Well, good morning, everybody. Thank you for dragging out on Saturday morning at dark 30. Glad everybody's here for what I think is going to be a great talk. We've got, obviously, present company accepted, four great speakers. And Jason, Ken, and Scott will really teach us a lot about biologics and how to stay out of trouble with them. So I think without further ado, I'll let Ken come up and introduce our first talk on PRP. Thank you. Good morning. Sorry, I have, you know, after the president's dinner, it's always hard to be the first speaker. So hopefully, you can hear my voice. So we're going to talk about PRP for the treatment of Neo A. Obviously, you can use PRP for many things, but we're going to concentrate on that today. So my disclosures, nothing really pertaining to this talk. So we'll talk a little bit about leukocyte rich and leukocyte poor PRP, as well as sort of this double spin idea, which is pretty big in Europe, and hopefully to come here soon, autologous protein solution. So PRP is, of course, more than just platelets. There's lots of important factors. Cytokines that are anti-inflammatory, growth factors, IRAP, all of those things together that sit in the buffy coat and really make a difference. So why should it work? What is the basic science behind why we think there's a clinical effect? We know that growth factors, according to Lisa Fortier, PRP can clearly stimulate cell proliferation and improve cartilage matrix. It can also increase the amount of hyaluronic acid that your synovial sites make. It has inflammatory mediators that can yield an anti-inflammatory effect and go against the cytokines in our arthritic joints. Fibrinogen can yield a scaffolding effect that it can enhance conjugal healing. And it actually even has a direct effect on chondrocyte proliferation in vitro. And of course, all of these important factors can work against the inflammatory cytokines. What about clinical evidence? Well, we've heard for many years now from many of my colleagues, especially in the total joint world, that there's not enough data and that half the papers show one thing and half the papers show another. But I think now we have a real cascading amount of data over the past decade. So there's a number of good supporting evidence that PRP is good for pain relief and functional improvement with arthritis. We don't have any real regenerative capacity yet. We even have level one clinical evidence on many, many papers that have been published in our journals that compare it with HA or corticosteroid or placebo. In fact, now we have over 40 systematic reviews that have been published, looking at multiple studies. Here's one that I think is really, really exceptional. It's 14 randomized controlled trials, over 1,400 patients, comparing it either with saline, placebo, HA, or corticosteroid. And in every one of these studies, PRP statistically significantly improved the Womack score and physical function scores, as well as all of the sub-scores at three, six, and 12 months. This is a more recent one, level evidence one, systematic review, again, comparing multiple randomized controlled trials. This one had 30 trials that met the criteria, over 3,400 patients, following up at three, six, and 12 months. At each one of these, PRP at three, six, and 12 months was by far statistically significantly better, and then each of the other treatments had their second and third position, depending on the number of months. So basically, intraarticular injection of PRP demonstrated the best overall outcomes, compared to steroids, HA, and placebo, with NeoA at all time periods. Even the Academy, which is a very skeptical group, in 2021, published a technology review. They looked at their own group. They didn't do CPG, but they did this technology review. They found eight high-quality studies against placebo, 18 against HA, and two even against NSAID, and in all of these, except for three studies against the HA, the PRP was best in WOMAC and in Vascail. So they felt that more larger studies needed to be done at that time, but I think we are starting to get those studies. Even our own peers have looked at this now in multiple groups. The NFL team physicians group, as well as ESCA, have done consensus studies, and all of them have come up with either grade A or definite recommendations that for NeoA, PRP is suggested, and in fact, grade A recommended. But I think we need to start drilling down a bit more on what's in our PRP, and that's really, I think, where we're heading now. We're starting to understand that we know there are some patients who are responders, there are some patients who are non-responders. In addition, PRP is not equal, depending on which machine you use, depending on the human you're taking the blood from, even depending on the time of day from the same human. So we need to start drilling down on what's in. So first thing, the most simplest thing, is we need to start at least knowing how much we're concentrating. You know, are we giving someone, how many billions or millions of platelets are we giving? Are we truly concentrating the plasma? Because some of the stuff we used in the early days when we had to give three injections, maybe we really weren't concentrating enough. Maybe dose really makes a difference. So having some type of cell counter, this is the one I have in my lab, so I can at least look at the number of platelets in the blood, the number of platelets that we actually ultimately inject in the PRP, is worthwhile to try to define. In addition, you get a good count of the white cells, so you know what it is, white cell rich or white cell poor. Why is that important? Well, JAMA, of course, published this big article, very well publicized in the lay press, that showed no statistical difference between placebo and PRP in a very well done randomized controlled trial. But if you looked at what machine they use, it's a machine many of us know that only concentrates platelets about 1.6 times. I'm not sure I'd really call that PRP. I think that's sort of platelets, but it's not maybe platelet rich. So I think it's important to know what it is you're injecting. Now we're starting to get more detailed studies that actually report not just how many times we're concentrating, but actual dose. How many platelets are we injecting? And now I think we're gonna start to see responders versus non-responders have a better sense. There's a very good paper in KSSTA in 2022 by Chu, that showed that intra-articular injection of platelet rich plasma decreased pain and improved function and they had a RCT with 300 patients, a very large group, every one of them had a 50 cc blood draw, two spend technique, yielding 4.2 billion platelets in a five cc injection. Okay, now we're starting to understand what we're injecting. Now we don't know every cytokine or growth factor, but at least we understand that we are concentrating platelets. And when they found statistically significant improvement at six, 12, 24 months, but at this dose, even at 60 months. Dose may be critical again to long-term results. Another good study in Science Reports of Nature that was done by Bancel and Leon, another randomized control trial here with 75 patients in each group, PRP versus an HA, 10 billion platelets in an eight cc injection. This is a large concentration. This may seem to make a major difference. And in fact, when they looked at all their studies, including WOMAC, IKDC, six minute pain-free walking, PRP beat out HA in every one of these groups. And in fact, they looked at the synovial fluid and found significant decline in IL-6 and TNF-alpha in the PRP group at one month. But the results lasted up to five years, once again. Next question we have to think about is can we proactively improve the PRP that we're injecting? Can we make a difference for the patients? And Adam Anst gave a great, published a great paper as far back as 2019, showing that 20 minutes of aerobic exercise can alter the concentration of the PRP. Vigorous exercise can increase the platelet concentration that you come in with. It can increase the progenitor cell concentration, all of which is a very easy thing to have your patients do. What else has been reported to improve PRP? Eating leafy green vegetables the week before, iron and vitamin B, all can increase your platelet function. You have to decrease the amount of smoking and drinking if you can, because those have negative effects on platelet function. The day of, maybe decrease caffeine, as that can decrease platelet activation. And I think most of us tell our patients to avoid NSAIDs for a number of weeks, at least after, if not for a week before as well, as well as any of these other anti-inflammatory cytokines. Why is that? Why do we not want anti-inflammatories? Because we believe firmly that to begin the effect of the anti-inflammatory effect, you have to begin with an inflammatory moment. That's why patients often have pain or a little swelling for a day or two after. So if you avoid that, you may not get to the actual curative or helpful part of PRP. What about autologous protein solution or autologous condition serum? What is that really? There's been several studies, two by Elizabeth DeCone in Europe, both six and 12, sorry, one-year and three-year results. And then we did a study along with a large group in the United States as well. Autologous protein solution means you're taking a PRP first spin, and on the second spin, you're taking that same PRP and putting it into a tube with polyacrylamide beads. And by using those beads, you really increase the amount of IRAP at the end result, as well as the amount of TNF, anti-TNF. And if you look here, you can get a very consistent amount. You'll notice, though, that this is a white cell rich injection. Now, up till this date, we talked about white cell poor being better for arthritis, white cell rich. Scott will talk to you about being better maybe for tendinopathies, but we're not so sure that that's true anymore. And this study is one of the things that helped to sell me on the idea that white cells may be important because white cells are not only inflammatory cells. White cells are monocytes. M2 monocytes can be very, very effective in decreasing the inflammatory effect. So we know that we can get a very consistent amount of IRAP in these injections. So in the European studies, they showed statistically significant benefit at one year, one, three, six months, up to 12 months over placebo. And even in the three-year extension study, so the same group that was in the one-year study, the PRP group was followed for three years, and they had significant clinical improvement still at the three-year measure on all of their scales and less cartilage wear in those KL1 and 2 patients, meaning less narrowing on the X-ray. Our study, not as effective. We had very, very good clear safety. We had 12 months show that they decreased WOMAC, but unfortunately, we had an extremely strong saline effect. You know, saline placebo can be very, very effective in a lot of patients, so in the end, we could not show enough statistically significant benefit for the FDA to approve this in the US. However, if you looked at the number of patients who dropped out because of pain, twice as many patients in the saline group dropped out because of pain than the APS group. And we found that if you had an IL1RA, that's the IRAP, ratio to IL1B in the patient's blood, greater than 1,000, this had a very, very high responder rate. So again, dosing matters in all of these things. We have to start being more accurate in defining our dose. So what about leukocyte-rich, leukocyte-poor? We used to think it was very clear that leukocyte-poor was better for OA. There was a good randomized controlled trial comparing leukocyte-rich and poor in Italy at the Rizzoli Institute by Dr. Zaffinini and his group, which showed really no statistical difference. More importantly, in the study that I just showed you, where we're clearly getting a white cell-rich, very high white cell count, large amount of monocytes, M2 monocytes, we noticed that we do get an inflammatory response, but we also get a much more longer-lasting healing response. And if we look at the most healing properties in our body, there's always an inflammatory response that occurs immediately after injury, and then hopefully we get to that anabolic curve that brings us to healing. Interestingly, Tom Buchelt, who's at Duke, he's a pain specialist, he believes that that post-injection inflammation is needed to stimulate the downstream anabolic process, and we really ought to start thinking about that down the road. Still questions. So we have a lot of work to do. We have a lot of data that shows it works. I think most of the people who do a lot of sports medicine, and certainly many of our colleagues, have come to realize PRP's an important part of the armamentarium for treating our patients on a daily basis, those that don't want surgery, especially for Neo-A. But we need to learn a few more things. What makes some patients responders, and what makes others non-responders? Scott's done a lot of research on this, and many of us are now performing research in this area, and you'll be hearing more, I think, over time. What cytokines and what factors in the PRP are the ones that matter? And if we knew which were the cytokines and factors that matter, could we enhance those specific ones for patients before they get their injection so we can push them to being a responder rather than a non-responder? Then there's lots of questions about the benefit of HA. Some people feel that concomitantly injecting HA may have a scaffolding effect that holds the PRP in place a little bit longer, again, maybe giving a little longer. We need more work on that. And is there any benefit to these other concomitants you can get from platelet-poor plasma, like alpha-2-macroglobulin and IRAP, which is also sitting in the monocytes in the PPP. And towards that end, we have many groups that are working on this, and I'm very proud to say that the Biologic Association, which Scott is currently the chair and all the other speakers here have been chair, and we are very, very proud to say we have a great collective of all these great institutions that are working together to look at our PRP patients, the Biologic Registry and Biorepository Project now, and as JT mentioned at his inaugural address, we're now also working with the SOMOS people and the military in this area to try to look at multiple patients that get this, find big populations, many different types of PRP, and look at what was in the blood, what was in the PRP when we injected it, and comparing that with patient-reported outcomes. And these seven institutions will hopefully have that kind of data in about another year. Thanks very much. It's been a pleasure. I think we now know we can use this. It's been accepted by our peer groups, and it's an effective treatment for NEOA. Thank you. Well, I don't know if this is working, but let's see. Right now, I think we're going to find that as we get more dosing studies, we can give accurate numbers. But I would say, in my experience, it's about 79% to 80% of our patients are responders, and 20% feel that they did not respond, and they're not happy with their result. And I think as we can start to figure out what dose is the best, and secondly, how can we improve those cytokine profiles pre-injection, we'll hopefully be able to move that curve to more patients being happy. But I would say that's the number I give most of my patients. What percentage of people end up having no pain at a normal? Well, I don't think we look. We're not regenerating cartilage. We are not causing everyone to have no pain. I would tell you that many patients who have total knees still have some pain, so I can't tell them they have no pain. But I would say the 80% that I'm talking about, say they have a real significant difference in their daily lives. Less pain, they may still have weather-related pain here and there, but they see a real difference in how much activity they can go, how much walking they can do, how they do on the golf course. All of those things make a difference to my patients. Is it reasonable then to tell patients 70% to 80% of you will get partial relief, nobody gets full relief, even for a week, or a month, or six months? Well, I think some people get what they consider full relief. How much, what percent? But I can't give you a real number on that. I don't know if any of my partners can tell you. I don't think we know that answer. It's a reasonable question, but I can't give you any data to support that answer. Yes? One more. Has there been any progress or work toward reimbursement from Medicare and the commercials? Well, you know, most of our patients pay cash for this, but I will tell you that we notice, at least in New York State at this moment, all of a sudden, there are insurance companies that are paying for this, because the patient will come in and say, you know, I heard my friend got coverage, so now, in our institution, we're checking on every patient. We tell them it's gonna probably cost this much, however, we will check with your insurance. And there's one or two of the commercial insurers now that are paying for this. I mean, I don't think Medicare's paying for this at all. I mean, not for me. But there are one or two commercials that are starting, and I think the more the data comes out, and the more the patients drive that, that may change. But still, it's mostly a cash business. All right, let's keep this rolling. Scott, if you'd come up and talk about the soft tissue indications. All right, good morning. Great, and where's our, is this here? So, I'm going to go over Tendon now. So, Ken nicely set the stage for you here. This is our disclosure to support our laboratory research program, HSS. When we talk about Tendon, I thought I'd just one slide to kind of set the stage. I think in all these areas, think about the underlying tissue we're trying to treat. So, tendinopathy is complex. And how do we go from this normal tendon to this very abnormal tendon? We know there are changes in the structure and the composition of tendon. There's dysregulation at the cellular and molecular level. And just to give you a sense of what's going on, because this really is important to set the stage and understand how we're going to use biologically to treat tendon injury. So, we know there's alterations in tendon matrix. There was probably, this is probably due to disaccumulated microscopic damage that occurs over time in tendons. These altered matrix changes the environment around cells. There's altered mechanotransduction that affects cellular behavior. We know that there is inflammation. You don't see inflammatory cells in tissue biopsy, but so-called molecular inflammation, a number of inflammatory mediators play a central role in this process. And in fact, there's a lot of focus now on the role of immune cells and various inflammatory mediators and how they interact in tendinopathy. And there's a number of these important inflammatory mediators that really play critical roles. And I put this out here because this will kind of set the stage to talk about using biologics for tendinopathy or tendon injury. I think in any talk in biologics, start by asking, you know, what are we trying to treat? What is the biologic targets? And here I can list a number of important biologic targets. And we may want to affect cell proliferation, matrix synthesis, cell migration, new blood vessel formation, remodeling of the matrix, certainly the location or the number of inflammatory mediators. Maybe just we want to affect the pain mediators or stimulate the intrinsic stem cell niche that exists in many tissues. These are all very important, but they're all very different. And we need to think about what are we trying to treat with biologics here? I think in addition to identifying this biologic target, if you will, we need to define, you know, what are we putting in the patient? What's the composition and the biologic activity of these different agents? And only then can we match the biologic agent with the desired biologic target. Ken mentioned at the end of this concept of precision medicine. That's what we need to get to in this field due to this tremendous heterogeneity in all these different formulations. Clearly one size did not fit all. The same orthobiologic preparation would not and should not be expected to have a positive effect on different tissue types. Acute versus chronic process, age and gender probably have important roles. So these are all important considerations, I think, when you approach this whole area of biologics. Obviously we have various blood products you just heard about, and Ken kind of went through those nicely. And obviously cells can be derived from bone marrow, from adipose tissue, and then some of these perinatal sources. We'll kind of go through this briefly here. I think you already heard this. Ken kind of set the stage nicely, but just the kind of basic, there are two types of PRP. There's plasma base and the buffy coat base. And the important distinctions here are not just number of platelets, but as you heard earlier, the number of white cells in these different formulations. I'll mention here I have no relationship with any of these companies. Now Ken went over this, but I think this is an important concept. This leukocyte-rich versus leukocyte-poor, frankly, I think is a very rudimentary concept. It's a place to start, but we need a much more refined analysis. Think about the leukocyte differential. Maybe we want to eliminate certain inflammatory cells, but concentrate others. In particular, the monocyte macrophage lineage and T-regulatory cells. So white cells are very complex, and there are a number of different immune cell subtypes. So just lumping them all together, leukocyte-rich versus poor, I think is a very rudimentary analysis here. Probably the ratio of platelets to white cells may be more important. And importantly, PRP is complex. Again, the whole basic pro-inflammatory versus anti-inflammatory dichotomy, I would submit to you, is really an oversimplification. In fact, interestingly, the activity of PRP may be context-dependent. PRP can inhibit inflammation in a pro-inflammatory environment. Well, in contrast, PRP can actually be pro-inflammatory in the absence of inflammation. So the biology is complex. We need to be careful making dogmatic statements where we really need much more information. Besides platelets, there are a number of important signaling molecules in the plasma portion. So again, PRP, very, very complex, and there's a lot we don't know. So we're focusing here on tendinopathy. Again, suffice to say, the simple summary right here, like a lot of the data in this area, there's tremendous variability in the reported clinical outcomes. This all goes back to the heterogeneity in these different formulations. So concentrating just here on PRP for tendinopathy, putting some recent systematic reviews to try to give you a 30,000-foot view of the landscape here. This is a well-done study, 33 randomized trials in this meta-analysis here, and you can see the different tendons that were in tendinopathies were analyzed here, quite variable. They concluded that the quality of evidence of all these comparisons is as great as low or very low. So that's kind of where we're left with in this field, and they concluded that, in fact, in the majority of comparisons, the effect size was comparable to that seen just in the control group. So not a lot of support there. So based on this relatively recent systematic review. Ken kind of mentioned as well, the general accepted dogma has been to use a leukocyte-rich formulation. So kind of turn on the biology, if you will, and make a chronic process acute. This goes back to work from Jane Fitzpatrick in Perth, Australia, a widely quoted paper. This was a meta-analysis as well of different studies looking at PRP and other autologous blood formulations for tendinopathy. 18 different studies, and they found a strongly positive effect for a leukocyte-rich formulation for tendinopathy. So based on this, and they found no difference in all the different control injections, including steroids. So they concluded that there's good evidence to support the use of a single injection of a leukocyte-rich for tendinopathy. That's where a lot of us started using leukocyte-rich in the setting for tendinopathy. If we hone down now just on rotator cuff, look at PRP, again, tremendous variability. And here's some four pretty well-done studies that I kind of chose to kind of give you a sense of the field. These are all randomized trials. This group from Turkey, placebo-controlled, double-blind, so well-done study. Injection, this is all essentially treating subacromial impingement, cuff tendinitis or bursitis, you want to call it. They found no differences here, so I didn't support it. This group, Andy Carr in the UK, took patients at the OR, did chromioplasties, and then randomized them to receive a PRP injection or not. And then they did a, they found no difference in the outcome scores. They did a biopsy of the tendon on ultrasound. You hardly do that here, but their patients let them do it. This group was under ultrasound, took a biopsy of the tendon at three months. They found those treated with PRP, there actually was increased apoptosis and decreased cellularity, suggesting potentially a deleterious effect. This group from Switzerland, again, another well-done, randomized, double-blind trial, no difference in outcomes. And at 19 months, the incidence of adverse effects, including a stiff shoulder, was higher in those treated with PRP. And lastly, a group just last year from China, a systematic review, PRP versus steroids. So in short term, steroids work, we all know that. Over the longer term, no real difference between groups. So if you look at this data, and you can look at other studies out there, my conclusion is hard to recommend PRP for the treatment of cuff tendinopathy, subacromial impingement right now. If you look at some systematic reviews in this area, the group from Pietro Randelli and Giuseppe Filardo in Italy have done a lot of work in this area, a nice systematic review. So the conservative group, that's your subacromial impingement group, subacromial injection. Again, they concluded it was high heterogeneity, no real consensus in favor of PRP. And then Ewen Hurley in Dublin, Ireland, similarly, a systematic review, just using PRP for non-operative treatment for cuff tendinopathy, five trials. Essentially, two of the studies found PRP superior, one found no difference, and two PRP was inferior. So you get this mixed data when we try to look at these well-done reviews. They concluded that PRP was really not beneficial here. So my summary, if you kind of look at the wealth of the data that's out there, certainly tremendous variability, as we know. And that's because if you look at all the data, there's very heterogeneous groups of patients that are treated, different anatomic areas. I think different tendons probably react differently. The biologic and biomechanical environment is different for different tendons. Obviously, variability in the PRP formulations, the concomitant treatments, the rehab, all that, is totally a black box and probably has a role and plays a role here. So there's a lot we don't know in this area. Bottom line, there is some limited support in literature for a positive effect for leukocyte-rich PRP versus poor. But again, we really need more data. We really need to characterize what we're putting in the patient and compare that to the clinical and imaging outcomes in our patients. Ken mentioned nicely here the ACS, so I kind of go through this very briefly here. But this is basically the autologous condition serum, which is where blood is heated and incubated overnight with these chromium sulfate etched glass beads. What does that mean? Essentially, this process of incubating blood overnight when it's heated concentrates IL-1 receptor antagonists. Ken mentioned that's a potent anti-inflammatory cytokine. This is the Regenikine in the US. It's called Orthokine in Europe. Not yet FDA approved. But there is one study, this group from Turkey that I thought I'd show you, because using this autologous condition serum for cuff tendinopathy. 32 patients, typical kind of supraspinous tendinopathy. They used the Orthokine. And they randomized them, again, well-done study, double-blind trial against steroid injections. Actually, they did three weekly steroid injections. I don't think most of us would do three injections of steroids in a row. Both groups improved in four weeks, but at about six months, those treated with autologous condition serum did have a positive outcome. So certainly, something like this would be safer than using steroids. So a little data to use to support a different autologous blood formulation. And then Ken mentioned, again, these other formulations that are being developed. So I won't go through this too much. The autologous protein solution, it's a different process where you first separate the cells, and then you go through this polyacrylamide bead column that Ken showed you there, that where essentially, you are concentrating IL-1 receptor antagonist, which we know is a potent anti-inflammatory cytokine. No data now on using this, though, for tendinopathy. Alpha-2M, alpha-2-microglobulin. Keep your eye on this. We know that MMPs, matrix metallopodiases, have a very important effect on tendon matrix, as well as their inhibitors. It's a very complex interaction between the two. Alpha-2M is a broad-spectrum MMP inhibitor. And there's a way to concentrate alpha-2M from autologous blood. There's some techniques that are out there. None yet clinically used. No clinical data. This is a study we had done some years ago in a small animal model, a cuff repair model in rats. But essentially, half of them, we did a cuff repair, and then we treated half of them with a purified alpha-2-microglobulin. Essentially, we found a positive effect. It affects histology. We see changes in the histologic appearance at the healing tendon bone interface. And importantly, reductions in the amount of, we can quantify collagen degradation, the graph on the bottom right. There's degraded collagen fragments. That's improved with alpha-2M. So these are techniques being developed to concentrate alpha-2M from peripheral blood. And this may offer a way to affect tendon matrix. So it's something to keep your eye on, as well. So my current recommendation, as far as PRP for tendinopathy, there's some data out there, but it certainly needs further investigation. If you're gonna use it, probably try to use a leukocyte-rich formulation. Generally, an ultrasound-guided injection, I wouldn't put anesthetic deep with this. You should do a single injection. If patients don't really improve and wanna repeat it, you certainly can. You get into cost and logistical issues, of course, doing repeat injections here. Repeat injection may improve efficacy. We have data in the knee, for knee OA, that a series of injections can be more effective. We don't really have such data in tendon. Post-injection protocol. You know, this is, frankly, an area we need a lot more data here. The recommendations for rehab are largely empirical. They're based on very little data. You know, this idea of holding NSAIDs, there's very little data to support that. It's pretty arbitrary. You know, it's very, arachidonic acid metabolism and thromboxanes and are all very complex, so not a lot of data to support these recommendations. Most of us will recommend light activity for two or three days, followed by gradual progression. Obviously, eccentric exercise we know is important for tendinopathy, but we need more data on the interaction between mechanical loading, that's your rehab, and the biologic response to all of these agents. So this is an area that really needs further data. That was tendinopathy. What about cuff repair? We kind of turn our attention now to cuff repair. PR, there's some good meta-analyses now that suggest that PRP can improve tendon healing during rotator cuff repair. Thomas Vangs-Ness at USC, this is a study where they looked at PRP. The re-tear rate based on imaging study was lower in those treated with PRP. This group from China, 10 randomized trials, PRP reduces the re-tear rate as well. Again, this is all based on imaging studies, MR or ultrasound as outcomes. Importantly, the platelet-rich fibrin, PRF, a different formation, did not have a positive effect. Ewan Hurley in his systematic review, PRP, again, improved healing rates. And similarly, the platelet-rich fibrin matrix did not have any benefit. And lastly, this group from Athens, Greece, PRP group is superior. So bottom line here, PRP appears beneficial to improve structural healing following rotator cuff repair. I'll lose the bottom of our slides there, don't we? This is a study we had done some years ago. This is this platelet-rich fibrin matrix, which I wanted to put this up to distinguish. That's a different preparation. This is a, you add calcium chloride back to the prep and it essentially makes a fibrin matrix out of your PRP. So we had 79 patients who were randomized to receive PR, this material or not, just after standard cuff repair. Essentially, the patients and evaluator were blinded. We didn't find any difference. No differences in healing based on ultrasound. There were differences in patient part outcome measures. In fact, using a logistic regression analysis, we found that those patients that got the platelet-rich fibrin matrix had a higher rate of a defect of non-healing. So this platelet-rich fibrin matrix material, I wouldn't use. Lastly, some cell therapy approaches. I think to set the stage here, we have a lot of interest in stem cells. We don't know about what truly is a stem cell. Obviously, this goes back to Arnold Kaplan and actually goes back to Friedenstein and Owen in the 70s, but Arnold Kaplan wildly got accredited with this concept of mesenchymal stem cell or the cell that can be differentiated into a number of different cell types. Think about the universal stem cell criteria, though. These are threefold. These are unspecialized cells. Importantly, a stem cell undergoes self-renewal. So there is, a stem cell will divide. One daughter cell goes on to differentiate. The other daughter cell stays the stem cell. If it didn't, you would deplete your stem cell pool. That's a very unique factor that defines a stem cell, and then, obviously, the multipotent differentiation capacity. Point here is that currently utilized cell sources contain few, if any, stem cells. We're not using stem cells. You can call them connective tissue progenitors. You can call them stromal cells. Don't call them a stem cell. More recently, in recent years, it already became clear to us that the biologic effect of any cells, whether it's the adipose, bone marrow, act via probably a paracrine effect. Cells produce a number of anti-inflammatory and immune-modulating factors that modify the local environment. In fact, this is a quote from Arnold Kaplan and Edwards. We changed the name of MSCs to medicinal signaling cells to, again, make clear this concept of this paracrine mechanism. In fact, there's very little evidence to suggest that cells even intercalate or engraft into the injected tissue. Rather, they act in this paracrine mechanism here. I submit to you we have almost no ability to use a true, quote-unquote, stem cell. Again, the number of true stem cells by any criteria is vanishingly small in any of our formulations here. You know, people talk about MSC. An MSC, the S is stromal cell. Definition is based on culture-expanded cells, criteria put forth by the International Society for Cell Therapy. So it's culture-expanded cells, not what you and I use routinely in our clinics or our operating room. This is very different than the cell populations that are contained in freshly harvested tissue that are not culture-expanded. These minimally-manipulated preparations that we use need to be distinguished from sorted, culture-expanded cells that are produced in the laboratory. Again, very, very different. I would submit to you the term MSC should only be used to refer to culture-expanded population cells that, in fact, meet these ISC, the International Society for Cell Therapy criteria. And we should not use this term to describe these heterogeneous populations of cells from adipose or bone marrow. So what can we use for cell-based therapies? Obviously, cells from bone marrow. We can concentrate it. We can use peripheral blood cells. We can use cells, of course, derived from adipose tissue. Right now, the adipose formulation, we can use the so-called microfragmented fat, the lipogems, with whom I have no relationship with these companies here. Distinguished microfat, this lipogems, from the stromal vascular fraction or adipose-derived cells. These are all different formulations. Stromal vascular fraction requires enzymatic digestion. We can't do that now under FDA regulation. It can only be done under an FDA-approved trial. And certainly, adipose-derived stem cells, that's cultured cells. So again, we talk about adipose. We're using this microfat, mechanical emulsification, very different formulation. Then there's these perinatal products, cells derived from amniotic fluid, amniotic membrane, placenta, umbilical cord bloods. In fact, these products contain a number of anti-inflammatory molecules, but virtually no viable cells, and like zero stem cells by any criteria. In fact, all these perinatal preparations now can only be used under an IND, an Investigational New Drug, since the end of the FDA discretionary period three years ago. So these are essentially off the market. These perinatal formulations can only be used in an FDA trial right now. But cells have some potential. Nothing heals without cells. I think cells have more potential than these other autologous blood-based formulations. And there's a little data out there to suggest that cells may, in fact, be structure-modifying, actually regenerate tissue. Couple studies to kind of whet your appetite. This group from Malaysia, just three patients, but treated with peripheral blood stem cells. And they used imaging to demonstrate, and this is Achilles tendinopathy. They found reductions in tendon thickness and inflammation, so a structural change. Similar group from Italy used adipose-derived cells, also in Achilles tendinopathy. Improvements in this tendon structure. And then lastly, Nicola Maffulli from London, some nice work. This is bone marrow-derived cells compared to PRP. And this is in patellar tendinopathy. And again, the point here, they used MR, and they found better improvements in tendon structure in those patients treated with cells. So these three studies demonstrate the potential for cells to actually be structure-modifying, not just symptom-modifying. If you look at some systematic reviews of this area, again, a lot of variability. This is a pretty well-done one from the Netherlands. Here's the different tendons that were treated. Again, a mix, a lot of heterogeneity, high risk of bias in a lot of these studies. And they concluded that evidence-based recommendations for the use of stem cell therapy for tendon disorders cannot be made at this time. So now a little more recent study of this group, another systematic review. Again, you see the different tendons treated there. Cuff, elbow, Achilles, patellar tendon. And they concluded that it's some promising results. Kind of the data was mixed. They found it to be safe. But again, not very robust data to support cells there. If you look at rotator cuff repair like we did for PRP, now we're looking at cells and cuff repair. There's some decent data out there. We can maybe augment structural healing. Philly, Pernod-Gouin, Paris had 90 patients. Cuff repair, half of them, 45, gave the injected bone marrow-derived cells. And a 10-year follow-up, there was intact cuffs in 87% of those that received cells, and only about half that in the control group. And in fact, the long-term cuff integrity was better in those patients that received more cells. So some support there. Group from Seoul, South Korea, 70 patients, 35 of whom received adipose-derived cells. Cuff repair, same way, imaging outcomes. You see they're better. The re-tear rate was about twice as high in those patients that did not receive cells. So 28% versus 14%. And the Rush Group, Brian Cole and Nick Furmer, recently 91 patients, half of whom received concentrated bone marrow aspirate at the time of surgery. They found a lower re-tear rate as well. Now, they found no difference in the patient-reported outcomes, which is something we often see in these studies, where the patient-reported outcomes don't really match the structural outcomes. But all these studies demonstrate the ability to improve structural healing based on an imaging outcome. If you look now at the lipogems, it's been developed in Italy, and Pietro Randelli's done a lot of work in this area. Just one study where they used this lipogems during rotator cuff repair. So again, this is this enzyme-free, mechanical emulsification technique. It's a randomized trial. Just 22 patients in each group. Essentially, cuff repairs and then treated just standard care or receiving lipogems at the time of surgery. Essentially, they found improvements in their patient-reported outcomes at six months only, but not later. You can see the graph there at six months. There are differences, but they're different. But at a year and two years, they are not any different. So no differences in later time points. No differences in MR outcomes. There's structural healing, no real difference there. So they concluded that injection of autologous microfragmented adipose is safe and might improve your short-term results, but no real difference at your longer-term outcome. Bottom line, cell therapy approaches seem to be promising to improve structural healing, which at the end of the day, probably you think we'd rather have a heel tendon than not, even though that doesn't always translate to improvement in symptoms. But clearly, we need further study in this area. And lastly, think about some metabolic factors associated with tendinopathy and impaired tendon healing that we need to control for, think about in our studies, and stratify patients based on all the different things. Just briefly, we know hypercholesterolemia has an adverse effect on tendon. Joe Booth did some nice work in that area. We know smoking, dose-dependent effect on tendon healing. Diabetes, higher failure rates. Osteoporosis, interestingly, higher failure rates reported in some trials. Vitamin D deficiency, lower serum vitamin D has been associated not just with muscle weakness, but changes in fatty infiltration in this group from Korea. Renal disease, effects of new biology, as we know. Fluoroquinolone and antibiotics, we know can affect tendon matrix. And lastly, thyroid disease. So all of these are important metabolic factors that are rarely looked at, or patients are rarely stratified based on these. Lastly, some currently available drugs we might think about that are available to you and I to maybe help tendon healing. PTH, parathyroid hormone. We know that PTH, based on preclinical studies, can improve tendon and bone healing. Some work in our lab and others. There's some clinical work out there demonstrating that daily injections of PTH improved tendon healing after cuff repair. So bottom line, it's reasonable to consider, but it's costly and usually not approved by insurance. I've tried on occasion with insurance. You usually get the approval like six months after their surgery. So it hasn't been really successful, hard to get approval. Statin use, we know statins are associated with improved healing rates. There's some data to support that. So if the patient's on a statin, maybe leave them on that. And then vitamin D, we know effects not just osteoblastic activity, but importantly, vitamin D affects muscle function. And there's some preclinical data and some clinical data out there. One clinical studies group from Korea, lower serum vitamin D related to higher fatty degeneration. And some of these large insurance databases that can look at tens of thousands of patients demonstrate that perioperative vitamin D levels are related to outcome. So again, this is a modifiable risk factor. So think about measuring vitamin D or supplementing. So in summary, orthobiologics, great promise for tendon. Needs further work. I think we need to identify biomarkers to characterize what we're putting in the patient. We know what's the composition, the biologic activity of what we're putting in the patient. Then on the other hand, we need to characterize the patient. All tendinopathy is not the same. I think clinical registries and biospecimen repositories will be helpful to move this field forward. Ultimately, change the regulatory environment may help us. You'll hear a lot more about this from Dr. Weber here. The ability to manipulate our cell formulations with either enzymatic digestion of adipose tissue or to carry out cell sorting and culture expansion may really change our ability to use cell therapy approaches. I think most importantly, the ability to select the desired cells and more importantly, eliminate competing cells from these heterogeneous cell mixtures may really help us move this field forward. I think this gets to the whole concept of precision medicine. You know, the right drug, right dose, right route, and the right time. Choosing the right biologic for the right patient. Back to my first slide on the target. What are we trying to treat? What do we want to affect here? That may affect what biologic we choose. And then things on the horizon, obviously exosomes, something a whole nother talk could be on exosomes that have great potential. We are learning about methods to stimulate the intrinsic progenitor cells that exist in many tissues. There is a stem cell niche in many tissues. There is a quiescent cells. How might we leverage those cells for improving healing? Lastly, the whole area of understanding the interaction between biologics and immune cell subtypes, because that has a critical role in biology. These are all areas of active research, and I'll stop there. Thank you. Yeah, it's a good point, there's, the general dogma, the concept is that, you know, multiple steroids can have an adverse effect on tendon, and they can, they can affect tendon matrix, but again, you're exactly right, Gus, it's so complex because it's based on animal models which are really imperfect models of tendinopathy, and so steroids can affect fibroblast biology and matrix, at the end of the day they do affect matrix synthesis, and probably the balance of MMPs, matrix metallopoiesis, you know, the matrix degrading enzymes, but you're right, it's really, we don't have great data out there, the animal studies are all over the place and they're limited, stepping back, you and I are clinicians, we've got a patient sitting in front of us, I think the current concept is, you know, I think steroids should be used judiciously, because they can, they can have an adverse effect on tendon biology, but won't always, and that's the problem. I agree. Because there's so many other factors in those patients. I mean, I usually tell patients, yeah, you have two, maybe three in the course of your year is safe. That's totally arbitrary. I have no basis to say that. It might be hard to get clinical equipoise on that, too. I mean, I don't want to be the experimental guy that gets 15 steroid injections to see what happens. But I think it's a legitimate concern. I did a lot of steroid injections in my practice, and they work pretty well, at least for that short term. All right, let's keep it moving. Jason, please come up and teach us some more stuff. Well, good morning, everyone. Bless your heart for being here on Saturday morning, bright-eyed and bushy-tailed. So we appreciate you guys coming and talking a little bit about the next frontier here. And we're all saying that there is significant progress. I think you'll see that with regards to cartilage as well. As of last year, it was a novel time for cartilage in the world, because we, for the first time, can make a demarcation into the therapy that we're giving. And certain biologics, we're now becoming clear, have really no regenerative capacity. And I want to just talk about it, because otherwise, there will be no time to talk about things that are available for us today. But including the micronized fat, there's no evidence to suggest that it regenerates cartilage. But there is evidence, and there's a lot of it, suggesting that it can be beneficial for our patients. And then we go to cartilage restoration. There are some new things in the world and coming around to the United States really soon. So I want to talk about those as well. So as far as the adipose preparations in the United States, these are our two. The one to the left is a series of breaking down the fat with mechanically, let's just say, and the same thing to the right, syringe emulsification. These techniques, and let's talk about the one to the right here, there's many companies now that have very similar devices to this that we can use in the United States. The question, and I'm shortening this a little bit, is how do they work? And the answer is that these are not broken down into the, quote, stem cells or the MSCs that reside in fat. These are fragments of tissue broken down to biologically active fragments. And so then, as the proof here, so this is the basic science, and I won't show you a lot of this today, but I wanted just to show you the proof of this. And that is, if you look at the big bar, that's lipopolysaccharide. And for all of us in medical school, that was that thing about bacteria that shot up inflammation in our bodies and allowed that bacteria to invade. So we use that in basic science to create inflammation. So we added cells, we put the LPS on there, and inflammation skyrockets. But then the question is, well, what if you did that same thing, but you put the micronized fat there with it, and you see it completely stopped compared to baseline, the production of inflammation? So it's mechanism one, that this tissue is bioactive, not for cartilage regeneration, but for decreasing inflammation. Pretty good data across the board. So this is 14 studies over 1,200 patients. And if you look at all these studies and plotting on the for or against pain relief, you see they're all the same. They're all showing a significant amount of pain relief, and we think that there's many mechanisms with which these bioactive fat fragments are working. But nonetheless, there's data right across the board to show this. And then in clinical practice, certainly we see the same results of this. I mean, there is definitely something here. It's just not cartilage regeneration. But then now let's draw the line. Are there things that we can use that are associated with cartilage regeneration? And I want to talk about those here today. The first is kind of defining our terms as far as what kind of cells are we really talking about. And we're going to talk about these progenitor cells. And as Scott gave a really good summary, we're going to be talking a lot about cells that are taken in other countries to culture and to create doses. And that's what's going to be happening in the United States around the corner. I'll talk about that. But then I also want to talk about these cells of slightly de-differentiated or younger cells. The juvenile chondrocytes are kind of one generation more immature than our cartilage cells within our knee. And then the question is, why does it matter? Are they truly different? And a lot of science here to suggest that's a totally different type of cell. And what I mean by that is that there are different genes that are turned on that have much more proliferative capacity, much more capacity to create matrix. And we see some of the differences that we saw. And the answer, however, to everyone's question is, OK, where we have all these products, which one is a true juvenile product? And the answer is any of them that contain these juvenile chondrocytes that are less than the age of 13. In our body, it's kind of the differentiating time where the biology changes of the cells. So it's an interesting part of it. When we looked at the cells of which genes are turned on, we found a lot of symmetry between these juvenile cells and the MSCs. Matter of fact, they share together turned on 250 genes. And when we compare this to our adult cells, it's not even close. That number precipitously drops. So there's a difference. There's a difference in the immaturity. And I think it's something, as orthopedic surgeons, we all observe in our young kids, that they regenerate their cartilage oftentimes. This is available to us now as a single stage procedure. Arthroscopic approaches, it's just a small learning curve, but totally doable. And there's lots of literature on that. And then that's going to do away with our harvest site, et cetera. That's one of the main benefits. And so here is the arthroscopic setup. This is in the trochlea. I'll play this here. You see a couple of things. Number one, a soft tissue cannula to keep the soft tissues away from this, all the salines out. What you didn't see is that we removed the calcified cartilage layer. That's key to any of these procedures. Calcified cartilage layer has to be removed. Fiber and glue, these fragments basically float in the fiber and glue. So you have to really work them down at the level of your cartilage. And that's the technique. So again, a very doable technique. It's another technology that we have. And then the question is, OK, what about those results? I've just spent, we're now sifting through years of doing this. And it's amazing. When we get the follow-up MRIs, definitely something here. And so number one, good imaging results. But here's the two-year outcome data. And we're getting more and more of this in that substantial improvements at the two-year outcome data. And of course, then it's just as important, where are we going from two years? How is this going to hold up over time? So that's something with these new technologies that we just don't know. But certainly, no matter how you look at it, very reasonable two-year outcome data. What about the progenitor cells? So these are the ones that used to be called stem cells. And we know they're not. And Scott did a great job of saying why. These cells are not completely stem cells. But they do have some regenerative capacities. So then the question is, well, what about the world that we're living in and the trials? Is there something here with these cells that are beginning to prove the case that we can actually regenerate tissue? And if you look at this, this is a meta-analysis of randomized controlled trials using these progenitor cells. And you see 10 of the 15 randomized controlled trials around the world showed significant increased cartilage thickness. And this is with quantified MRI. So obviously, we're not measuring X-rays anymore and joint space. But these are functional MRI. And as Scott also said, this is a very different scenario than BMAC or amniotic products, where there's zero trials to suggest that that is going to regenerate cartilage. So we've got to be careful of how we're comparing these. Here's another trial of a meta-analysis of randomized controlled trials. And it shows that the technology or the cell source that is most associated with a benefit of cartilage regeneration are the adipose-derived cells. And there's probably many reasons for that. And that we're getting more into the dosing. And you're going to see some numbers here as we go through with this. But around 50 million cells is probably the thing that has been the dose that has been most associated with an effect as we go forward. Why is the adipose-derived cells becoming the most popular source? And probably it's going to be a numbers game. And think about it. How many cells you start with dictates how many trips, doublings of those cells in the laboratory it takes to get 50 million. So there's probably going to be something positive about the number of cells that you can harvest from your initial getting your tissue in. Because the more time it's in the laboratory, the more time that these cells change because of being in the laboratory. So I want to, again, really just talk about where this whole thing is going. This is an Australian trial that did the following things. Number one, they biologically, or let's just say from the joint environment, optimize the joint environment. So that was step one in this trial. So this is with arthroscopy. And this is where we could really intervening as orthopedic surgeons is to get the joint environment optimized. Clean up all of the hanging stuff and maybe even the inflammation to prepare for biology to have a better chance. Second, this abrasion arthroplasty or taking away the calcified cartilage layer. You can't add cartilage on to cartilage that has the calcified cartilage layer. So that's step two. And then step three in this trial was adding 50 million cells of their own. So this is the autologous trial. And so then significant improvements. This is grade four trial. So this is what we're trying to do. We're trying to regenerate. And so some really good preliminary results with this. Well, why am I telling you this? Well, because we have a couple of companies in later stage trials of using autologous cells, sending it to the laboratory, and then being able to give it back to us as surgeons to be able to use it. It's around the corner. We need to pay attention to the international stuff that's going on. It's not that far away because of these companies that are really going through the FDA process now to be able to use this in the United States. If you look at the world, there's tons of trials. And the trials now, there's so many of them they're starting to have a lot of similarities to one another. The curves are looking the same. And really, the summary of these randomized trials is, number one, pain down, function up across the board. And then as we were talking about, a significant amount of these, 10 out of the 16 or 19, do have significant cartilage regeneration per quantified MRI. So just again, the level of evidence is improving throughout the globe. And we owe our international partners a lot. They're able to do more than we are in the United States. But it's giving us a springboard of how we're going to have our strategies here in the United States when we're allowed to do this. This is from the Mayo Clinic. So this is another strategy that's going through the FDA process now. And so this is Dan Sarris' work of using a combination of, for the first time in the United States, allogenic adipose-derived cells at a known dose and at the same time using some of the patient's own cartilage. For the basic scientists in the group, this is an experiment, an actual application of something called co-culture. And that is something we do, is that you put an immature cell and you put a mature cell and you put them together. How does the immature cell know what to do? Well, there's cross messages between the mature cell because that is a defined cell, like a chondrocyte. So then this is the strategy of mixing in a little bit of both to really get some in their clinical trials. This is a phase 3 trial, I believe. And so then you see that they're having their dose of their cells, the autologous chondrons. So they're breaking down a little bit of the cartilage to create a mixture with, again, the curves are looking the same, aren't they? These trials are pretty reproducible. So this is going somewhere. This is our trial where we just finished up. This is a trial to do just the opposite. This is to figure out, do we really need a certain dose of cells to be successful with regenerating cartilage and cartilage defect. Here is the trial, and here's how it goes. It looks very similar to the technique of the juvenile cartilage. The calcified cartilage layer has been removed. Here are the cells being pumped in. And again, this is a gamish of things, right? FDA does not allow a pure cell mixture. So this is the fat fragments broken down into an acellular matrix. And so we still have the second part of our data that's still in Europe, because these are, to the very best of our ability, unbiased trials, because all of the MRIs are sent immediately to Europe for analysis. We don't know the true number of the cells that was not allowed by the FDA, but from previous trials, we can estimate that are around eight million on this. And so we're just getting our dosing, right, on all the different 50 million, all the way down to the eight million. And this is, again, preliminary data, because we don't have our final data yet, but it's suggesting no clinical difference at one year, but you see that we're starting to diverge in the same way. This is a randomized trial against micro-drilling. You see the difference is starting to become effect at two years. And then this is how the technology is done, where we're measuring the cartilage defect in comparison to the surrounding areas of cartilage, and we're measuring the physiology of that cartilage through the functional MRI scanning. And again, our goal is cartilage regenerate to be the same as the native cartilage that's healthy next door. So that's how these trials are going, and you see with adipose-derived cells that we're creating a more normal cartilage than the micro-drilling, at least per the MRI parameters that we can see. Two final concepts that are gonna be coming also available in the United States. This is a company in phase three. This is Cardistem, and this is one from Asia, and what they're using for the first time in the international states, 50 million umbilical cord mesenchymal cells. So this is interesting because this is also leveraging the subchondral bone. So some of you will be looking at this and say, well, that's pretty cool because I can see that regenerative cartilage, and some of you will say, oh my gosh, what are you guys doing? Look at that subchondral bone. And this technique requires really large bore holes in the subchondral bone, and that could be either A, something beneficial as I'll show you in the next technology where it's venting the subchondral space in arthritis. That may be something that's really legitimate to do, and then allowing some cells from the subchondral bone as well as, again, the allogenic umbilical cord cells. So again, the curves are looking the same, right? All look the same, so there may be something very promising. I have a little bit of trepidation with this technology just because of the way that the bone looks, and again, that's the foundation to our house, which is the cartilage, so stay tuned, but it will be coming around the corner. And then, oh, this didn't transfer over, but what I went down, I left during Ken's talk. Sorry about that. I left because what I put on the slide, somehow they were deleted of agility, and it never made it up here on the transfer. I don't know why, but I wanted to just talk about it really quick. You hear about it. That is the coral, the biphasic coral, and Ken Zaslav has done a lot of work on this, and it is the only FDA-approved ability for us to use that in cartilage defects and osteoarthritis. If you look at their trial results, it's very impressive across the board with regard to a couple things. Number one, Phil on MRI, and I had all of it here, so I apologize that it didn't come up, and their results, and guess what? The curves look the same, all right? So then that's great, and maybe Ken can talk about this a little bit, but that also leverages creating these bits of coral to be down in the subchondral bone. A, that's good. We're venting. We're equalizing pressure. We're getting cells from below, and it's especially important in this product because it's an acellular product, and yet the MRIs show significant improvement in the cartilage layer above. It is impressive. So then this is either good because we are leveraging that subchondral bone and we know that that's pathologic in osteoarthritis, or there can be issues with drilling into the subchondral bone, as we know, and we've learned from microfracture. This is a great journey that we're on, but what you see in summary is that we're getting somewhere. We have more choices now as orthopedic surgeons to be able to leverage biology. We're running behind the rest of the world, yet the rest of the world gives us a great launching pad, so we understand that when we can start our trials, which is around the corner, that we'll be much more equipped to be able to do so. So thank you guys very much, and on to the regulatory. All right, we're running a little bit behind, so I'm just gonna plow in here. I'm sure the speakers will hang in there for questions if you want to come up at the end of the talk, so if I can have my slides. Steve Weber, last but not least. So just while we're loading up, my background is I worked at FDA for four years and got to see the evil empire from the inside, and I can teach you a little bit about what's going on here and maybe more important, how to stay out of trouble as you try to incorporate these in your practice. No disclosures of note. I agree, at the end of the day, first thing in the morning, this is like watching paint dry, so my apologies for going through this, but it's important to know. This is a huge market. These are some numbers that I pulled just for this talk, but they're not microscopic, well over a billion dollars in orthobiologics. So what is a biologic? And it's a little hard to wrap your head around. They can be vaccines, blood and blood components, allergens, somatic cells, gene therapies, tissues, all this stuff, and basically they can come from natural sources or they can be manufactured. So it's a little challenging to get your head around, but for the most part, we're comfortable with what orthobiologics are. FDA manages these in three different departments. For example, CDRH did physical supplementation until 2018. A lot of them are done within CBER, the biologic division, but some of these are regulated as devices. So it's challenging. And some of these are combination products where you get two or more centers involved. So for the most part, what we're talking about are human cellular and tissue products here with some exceptions. And these are articles that contain human cells or tissues as they define them. FDA started in 2005 trying to divide these into the two groups, and you've heard some of the speakers talk about these already. The 361 products, which basically are minimally manipulated and felt to be relatively safe, and the 351 products that are more complex and require much more formal regulation. So these are the basic categories. 361s, we talked about a little bit. They're felt by the FDA to be safer. We're gonna go into those criteria. And the 351s that are felt to be more risky. So again, you get into these crazy federal register numbers, and like I said, keep thinking about that paint drying. But these are the rules. They have to be minimally manipulated. You heard that. They have to be for homologous use, and that gets really confusing. For example, as an orthopedist, I don't consider fat cells and cartilage cells to be homologous, but yet FDA does because they're both structural tissues. You can't combine cells. We heard about that from Jason. And for the most part, these have to be autologous to fall under 361 products. So minimal manipulation, again, that's a tough one. What is it? For a while, FDA was saying, if you homogenize the tissue in some fashion, now it's manipulated, but they've kind of softened on that a little bit. And for cells, you can't alter their relevant biologic characteristics. So homologous use, again, mentioned that already. And it just has to do with FDA's concern about safety for non-homologous uses. So if there's 361 products, as we discussed, they have to comply with tissue practices, they have to register, and they have to label them according to FDA regulations. But these 361 products are not formally approved by FDA, but they simply self-designate, and that's a scary process for the regulators. When I did the biologic dashboard for AOS, there were over 800 products on that list, and they're all self-regulated. So they come out and they say, we're a 361. Okay, who's mine in the store? Well, it turns out nobody is. So here are some examples. Again, we heard about these a little bit, the 361s, basic stuff. But if you get into cultured cells, nerve cells, gene therapy products, these are all 351s, and they're much more intensively regulated. So here's another one, the same-day surgical exception. Basically, if I wanna start a company that manufactures 361 products, I have to be regulated. But if I do these in my surgery center or office, there's an exception that allows me to do these without that type of regulation or regulatory compliance. So as you get into this, it gets confusing. So example, what is and what are not HCTPs? PRP is a blood product. It's not regulated by the FDA. The things that make the PRP, the centrifuges are, but FDA doesn't look at this. And Newt Beitzel and Dr. Mazoka did a pretty good review about regulatory issues with this. Amniotic fluid is not a HCTP, but it's a body fluid. But it is required to have a biologic license to be administered right now, and we'll talk about that some more. Adipose tissue, again, is a structural tissue. So as long as it's minimally manipulated, as with the lipogens system, it's currently not regulated. So why do we care about any of this? I mean, a lot of rules, it's confusing. I got other things to think about. What's the point? And the problem is FDA goes after people that don't follow the rules, and they prosecuted numerous people for stem cell violations in particular. So these are well-documented, JBGS 2019, that had a detailed outline to limit illicit stem cell clinics. And Kingery looked at websites, almost 900. 95% of the websites that they looked at had at least one statement of misinformation. The average was almost five. So you need to be careful. So if you use stem cells in your advertisings for your orthopedic practice, and you get called out, it's an automatic warning letter from the FDA. And you have to understand, FDA doesn't have people that spend hours and hours going over websites. The people that turn you in are the guys down the hall that don't like you. So you have to be really careful. And that's how I saw all these come through at FDA. Another thing is an untitled letter. These just send out warning letters. Untitled letters are a little softer because it doesn't automatically involve the DOJ. And so we're seeing a lot of these come out these days. So, and again, we get into enforcement discretion. Scott talked about that a little bit. Because all these rules were understandably very difficult to figure out, FDA said, well, we think you're not doing the right thing with some of these products, but we're gonna let it go for a while, or do what they call the enforcement discretion. But that all ended in 2021. And the list of things that are now illegal to do without an IND are stem cells, stromovascular tissue, exosomes, Wharton's jelly, and almost all these amniotic products are now illegal. What's more important, if you have, are billing or ever billed CMS for these products, CMS wants their money back. So that's, and you can't bill the patients for it. So there's some of these big clinics that did a lot of these were on the hook for millions of dollars in what they call clawbacks. So be aware if you've used any of these, you know, circle your wagons because they're coming after you. So again, AAOS did the biologic dashboard to try and identify what's legal and what's not. It's been upgraded this year. It's a great resource. Jason and I were part of the committee that was involved with this and use it to figure out what you can do and what you can't do. So this enforcement discretion we talked about already, and it's just gotten worse really because of enforcement discretion. And we talked about clawbacks and prosecution. You say, well, nobody's really gonna prosecute me, but that's not true. They've had successful prosecutions, for example, in Missouri, where he not only got prosecuted, he went to jail. And the big take-home message, and maybe I'll end here because there's time, is don't rely on your rep to tell you it's okay. They are not your source of information here, and they will tell you anything to get you to buy and use their product. And they're off the hook. It's not on them, it's on you to understand. So again, the take-home message at the end of the day here is know your stuff, understand how it works, consent your patients appropriately, and use resources like the AOS Orthopedic Biologic website to find out what's legal and what's not and what your options are. With that, we're on time. I'll call it quits. Thank you guys so much for coming and getting out early. Thank you.

Platelet-rich plasma

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tendinopathy

rotator cuff injuries

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