and not me, right, to follow that. That was fantastic. For those of you who don't know, I think most of you do, T. Mormon is now chairman at North Carolina. He's done a lot of research in the adipose-derived cellular tissues, and now he will give his talk without saying the word stem cell, so thank you. Thanks a lot, Jason, and yeah, it is hard to follow you, Arnie, and like Arnie, I'm a fan of fat, and the teal here is, for those of you who know me, kind of unusual, because I've always been a dark blue guy for the last 20 years at Duke, but have signed on for a new challenge down at Atrium Health, succeeding Ed Hanley, and we're putting together a musculoskeletal institute with North Carolina Atrium Health and CNSA, the neurosurgical group there, so come see us in Charlotte, and hopefully we'll be having some fun with that over time. I need to disclose that, like Arnie, I am a consultant with Lipogems, who's one of the companies, who will be looking at their product over the next couple days, along with many others. I also need to disclose that I remain an unapologetic Duke fan, so you can hold that against me if you're one of the many Duke haters out there. As far as, is adipose, why do I believe in fat? Well, largely because of Arnie's work, but there are three main things that have convinced me. First of all, there appear to be an order of magnitude more activated cells in fat than there is in marrow. Secondly, these activated cells don't decrease over a lifetime in fat like they do in marrow. So in other words, a 20-year-old's fat is probably just as good for our purposes, or I'm sorry, a 50-year-old's fat is just as good for our purposes as a 20-year-old. And I do live in North Carolina, we have Bojangles, Biscuitville, and we have an abundant source of fat, and people don't seem to mind getting rid of it. So as far as the sources of adipose that we have, as has been well pointed out by people preceding me tonight, the FDA has mandated minimal manipulation of cells. So that's kind of left us with three ways of procuring the cells. The first is the centrifuge, and this is the harvest system here, and there are others that use the centrifuge as well. You can use filtration, this is on the lower right. The tulip system that allows you to fragment cells with filtration. And then there's the lipogem's method, which uses microfragmentation from ball-bearing cylinders that you see in the upper right. And these are approved by the FDA for our use. One of the advantages of preserving, I'm trying to use the right terms here because I don't want Arnie to get after me, but I'm gonna say stromal vascular niche. In other words, the microarchitecture of the fat cells. And it's probably an advantage of some of the techniques that don't use centrifuge, because that tends to fragment the cells based on the tissue analyses that we've done. But the optimal size for the cell orientation is probably still not entirely worked out, but preserving the microarchitecture of the cell probably improves the viability of the cells and gives you a higher likelihood that they're gonna be effective for the purposes that we've designed them for. So what's in the fat? What's in the mixture that we're using? Well, most of it is fat. There are adipocytes, and that's the majority of it. There are the pericytes that Dr. Kaplan talked to us about. And I'll tell you, I'm gonna go out on a limb just to tell you that in our sample analyses, we are seeing 50 to 100,000 MSCs. And whether those are medicinal signaling cells or mesenchymal stem cells, we can still argue, but we are seeing those cells, and they do grow in culture. So there is something there. And then the whole concept of exosomes, or as the Italians refer, secretomes. This is a whole new language for us in orthopedics, but certainly from our perspective, these exosomes have an important effect as an IL-1 inhibitor. So it's almost like a corticosteroid injection or a natural anti-inflammatory effect, and that's what I've seen in my patients in the early phases after the injections. So what are the indications? Well, these are evolving, and really, truthfully, nobody knows. I've done 180 of these cases now, and I can give you my experience. I think the indications are early shoulder OA, early knee OA, and where's Tom Van Ness? So as Tom pointed out, don't forget what we've learned. I believe that mechanics trump biology every time. And if you've got a patient with kissing lesions, these people like we see in Texas and North Carolina that can't catch a pig in a ditch, you know, they're so various. And they've got true bipolar lesions with grade four. I don't think that patient's gonna do that well unless you address those other issues as well. So I really believe in dealing with the mechanics as well. Soft tissue healing. Had a number of athletes with giant hamstring, intramuscular defects, packed tears, intramuscular. Those have done very well in my hands. I really like it for that. Chondroinjury in the hip, Fontana. I'm gonna show you his study in a minute. That's pretty well documented now. Brian here's been working on microfracture plus. Can we extend the healing potential of a microfracture or other marrow stimulation techniques with cells? That's pending. And right now there's seven NIH-registered clinical trials in orthopedic surgery using lipogems. Four of these are involving NeoA, two shoulder, and one diabetic foot. So there's a lot that's gonna be coming out right now that we don't have the information on. And this is just a reminder. Don't forget what you've learned. Anatomy and mechanics are very important. So we need to address those issues as well. So I'll move to the literature. And there are several articles I think are worth discussing. This is Pietro Rendelli. Now Pietro's got a great prospective randomized trial that's gonna be coming out soon on whether or not the adipose cells help with rotator cuff healing. We don't know the answer. He won't give me any information. I've been badgering him for two years on it. He now has two-year follow-up on a big series of patients. And we'll be getting that information soon. That'll be very helpful to us. But what we do have is we do have his work on the, these are supraspinatus explants. So he's taken samples of cells, treating some with lipogems, some were control, and following them out and looking for what type of factors were expressed and if there were any differentiation and migration capabilities relative to the treatment with the adipose cells. And what he found is that the treated cells significantly increased expression of VEGF. And they also released factors which increased cell proliferation. They didn't appear to have an effect on stem cell marker expression or differentiation capability, but did increase cell proliferation. I think this is the best study we have to date on the lipogems technique. And this is Fontana's study. And this is 194 patients. And these were all patients that had grade three and four acetabular defects in the hip. And he did arthroscopy on all of them. 77 of them had microfracture. And 117 had the lipogems with a debridement. And when he looked at the patient populations as far as following them, the Harris-Hipps score, the modification of that was what was used for the evaluation. And they were both about the same, about 48 pre-treatment. After the treatment, both at six months and one year, significant improvements were noted, both in the microfracture and the lipogems group. And if you looked at them in a year, the average was 84 in the microfracture group, 94 in the lipogems treated group. But where they really differentiated was when you followed them out further. So it reminded me a little bit of some of the early work we did in cartilage transplants, where microfracture looked pretty good early and later on it didn't look as good. I know that's controversial. But if you look here at the follow-up on this study, when they took them out to two years, the microfracture group had fell off to about 75 on average. Still a lot better than pre-treatment, but not nearly as good as the lipogems group, which was still at 92. The other thing that they measured was just conversion to hip arthroplasty. And this is a little bit arbitrary. You might say some people were more stoic in one group or the other. But the group that had the lipogems had zero conversion to arthroplasty versus about 8% in the group that was treated with microfracture alone. This is a softer study. This is a prospective trial, but it's a single-arm study, no control group, looking at degenerative meniscal tears and injection of lipogem. And if you looked at it, this is one of the themes that I think you'll see in most of the literature in lipogems is it appears to be pretty good for pain. Not necessarily a big improvement in function, but here you see the KUS scores did improve, but the pain scores dropped pretty dramatically. Only a six-month follow-up in this study, not a lot to hang our hats on, but looks like it's probably good for pain. Bunch of studies are coming out now. Some of these are just out in the last couple months, so I haven't really analyzed them carefully, but this is one that's been out over the last couple months that I want to talk about from New Dets. And this is just looking at the effect of the autologous microfragmented tissue from fat on proteoglycan synthesis and knee arthritis. And this is one of the things that I think is, you know, what we all were looking for at the beginning is, okay, so is this going to increase cartilage thickness? Is it going to increase proteoglycan production or in any other way really stimulate a healing response in the knee that we can measure? So these guys did a good job looking at 17 patients prospectively over a year collection period, and these are 32 knees were enrolled. And they looked at patients here using D-Gemeric, which is a marker of proteoglycan synthesis. And so, and they looked at them at 12 months. So again, not long-term follow-up. But what they found is that really, if you looked at it, about 54% of the patients had an increase in the D-Gemeric index 12 months after the fat transplant was performed. So what you get there is an increase in the volume, increased proteoglycan production. Now, and full disclosure, there didn't seem to be a big effect in grade four lesions. Obviously, that's where we want it the most. But again, this might push us a little more towards those patients that have a little milder disease. Interestingly, about 14% actually had a decrease in their D-Gemeric. So again, not a panacea, but pretty positive that about, that over half of the patients had an increase in volume. Now this, I apologize for this slide. I haven't, I just got this today, so I haven't had a chance to really put this into my format. But there were no adverse effects in the study. And again, if you look at the, down in the small print down here, you can see that the pain score is markedly improved over the third follow-up. So again, pain relief seems to be consistent with this, in addition to production of the proteoglycan. So this is our study, and this was my first 30 patients published just in the Duke Orthopedic Journal. And we were looking at safety. And obviously, that's one of our first concerns. Is it safe? Were there any complications or problems? And what we found is at the harvest site, about 30% of people had some mild pain and discomfort, and 20% of them had ecchymosis. I'd say it's probably more than that if you get aggressive with the harvest. But one of the things that we learned from the Italians is use an abdominal binder for 48 hours, and we can talk about that when we get to the lab tomorrow. Some of these patients want both of their knees injected. Maybe you're scoping one, injecting another. Maybe you're injecting a shoulder, scoping a knee. What I've learned is to tell them that they're probably gonna have a little soreness at that injection site, and the non-operated side a little bit, and 20% of them are that they may have that, because one out of five had that. And we didn't have any infections, no wound complications, no recipient issues, no major complications related to the study. What about our patients? So I have patient-reported outcomes, two-year follow-up on my first 30 patients, and here they are. So if you look at them, about 70% of them are happy with the treatment. 30% are not. Again, pain seems to be the area where we had the best effect. About 80% of people were pleased with their pain relief over the course of the treatment, two years out. Now, when you get into functional activities, you know, here we're pretty good. About 75% of people felt like they had an improvement in their ability to do yard work or light recreational activity, but when you really got into sports and things, you know, it fell off quite a bit. Only about 60% really had a meaningful impact on their ability to do recreational activities. So I don't promise them they're gonna get a big functional improvement from this, but it does look like they're getting good results with pain. This is a plug to keep your eye out for that Rendelli study on the shoulders. I visited Pietro, he's a very good shoulder surgeon. The study's very well-controlled, and I think we can hang our hat on what we find with that. This is the sample study we did. This is Matt Hilton, who's a stem cell biologist I work with at Duke. Matt's very good, and if you look at the first 10 samples, these clusters of adipocytes were alive. There were five to 15 million cells. 50 to 100,000, Matt felt, were mesenchymal stem cells, excuse me, medicinal signaling cells. 87 to 90% viability, and we did grow MSCs in culture from what was obtained. So there is sorting ongoing with that. What have I learned? Well, I think that this concept of the exosomes, I think, is really interesting, because there's something that happens early that's really positive. My patients are doing a lot better than a standard scope would do, and I think it has to do with that anti-inflammatory effect of the secretomes or exosomes. That sends the last about six weeks, and my patients have come back to a baseline, and then they start getting better again around three to four months. And I'm interested to hear what Arnie's concept is there, if that's a real observation, and what might be explained on the cellular level there. As far as liposuction, we don't learn this in orthopedics. It's something where it's not that difficult, but there are tricks, and we're gonna learn those in the lab tomorrow. I'll teach you what I've learned about to doing, not to doing, one of which is to apply compression for about 48 hours. I think that helps with the result. And in my hands, the indications, some shoulder OA, soft tissue healing, chondroinjury in the hip, and maybe there's an extension of microfracture. So bottom line, does this work? What about fat? I think it's really promising. I'm not gonna get in an argument with the Mara folks, because I'm not sure that there aren't indications where Mara's gonna be better, maybe in fracture healing and some other areas, but I believe in Arnie's work, and I'm a fat guy. Pain relief has been relatively solid. I think we can hang our hat on that. We're still learning about the indications. Don't forget about alignment. I think Tom's point's very good, that that's important. So based on my first 160 to 180 cases, I think early shoulder OA's my favorite indication. In sports medicine practice, we all get these folks post capsuloraphy that have early OA in their 20s, 30s, and 40s. I've got great results in those groups. I've been really happy with them. Big soft tissue defects. A lot of our football players that have had the muscle tears, I like it there. Chondroinjury in the hip. And again, chondroinjury in the knee, that 10 or 15 year post ACL with some mild degeneration, normal alignment, I like it in that group as well. Here are my references. Come see us in Charlotte. Thank you.

adipose-derived cellular tissues

orthopedic procedures

fat cells

microarchitecture preservation

fat cell therapy