to get your data. Everybody wants two-year data as you've heard. And so it takes about two years to enroll, two years to follow the patient, and then two years to complete the follow-up on that last patient. So we're looking at a lot of time. And that equals 20, I don't think anybody can get out of the market right now with $20 million. I think it's closer to the $100 million side. So you can see there's really a big barrier. And that's why with the PJAQ, you're not going to see an RCT if it's just too expensive. It's already on the market. Here's three projects that I've participated or tried to participate with. So de novo ET. So this was the NT that you heard before, the mince cartilage. Well, they actually took even younger infantile articular cartilage cells. So just the cartilages. And they would grow so robustly, they would make a little disc of cartilage just without any scaffold at all. And you just glue it in place. So we did some of those. We did a phase one, and then they canceled it because they said, we just don't want the return on investment. We've got PJAQ. We don't even have to do a study. We'll put all of our money into that case. We actually had an RCT. It did quite well. We were starting to do the final phase three trial. And the bean counters got together and said, you know, if we're looking at return on investment, it's going to be about six to eight years and blah, blah. They said they'd already invested, my guess, they've already invested $20 to $50 million, and they canceled it just for return on investment. It's doing well. We actually published it with Brian Cole. So that's very sad. And then ChondroSelect, this is sort of a Macy alternative, and it didn't make it from Europe to the U.S., even though it was working in Europe, just because of investment. So here's some 351 trials. Agilis-C is currently undergoing. This is the coral product. The initial studies that came out of Europe look quite well. Now we have Europe and U.S. So you'll be hearing about these studies as we go along. Gelrin-C, Regentis, again, we're talking about money. I hate to keep bringing this up, but it's a reality when you're trying to do these. So this is a company, this is a peg-legged fibrinogen that's used as a scaffold. So it's one of these, this is really sort of the microfracture plus on steroids. So it's a very robust scaffold. It is currently on hold. So they have their RCT going, but they don't have the money to pay for it. Esculap, they're working right now. It's a Macy alternative. It's been in Europe for almost 10 years. And it looks to me like it's going to be very equivalent. So you'll have two different products probably, but just their enrollment has been slow, as we would expect. All these studies, in fact, I think all of us, when I used to participate in studies 15 to 20 years ago, I could enroll, you know, 20 or 30 patients a year. And now I don't see those patients because the simple isolated lesions that you need for the studies, we just don't see them. I'm seeing all these. I still see cartilage patients, but they usually don't have a meniscus, they're malaligned. It's a large lesion, it's failed something else. So these studies have really slowed down. Cardostem, that's an umbilical cord. It's sort of on hold right now. Jason Dragoo is doing an adipose derived stem cell treatment. Again, this is a microfracture plus. Alberto Gobi led in Europe, and now he's overseeing the Hyalofast. So this is another marrow stimulation with a scaffold type of approach. And then finally, you've probably all heard about Neocart. I participated in that study. These patients rapidly returned to function. I was very happy with the product and the manufacturer. Once again, this is an RCT, and you have to say a priori what you're going to look for. So you have usually two primary endpoints. It's usually pain and sport and function. And then you'll have secondary endpoints like MRI and the rest of the PROs. And then you have to say, well, I'm going to treat these different lesions. You just heard, well, I don't do microfracture very often, but I'll do it if it's a small little lesion. They allowed lesions down to 1.5 centimeters in their study, which is fine. But we all know that there are some of those 1.5 centimeters are going to do fine with microfracture. So that was one thing. And then they thought, oh, we're so good, we're going to be able to show our data at 18 months. So those were the two things. And there were multiple old people on the panel. We said, look, guys, you've got to go to two years, and you've got to use only 2 centimeters and above. And it worked, but it didn't work superior to microfracture. So this company basically is gone. And this is after they spent millions and millions of dollars on a product that actually works. So the options around doing that is the 361. I misspoke earlier. The option around is 361, and that is FDA allowed. So it comes under the allograft. So minimally manipulated homologous use, not combined with other materials, drugs, growth factors, et cetera. And so these are the gray areas. Now, the FDA announced guidelines for all biologics, and they were concentrating more on orthobiologic injections. But this includes the whole gamut of cartilage that we're working with. And this was in November 2017. Basically what they said, we know there's a lot of gray areas, and we're going to tighten this up. These are no longer going to be gray. We're going to call these black and white, and here are our guidelines on what is black and white, and we're going to enforce them. They were going to enforce them November 2020, but because of COVID, they extended that to June. They just put out a document June 3rd of this year, so just last month, and said, OK, we're now enforcing it. So their guidelines on 351 and 361 products, they're really clamping down. I did not mention there are a few studies out using amniotic membrane to actually use the sheets and to form cartilage. Certainly, there's a lot of amnion. I participated in a study of amnion injections. Those are not homologous. I mean, there's no amnion in a knee, so that's cut off. You can't do amnion suspension injections into the knee, and you can't use the sheets in the knee for a cartilage defect, because the FDA is now going to enforce it. So it's really tightening things down, and if you just look at these gray areas, there's separation of blood products manipulative. That's probably right now. So the FDA, for example, PRP, it's kind of off topic, but PRP, the FDA doesn't regulate PRP. What they regulate is the product, the centrifuge, how you make it, and so that is the FDA-approved product. Same thing with bone marrow aspirate concentrates. They're not regulating that. They're regulating the products that you're using to make it, and so it really is now that it's a doctor's own medical judgment on how to use these products. Fat, is that homologous to the joint? You can say, well, it's a cushion. It's protective, and so that's still one of these gray areas remaining, and specifically for fat in the knee, there is a fat pad, so you can make an argument in that case, and as I said, placenta and amnion, they're out now. So does that mean, so I've got a product. It does go through 361, just like you saw the P-Jack and also the putty type of cartilage. So those are FDA allowed, and they're still allowed even after the guidance, but will insurance pay for it? And the answer is no. They look at CMS medical policies, private payer policies, and looking at those, any time that they can, they're going to deny it, and so they typically require, so there is, if you'll look up in Anthem or United, they have a, and it's on their website. It's a policy on policy, so it tells you how they make up their policies, and they usually want two or more independent studies with adequately powered randomized controlled trials. So that kind of throws out most of this stuff that we're talking about, and they want longer, long-term outcomes, and we all know these are, they're kind of hiding behind, they would like to limit the expansion of these things, but you know, on the other side, we all want safe and efficacious and things that are durable, so you know, you can't beat them up, but just because it's a new product and your rep says, this is great, you could use it right now, it's FDA allowed, you're probably not going to get paid for it. So 361 products, as you've heard, these are all these 361 products that are FDA allowed, they're not FDA approved, so that's sort of how you would, you know, like to be thinking about these things. So once again, back to this philosophy, so how do you add new products in your practice? So I've been doing this cartilage stuff for about 25 years, and initially, I was just thrown with all these new products all the time, and it was like, okay, well, how do I start? Well, first of all, I tried to participate in randomized controlled trials, because that's, it's really insightful when you're on the inside looking out, you can actually say, well, you know, because nothing works 100%, and so really paying attention to the failures. So Seth Sherman and I published the evaluation of novel cartilage treatment options for clinical use, and it was just sort of a philosophical overview, develop a personal system to look at these, because sometimes these products are so new, especially with P-Jack around, I mean, we were using P-Jack for 10 years, and there was really three or four articles of just very small case series at that time. So this is just my approach, so I always like to go back and read the preclinical literature, because I want to know what it's doing in animals, and I want it to be in large animals, I mean, you can put anything in a mouse, and it's going to do fine. But, you know, when you're talking about goats, horses, that's a little bit more critical, and it's going to translate better. So you can certainly read their white papers and sponsored case series, but you've got to do it with a critical eye. Certainly, if he's showing this oval osteochondrolograph, he showed the best one I've ever seen to date, you're not going to show the worst one, and that's the same thing when the industry is showing you their white papers and case series, they're going to be the best that they have. And then I like to, you're going to find out, you know, there's the design surgeons, or, you know, who's leading these studies, go out and talk to them. I mean, they're just real people, you know, Brian Coles and about every study that's out there, he's very approachable, just go out and say, well, what do you think about this new product, and he'll tell you the truth. And then once you go past that level, go down to the early adopters, because there are a lot out there that they may not be participating in a trial, but they're putting a lot of these products in, and they're going to have a really good flavor on their early experience. Certainly, you can attend podium presentations like we're doing now. And then finally, what I like to do is I sort of always look, even when I'm not doing a study, I'm collecting patient reported outcomes, I just do that on all my cartilage patients, and have my own little sort of personal database, and I'm looking at it. So, when I get a new product, they all look good, you know, you're always so happy, you know, and it's going to have some problems down the road. So, I only do 10 or 20 patients at a time, and then I'll take a little break and just follow those patients over the next year. And if I start seeing problems, then I go, whoa, what's going on? Or if they're doing fine, then I'll go ahead and expand it. So, evaluating your results. You've heard this over and over, you know, nothing ruins a good result like follow-up. So, this is a cautionary tale. This is one that I was involved with, Andreas and I were both in this study. And once again, on these 361 products, this is a gray area in that it's an allograft, but it was decellularized. Thank you. Ah, yeah, this really choked me up. So, they were decellularized. So, this is a dead piece of bone, and it has a cartilage cap, and the cartilage cap is decellularized. So, it's dead. So, dead on dead. And if we look back, you know, to the literature and you say, where did they ever use dead cartilage? Yeah, frozen allograft. And that was used, Mencken was doing that, you know, 30 years ago. And there were reports that in some cases, oh, these patients did quite well. Well, Mencken's cases, many of those were probably large tumors. And so, we're going to cut your knee off, or we're going to put this allograft in. And they were so happy, you know, so you just have to look at what you're comparing it to. But as we said, once it's a 361 product, then it's like an allograft. And so, the FDA does not say this is approved or not approved. They just allow it. So, because of that, the company brought to us this product. And they said, well, we did this horse trial. We want you to put it in humans. And so, we're going, well, we've got to step back a little bit. We don't want to just take, they just wanted to take it to market because it could be. I said, no, if I'm going to participate, I want to do a randomized controlled trial. And they said, no, we can't afford that. I said, okay, we'll just do a series. And we'll get some of my buddies in and we'll do a multi-center series. So, that's what they allowed us to do. And so, if we looked at it, they did great. They look fantastic at the time of implantation. The patients were doing fine at six months. And then after that, they started trickling in with, you know, pain, swelling. And so, if we publish this in 2016, there was a very high failure rate and acute delamination was even reported by others. So, we did find failures at structural damage of the graft by arthroscopy or MRI. And you can see 72% of these were failures. And so, when I presented this at OSSM, basically, I heard that all the reps of this company were bad-mouthing me. It is like the failures were because I was an idiot and didn't know how to do it properly. And I was a klutz surgeon. And so, I had to endure that for about a year. And then, everybody else started noting these failures. And now, I think they've finally taken the product off the market. And you've known, I'm not going to name any names here. But this is what it looks like. So, once again, at one year, you're starting to see these. But these patients did quite well. And we saw that with the TruFit that was earlier. So, a lot of these things look really good for a year, 18 months. And then, it tapers off. So, on current options, I think what I'm going to do, I'm going to stop. Because I think it would be more fun to go through case studies and have discussions. Because basically, there have been so few advances, these current options have been well thought out by the other presenters. Thank you.

cartilage treatment

allografts

FDA approval

361 classification

randomized controlled trials