where I'll be headed on a rocket sled after this talk after being gone for a week. My charge is to give you my take on autogenous cells. What are the options and what are the effects? As a disclosure, I am a consultant with Lipogems, who's a company that does have a product in this market. My coach in football used to always tell us that, you know, grass drills are sort of the basis for everything that you do and you do them over and over. You're hearing over and over this morning about the FDA today, so pay attention to this. You know the ground rules, which are that we're to use autogenous tissue only, minimal manipulation of the cells, which means you can centrifuge it, you can filter it, or you can or you can micro fragment it, homologous use only, which means that the recipient cells need to be the same as the donor cells, and no enzymatic alteration. This is the enforcer. This is Peter Marks. Peter runs the Center for Biologics Evaluation and Research. This is the FDA's enforcement arm for orthobiologics, which fall under Title 21, Section 361, which you've heard a lot about, and as of June 1st of this year, the discretionary enforcement, which is, you know, code for we weren't really going to look at this too hard up until then, is expired. So from here on out, be very careful, and I know Thomas emphasized that, but particularly when you're talking about amnion products and other allograft tissue, that's going to be heavily scrutinized. A lot of these companies are already in trouble about that, so just keep that in mind. Unfortunately, we've got a lot of good resources to draw from and sorting this out. The Biologics Association, which was the first day of this meeting, is the best of these groups. I might be biased, but, you know, this is AOSSM and ANAS both contribute folks to this, and that group has a lot of good information. Ken Zaslav, who's the new president of the BA, is circulating to all the registrants the latest FDA stuff. I think that's going to go out today or tomorrow, so if you were at that meeting, you ought to be on that list. If you're not, you can email or check on the website for the BA. Our Academy also has a website with a regulatory dashboard that goes over all these different products and therapies and tells you where they lie on the treatment spectrum in terms of approval. I'm going to highlight another thing that was currently mentioned by Arnie Kaplan. Arnie was at our meeting of the BA this year, and he's the father of American stem cell biology, and he's urging us all, because the true definition of MSCs, which I'm going to talk to you about in a second, is so narrow that the majority of these therapies that we're talking about, whether it's bone marrow or fat, they're really very low and true MSCs, but there appears to be a paracrine effect, and so he's urging us to use the term medicinal signaling cells for MSCs for that purpose. So this is a strict criteria for what is an MSC. It has to adhere to plastic and culture. It's got to have marker expression over 95% for CD105, 73, and 90. It's got to have less than 2% of these other markers, and it's got to be able to differentiate into adipocytes, osteoblasts, or chondrocytes. It's a very narrow definition. Well, what's my take on the cellular therapies in sports medicine? I think that where we are now, PRP and adipose are the two best options that we have, and I'll focus on these. PRP has been around since 2006 when it was first used in tennis elbow, and there's 6,000 references out there. I'll simplify this for you. About two-thirds are favorable for the use of PRP, and when you're talking about tendinopathies, it tends to be the leukocyte-rich version that's that's favored. So my bottom line on this is it's a great second line therapy after braces and OT. It beats corticosteroids nearly every time, and it's safer than corticosteroids, although you might tell your patients if you are using it, it's going to hurt more than corticosteroids for the first week. Often beats surgery. Doesn't always work, but it's a lot cheaper than the other cellular therapies. It's low-risk, and it's worth a try. What about OA? We're all sports medicine docs, so we're dealing with a lot of patients with early OA. Well, there's an emerging body of evidence. It's not perfect, but it's coming along that leukocyte-poor PRP is very effective for early OA and neutral alignment. So I think that's my take on that. This is from Mark Safran, and I think Don may have referred to this paper earlier. This is a scoping review looking at what we know about orthobiologics as it relates to Olympic and professional athletes. So these are the studies that were reviewed, 35 papers, and this was just published last month in British JBJS. 94% within the last eight years, 50% from the U.S. PRP is featured in 94% of these reports, and if you really look at the evidence, only 6% were level 1. Most common studies were on the elbow and hamstrings, and the sports involved were baseball, soccer, and football. And if you really broke it down to what where the evidence was, this is exactly what Don just told you. It's really level 3 evidence that we have for our pro and Olympic athletes, so we're not quite there yet in our literature. I'm going to move on to adipose, and why do I like adipose more than mero, and all due respect to Don. Well, first of all, there's an order of magnitude more activated cells and fat than there is in mero, and a lot of these patients who are treated in the treatment gap are in the somewhere between 40 and 70 years old, and if you look at mero in 40 to 70 year olds, it's not as good as 20 year old mero, but it's just as good as 20 year old fat, because there's not a big change in the activated cells and fat over a lifetime. And I live in North Carolina like Ned Amendola and others in this room, and we have a lot of patients that they go to Biscuitville and Bojangles and other places, so we got got a lot of tissue to work with. So three ways to prepare fat. You can micro fragment it, you can filter it, or you can centrifuge it. So what's my take? And I'm up to over 300 athletes that I've treated, and athletes and recreational athletes like those of us in the room, and my experience has been that it's really good for early knee OA, neutral alignment, it's good for shoulder OA, even in severe cases of shoulder OA, soft tissue healing if you got a big soft tissue defect, and that is an adjunct to whatever you're doing for a chondral defect, whether it's microfracture or other treatments. A lot of registered studies, some of which we're involved in now that are coming out, and I think we'll be hearing a lot more about it, catching up with PRP over the next few years. These are some potential indications where I've used it, just anywhere you need biological healing. This is a patellar tendon debridement, a lacrosse player. This is a patient that had a plafon fracture here, bad or intra-articular extension, just injecting the holes and into the joint. Again, don't know if that's going to work out or not. I spent a lot of time with the Italians on this. They developed the majority of the techniques involving fat, and they're ahead of us. This is Pietro Rendelli on the top in Milan, and this is Zorzi's group in the bottom in Verona, and a couple tips from them. First of all, put compression on the liposuction or lipoaspiration site after you do the surgery, and I use an abdominal binder for 48 hours. A lot of argument about what the volume that you need to inject is. They seem to believe that 10 cc's for a major joint is correct, so that's what I've been using. Close the portal before injection, and they're ahead of us, Lou, on in terms of public funding. They've got their the Italian version of Medicare to fund it because they got more data than we do now, so there's hope, I think, for that. What about the evidence? This is Jerry Malanga's study. This is a prospective trial in shoulder OA, 18 patients, followed out 12 months. No post-procedural complications or adverse events, and improvement in all the different scores that you want to look at, particularly visual analog and ASCS. This is a level one study, one of the few ones that we have, and this is microfracture alone versus microfracture with the microfragmented fat, and they showed in this case that both of the groups significantly improved, but like we've seen in other studies, the microfracture results fall off after about a year, and the microfragmented group continued to be good. This is a study from that Zorzi group I mentioned, 30 procedures. A lot of these patients had big procedures. They had ACL, LCA, osteotomies, and meniscal work, and they followed them out one year, which is the gray bar, showed marked improvement in all categories, and then the black bar is three-year follow-up, and the results were durable and even improving if you look at Coos. This is a study that just looked at what the particular groups that might respond well to the treatment were, and they showed that the earlier stages of OA and patients with a higher pain score actually did better. That was a subgroup that was really helpful. Very interesting study here from Houdetz. We're all looking for objective evidence. They looked at degeneric MRI to look at proteoglycan concentration to see if there was an increase. They followed them out 12 months, and this is how they measured each of the facets in the knee, and what they found is that 53% of the joints actually increased in proteoglycan at 12 months. Of the 3.9% that decreased in proteoglycan, all of them were KL4 or greater, so it looks like there is some effect on the proteoglycans. This is Fontana's study that shows, like the other one, that if you follow them out, they do a little better long-term with adding the microfragmented fat, and that was a significant study at 24 months. These are my patients, about 75% improved over time. This is an early subset from Duke. Got a similar group, about 50 patients in Charlotte now, and the results are holding up the same. We're just looking at our two-year follow-up on that group, but about 75% get better and improve. It doesn't work for everything. These are recreational athletics. Only about 60% really felt like they were satisfied or very satisfied for that. Some were not, so it's not for everybody. A lot of these are early patients that had bad OA. Safety study shows that it's safe. Sample analysis shows that there's really only about 50 to 100,000 of the true MSCs. This is Matt Hilton from Duke's cell biologists there that did this study with us, so a little disappointing in terms of the number of true MSCs, but they do grow in culture. Excited about some of the new technologies. We heard from the Mayo people earlier, Aaron Critch and his team. They're doing actual MSCs and got some good early data, and this is a new GID trial, which is a stromovascular fraction study where we can get up to 50 to 100 million true MSCs, and we're going to participate in this study along with some of the other centers, so I think a lot of good stuff is coming. So bottom line, it's promising. It's safe. Pain relief seems to be solid. I think for PRP early OA in the knee, soft tissue healing, particularly around the elbow. For the adipose, shoulder OA, knee OA, soft tissue healing seems to be good. Be careful about the FDA things. Look at those websites. Good studies coming. A lot of unanswered questions still, but I'm very excited about the space. Thanks.

autogenous cells

sports medicine

FDA enforcement

mesenchymal stem cells

cellular therapies