Good morning. I think we'll get started. Thank you very much for coming to the Orthobiologics talk and for getting up at dark 30 in the morning on a Saturday to attend this. We'll try and keep it interesting enough to keep everybody awake, at least. I'm Steve Weber. I'm one of the speakers, and I'm going to summarize a little bit on orthobiologics based on my experience, four years of working at FDA, which was an interesting subject in itself. So, with that, we'll get started. I don't have any disclosures of note in relation to this talk, certainly. So, I think this is probably the take-home slide for those of us that don't have to deal with how this is regulated, which is about as exciting as watching paint dry. It's a different world at the FDA, to say the least, and it's not always clear. The problem with not understanding if you're going to use these products is you can get in trouble, and their, I didn't understand the rules, does not get you off the hook. So, obviously, this is our, the money slide, as it were, and the number of dollars that are involved with orthobiologics is staggering. You know, the numbers here, for example, predatory plasma at a 12 percent increase, and orthobiologics, U.S. dollars, what, 8.8 billion. So, these are numbers that I really never would have imagined 20 years ago. So, what is a biologic? And, obviously, we all kind of think we know what a biologic is, but the FDA has a somewhat clear definition of what biologics are. They can be all kinds of things, and some, obviously, not related to orthopedics, like vaccines, and recombinant proteins are not used a lot, but there's still some biologics in orthopedics that involve that. They can be all kinds of structures, sugars, proteins, nucleic acids, or combinations, and can be, obviously, living cells, such as stem cells. They are isolated from a variety of natural sources. They can come from humans, they can come from animals, they can be completely synthesized. So, understanding what is a biologic is a little murky, in my opinion, but it's still important to understand because the rules on biologics are what they apply to. So, FDA is a huge area. There are 30,000 people working in Silver Spring. I always said it's the only place I ever work where everybody held the door for you, had at least two advanced degrees, but it's huge, and the jurisdiction for orthobiologics can be varied. It's divided, as you know, into three major areas, which is CDRH. CDRH regulates some orthobiologics, but that's confusing because all the viscose supplementation products were in CDRH's devices, and that changed abruptly in 2018 when they moved them, probably appropriately, to the CBER, the Center for Biologics. Most of these, understandably, are in the Center for Biologics, and especially all the human connective tissue products are regulated by CBER. And some are regulated as drugs, not as many in the orthopedic world, and these change jurisdiction as well, and then, of course, it gets more confusing. You have combination products, so a scaffold that's impregnated with stem cells could very well be a combination product and regulated by two centers. So, one of the big things to understanding biologics is understanding what these HCTP, or human cellular and tissue products, are. And again, the definition is here. In 2005, FDA started thinking about how to regulate these better because of their unique nature, and these regulations have evolved in the subsequent 20 years, and hopefully clarified a little bit more, although it's not perfect. Basically, what FDA did is divide these human connective tissue products into two broad categories, primarily based on the risk involved, or at least the FDA's perception of the risk involved with these products. So, that gets you to the two categories, the 361s, where they're not felt to be extremely high risk. They are regulated for quality and things like that, but for most of us, the bottom line issue here is the 361 products do not require an IDE or IND, depending on jurisdiction, to be marketed. The 351s are felt to be more risky, and they are regulated as drug device or biologic products, and you have to get some type of pre-market review and approval for these to be legally marketed in the United States. So, lots of numbers. I love these Congressional Federal Registries. If you've ever had to read these things, they are completely opaque, so go for the guidances if you can. They usually come out simultaneously. These are the rules for a 361. It has to be minimally manipulated, and again, what do we mean by that? Well, that's up to the FDA when you bring your biologic to them and say, where does this go? For a while, they were saying anything that was obtained with a shaver was manipulated because it got chopped up by the shaver. That got softened a little bit. Whoops, I didn't touch anything. Boy Scouts honor. The manufacturer, it has to be for homologous use only, and that's another confusing area. Basically, the idea being that it's the function of the tissue is going into an area where it's functioning the same as it did when you took it out. The HTCPs do not involve a combination of cells or tissue with another article, except for a few odds and ends. And number four, it cannot have a systemic effect, or if it does, it's for autologous use only. It's an allergen in a first or second degree relative. We don't see that very much, and obviously in orthopedics, we don't see it for reproductive use. So, minimally manipulated, basically you can't change the original relevant characteristics of the tissue. And the processing cannot alter the relative biologic characteristics. And again, FDA decides this on a case-by-case basis, which each biologic they review. Homologous use, and this is confusing to me because clearly some of these things don't seem intuitively to me to be homologous. But the idea is that if they're not homologous, then there are more safety issues. And these 361 products have to be inspected, registered, and labeled their products. It's important to understand that all these 361 products are not approved by the FDA at all. And that was a big problem at FDA because they basically say, we're good, we're 361. And they self-determined that status, and unless the FDA for some reason gets called in to look at them, which it has, it's on the company to make that decision. And as part of the AOS DBT committee, when we were trying to set up the dashboard to figure out which one of these were approved and not, it's very difficult to sort out which of these companies, in fact, are truly compliant and which ones just think they are. And making it more important, they don't have to disclose any of this in their websites. They can say we're 361, or they can say nothing at all, and there's no regulation on that currently. So, these are just some examples, busy slide, but it gives you kind of a broad overview of what kinds of things are generally 361s and what things need more steps for the FDA to categorize as 351 products. So, this is another one that's very important for most of us, orthopedists especially. It's the same surgical procedure exception ruling. It came up and was further clarified in the 2017 guidance. And basically, it says if you're doing this in your office or surgery center, and you're taking it out of the patient, putting it in the same day, and that this qualifies as the same surgical procedure exception, and the FDA doesn't force you to approve it. It's sterile and make you comply with all the regulations that would normally be applied to anybody else that uses or manufactures a biologic. So, it's important to note in all this confusion as to what FDA doesn't think are HCTPs. PRP, for example, that's a blood product. It's not regulated at all by FDA. However, they do regulate the centrifuges. So, most of the centrifuges that make PRP get cleared through the 510K process and put on the market. It's interesting to note that PRP, all these centrifuges that make PRP were cleared to supplement bone grafts. And anything else is off-label. That's not illegal. It's perfectly appropriate to use products off-label. But it does create problems for orthopedists as far as consent. Adipose tissue, interestingly, is a structural tissue. And it's homologous. So, even if you put adipose tissue in the knee, that's still considered a homologous use, which strikes me as a little interesting. So, the LipoGEMS device, which is cleared by 510K for orthopedic indications, but they're telling you that it has to be used without any additional manipulation. So, why do we have to know the rules? Who cares? Nobody's minding the store. I should be able to do what I want. I'm a doctor. Well, the problem is it's illegal. And it's not to say that it could be prosecuted. It has been prosecuted. And there are lists of clinics that have been prosecuted for using all kinds of biologics illegally. And most of these are people that make claims about stem cells. And it's important to understand FDA doesn't have the manpower or time to search everybody's claims and their databases and their websites to see what they're doing. There just isn't enough time and people there. But it's important to understand the person that usually turned people in, in my experience at FDA, was the guy next door or down the hall. It's your competition that turns you in. So, be aware that that's where it's going to come from. And they will find you because if people in town think you're doing something shady, they're more than happy to take you out of the picture by reporting you to the FDA. So, there's a lot of documentation of abuse in our literature as well as other places. And part of what AOS has wanted to do over the last several years is to support orthobiologics but support ethical use of orthobiologics. PN, in their article in 2019, provided a detailed outline of how to limit illicit stem cells. Another JVGETS publication by Kingery reviewed stem cell clinics' websites and looked at a lot of them, obviously. Almost 900. 95% of them had at least one statement of misinformation with a mean of four statements of misinformation. And generally speaking, orthopedists were better than some of the other people, but they weren't great. And we'll get to that later, but inappropriate claims on your website is an important source of potential prosecution for you. So, another thing you want to look carefully, what claims are you making? And right now, there's only two products that allow stem cells in the United States. If you use a stem cell in your website or your advertising or any of your claims, that's an automatic warning letter if anybody finds out about it. Testimonials that say, I had stem cells at Dr. Warburg's clinic and they work great, that's not just wrong, it's illegal. They can't investigate them, but they can go after you for them. They can refer you to DOJ, which is not pleasant. They also have an Office of Criminal Investigations, and they've also prosecuted researchers. So there's a new approach. If they don't give you a warning letter, they can send you one of these, which is an untitled letter. Basically, from the FDA's perspective, they're easier to issue. They don't guarantee that they will prosecute you if you don't cut it out. And they're generally used for letters. They're not quite sure meet the threshold of a warning letter. But these are no fun to get either, and you really have to circle your wagons if any of these things come across your door. So another source of confusion was regulations. Many of the 351 products were legally marketed under what FDA calls enforcement discretion. And what that means is, we think you're breaking the rules, but we're going to let it slide. That all changed in 2021 when they ended enforcement discretion for a lot of products which you might consider using orthopedically. Stem cells, obviously, but for example, stromovascular fraction adipose tissue, that's now illegal to use in the United States without an IND or IDE. Exosomes, one of our speakers gave a really good article, thank you Scott, on exosomes, and Wharton's Jelly, amniotic fluid. Basically, any amniotic product that's not used in an intact sheet is now illegal. Even worse, if you billed prior to 2021 for these, I billed CMS for it, they are planning to take that money back. And some of these clinics have billed millions of dollars to Medicare for these products that are now illegal. And again, this big plug for something I worked hard on along with the rest of our group is this orthopedic biologics dashboard. It's up and running. You can queue in the product, the category of the product, and it will walk you through what's legal and what's not. Because it's really hard to keep track, and this comes from somebody that worked at FDA. So, please make yourself use this important resource to figure out what's going on if you want to use these types of products. And so, these enforcement discretion products were confusing, and several lay press articles have pointed out that enforcement discretion caused a bunch of shady operations to pour into the field. And this is another article from Turner. So, and they're big in the press. Patients want them. I mean, I'm sure you do, as I did, see people at least twice a week that want stem cells for this, that, or the other, with no idea of risks or benefits or anything other than some sports figure seemed to be getting them, so they must be good. So, these are the clawbacks, and Medicare in 2022 said they're going to take the money back, and all of it. And you can't go back and charge the patients for stuff that they charge to Medicare. And this basically was the companies telling practitioners that there were usable Q codes that could be reimbursed to Medicare, and that proved not to be true. And it's certainly possible that these could generate criminal charges, so I think this is getting a little cooler, but when this first came out last year, a lot of people were circling their wagons about what to do in this setting, and several clinics were understandably very concerned. So, there have been prosecutions, and these are not, again, this isn't pie in the sky, this is real stuff, this is a physician's assistant in Missouri who has prosecuted 10 counts of wire fraud and drug distribution counts, he went to jail. So, this isn't just a slap on the hand, and again, this is an important comment from one of the blogs, don't rely on coverage statements or representation from sales representatives, marketers or distributors, don't assume that the third party trying to sell you their product know if it qualifies for coverage or not. And that goes not only for Medicare coverage, but whether these things can be legally marketed at all. And it's not on them, if they tell you that you're good to go, and you do it, it's your problem. So, that gets us back to another thing, why are they being so hard on orthobiologic, why is the FDA telling us what to do? And a lot of doctors say, I should be able to do what I want, I'm a doctor, I've looked at this, the doctor agreed, he wanted it, what's the problem? And the problem is that stem cells, especially under the wrong circumstances, can cause significant harms. And you need to know what's on the FDA website if they look at these things. They've had, for example, stem cells injected in the eye that blinded people, maybe not surprising. There was a potential spinal cord tumor. You can get infections, especially these things aren't handled correctly, they can change into different types of cells, they don't work as expected. And this is from the FDA website, even if cells are your own cells, there are still safety risks, such as those noted above, in addition, if cells are manipulated, there's a risk of contamination of the cells. So, this is what FDA is suggesting patients read about, the stem cells you may want to prescribe to your patients. This was another article, not orthopedic, but looked at adverse events, and the Pew Charitable Trust article identified 360 adverse events. One of the concerns that worried me, five of these showed up in the FDA's adverse events database. That's not a good percentage. And again, reporting adverse events is voluntary for physicians, so we don't do it. But it's a problem, and most of these were on media reports, literature, and websites. So, harms have been identified. It's not just an abstract concept. And there have been some big stem cell fails, too. This was Peter Marks, we all know, is the vaccine dude, but he published this article, noting that we tried to use autologous stem cells to treat metastatic breast cancer, but it was ineffective, costly, and risky. So, a couple quick examples, just to give you ideas, not so much about recommending or not recommending the product, but what they go through to get there. So, this is a JILI-C product. It's for cartilage injuries. It's calcium carbonate, and this is a device. It's not a biologic, it's not a combination product. It went through CDRH. So, this is a PMA product. For those of you who don't know, that's the most complex type of FDA approval. They did a 24-month pivotal study. As you can see, the results were excellent, and this took five years to get approved in the U.S. It's been available in Europe since 2011, so it gives you some idea. Now, to put that in some perspective, though, Europe, in the last three years, has changed the way they regulate everything catastrophically with a process that they call MDR, medical device regulation, and all these products that were kind of CE-marked and put on the market now have to come back with clinical evidence. And so, the tables may have turned, and the FDA may be the good guy, not the bad guy, now, in terms of getting your product to market. So, another one is Cardocell. This has been around for a long time, and these guys... this is the indication-for-use statement, which is basically what the FDA and the company producing it feel it's good for. This has been used off-label, which is to say for uses that are not in the knee, for example, or a variety of different procedures. And again, off-label use isn't illegal. It's not even a problem. It just needs to be consented. So, it got an unregulated cell therapy approval in 1995. Genzyme got accelerated approval in 1997, but they never did any controlled studies until the STAR study, which was published in 2016. And what's happened, really, with all of these is FDA has tightened up the rules, partly because they perceive there's risk, that it's become more and more complex to get biologics, especially biologics containing cells, to market. And I think, moving forward, it's inconceivable to me that they won't require large controlled studies moving forward with any type of biologic, especially one that contains cells. So, Macy's, the only new one, it's come out as a biologic product. You can see that here. That's what the BL designation is. It's the first ever green light for this type of third-generation product in the United States. Cardocell was used off-label with a variety of membranes, as we all know. First U.S. use was in 2017. The summit study was how it got approved. So, these are very difficult to get approved. It's not easy. These randomized studies take forever. When you say it's a two-year study of cost, it takes four or five years to collect the data. So, these are not easy and are extraordinarily expensive to set up. So, there have been headaches with Macy. It was initially approved in Europe and was actually withdrawn from the market because it had reimbursement issues in Europe. And there was another stem cell product which never came to FDA, this Chondroelect. And hospitals in Spain and Germany were producing advanced medicines without EMA approval. And understanding, especially for device people, understanding that getting your product approved by the FDA is only the first step. You've got to figure out some way to get it reimbursed or it's not going to happen. And that can be much harder than getting FDA approval. So, this is the AAOS position on use of emerging biologics. And it's important to know this because this is what AAOS thinks you should be doing. And it's important to know that because this is what that attorney is going to come back and quote you when there's a problem with anything you did as an orthobiologic prescriber. You have to disclose. And you have to have a frank discussion with risk benefits and alternatives. So, to me, this doesn't sound like what I often hear in the surgery lab, which is, well, a patient wanted it, so he got PRP or whatever, stem cells. And this is why they do it, people like Kobe, who go to Germany to get advanced products that aren't cleared in the United States. There's a lot of press associated. So, I think the key thing to walk away from in terms of, well, what do I do with this, other than really try hard. If you want to prescribe it, understanding your product that you're prescribing is important, is informed consent. You need to explain to the patient what's going on. You explain the risks involved. And you need to explain to them that high-level data for many of these is still lacking. And I think it's a good idea, if it's going to be out-of-pocket expenses that can be substantial, you need to let the patient know. I mean, that's not something that should slide under the radar. So, in summary, most people are still awake, which is startling for this type of talk. Regulation of biologics provides challenges for practicing surgeons, especially the status of self-declared 361 products, where you don't really know what's going on there. And currently, there's no good way to know. Cell-based biologics are especially challenging. And, again, as I said, it's not just the FDA. Approval in Europe is going to get more difficult with the complete change in the way they regulate their medical products. It's not just the FDA. And, again, keep informed. Appropriate informed consent. Again, check the dashboard. Only use products that are legal to be used. And I think be a skeptic. I mean, we learn from our teachers, don't be the first and don't be the last. So, kind of stay in the middle in terms of what you want to use in terms of the biologic marketing. So, there's lots of information. Some of the FDA guidances are horrible to read. Some are better. This is better than most of them. And, again, the dashboard, if you want to look at that, excellent sources of information. And with that, you all survived. Thank you very much for your attention. We have a lot of time. Are there any quick questions before we move on? Sure, I suppose. I'm Steve Avalon. I'm a professor of orthopedic surgery in Madrid, Spain, since 2002. And in February of 2002, I did the first MACE that we went from ACI, autologous chondrocyte, to MACE on a membrane, with the MACE product that you see here today. This is October 2002. And I brought it back to all my friends here in the United States to study cartilage, because I study cartilage now. And I said, hey, look at this. This is your ACI on a membrane. Here they were using the membrane, but a little bit off use. Well, this is October 2002. In May of 2000, in summer of 2005, I presented at this meeting my first 50 cases of MACE, with really the same success as ACI, no better, no worse, but 90% success on a mediofemoral condyle. The fact is that the membrane has been used on burn patients for 20 years before 1995, and the cells have been used in the United States since 1995. But to take the two cells and put it on the membrane, it took from 2002 to December of 2016, took 14 years to bring it to the United States, where both procedures, the membrane was accepted and the cells were accepted, and the guys here were actually doing it off-label, taking the membrane and putting it on the cells, but yet it took 14 years and lots and lots of money. And from a company perspective, the company said, we don't want to spend $50 million to bring MACE to the United States, so the rest of the world can use MACE, because they had approval, and the United States is going to have to continue to use the first generation product. So you don't want to have an FDA. You need to have an FDA. We don't want to have human experimentation. But if it costs so much money to bring something to market, $50 million now to do a pilot study, if you want to use an adenovirus, gets you to do a pilot study on 20 people to see if it's safe. So somehow we have to speed up the process, and unfortunately it's not going to be my generation that does that. Thanks, Steve. I guess one defense of the FDA, not that I always defend them, is Peter Mark pointed out in his article on biologics, is if the effect size is large, in other words, you've got a big advantage with the biologics, you only really need a very small population. He quoted 50 to 70 patients. So if these things really are gangbusters good, then it's easy to get them to market, relatively speaking, because the effect size should be large. But you're right, they don't want to spend the money, and the only thing worse than spending the money and succeeding is spending the money and failing. So with that, our next speaker, far better than me, Scott Rodeo, is going to talk about his experience with orthobiologics. Hi, good morning. Thank you. Well, actually, that's an easy talk to stay away from. I think we should. I think I would really pay attention to that information and even look at Dr. Weber's handout, because this is such a rapidly evolving area, and the regulatory environment will continue to evolve. I'd also encourage you to look at that AOS position statement. I mean, it calls for and suggests that we consent our patients, and we started doing that at HSS, but we hadn't for years, and I think many of us don't. Let me get some slides up here, right? It escaped. There we go. And even just the – there's a very important point Dr. Weber made there about PRP. So we all use it for NeoA. So people often ask, are these things FDA approved? Well, almost none of these things are approved. As you heard there, the devices for PRP preparation are cleared by the FDA, but even that's only as a supplement to bone grafting. So when we make PRP, that's off-label. So these are all important facts, I think, to kind of keep in mind. So I'm going to focus a little bit more on tendon now. I'll give you some overarching thoughts here on this field as well, and then kind of focus a little bit on tendon. Let's see, I guess this is the one here. Forward there. Click on – got to be smarter than the computer. I can just do this one here, like at the bottom. There we go. Okay, so we have – this is support for our laboratory research program here. So I'm just going to set the stage with one slide here. I don't want to get in the weeds too much on the basic biology here, but talk about tendon. How do we go from this normal tendon to this very abnormal tendon? We know in the setting of tendinopathy there are distinct changes in the structure and the composition of tendon. At the most fundamental level, there's dysregulation at the cellular and molecular level. Tendinopathy we know is characterized by, obviously, alteration in the tendon matrix, and that's probably due to accumulated microinjury that sort of accumulates over time. It may start early on and be completely clinically silent, but this damage sort of accumulates over time here. These matrix alterations start to affect the local cells, alter cellular behavior. Ultimately, we know at the molecular level there's inflammation, although we don't see inflammatory cells on biopsies. Inflammation plays a fundamental and critically important role in tendinopathy, so that's important to understand. In fact, there's increasing focus now on the role of immune cell populations and all these different inflammatory mediators. A number of mediators, and we're not going to get into the weeds, all these different signaling molecules, but they play crucial roles in modulating and changing the matrix. So just with that backdrop, this maybe helps set the stage to understand how we're going to maybe use biologics to impact tendon. To that point, the first thing I think we should always encourage when we start thinking about biologics is what, in fact, are we trying to treat? What are our biologic targets? For example, do we want to affect cell proliferation, matrix synthesis, cell migration, new blood vessel formation? We're modeling the matrix. I mentioned inflammatory mediators that play a role here. Pain mediators, or the intrinsic stem cell needs to exist in many tissues. All these are very important and relevant processes, but they're all very different. So at the end of the day, what are we trying to affect here? At the same time, in addition to think about what we're trying to target, we need to define the composition and the biologic activity of all these different agents. Only then can we combine the biologic agent, whether that's PRP or cells or some emerging small peptide, only then can we combine that with the desired biologic target. One size does not fit all. We use the same PRP for meniscus and bone and tendon and ligament. Well, that makes no sense, right? So the same orthobiologic preparation would not and should not be expected to have the same positive effect on different types of tissues, certainly acute versus chronic processes, age, gender, medical comorbidities. All those things are critically important factors, of course, that will affect the outcome here. So this is just a little backdrop to kind of consider when we get into this field here. So what can we use? Well, you're well-known to individuals in this room, all the different autologous blood products. PRP, of course, is the basic example. But there are a number of others, and I'll mention some of these very briefly to give you a sense of the emerging other autologous blood products that are out there. And then, of course, we can use cells from bone marrow, from adipose. And all these perinatal tissues, as mentioned now, are essentially, for you and I, off the market unless they can only be used in a clinical trial under an IND, Investigational New Drug, under Section 351, as you heard. Obviously, just to kind of set the stage here, PRP, there's, you know, your plasma-based formulations, which excludes red cells and white cells and generally has a much lower platelet concentration. In contrast, your Buffy coats includes both the plasma layer and the cellular layer. You will get higher platelet yields. That's usually associated with higher leukocyte contents. I'll start by saying I have no relationship with any of these various companies that you'll see here. So with this in mind, many of us think about leukocyte-rich versus leukocyte-poor for PRP. I will submit to you that that is a place to start, perhaps. It's a very rudimentary classification. We need a much more refined analysis. I think we should consider, certainly within white cells, what type of white cells are present. In fact, we may want to concentrate macrophage populations or some T-regulatory cells, but eliminate other cells. Neutrophils in particular. Probably at the end of the day, it's probably ratios of platelets to leukocytes that's more important. So again, I think it's very complex. There's just a lot we don't know. In fact, the basic pro-inflammatory versus anti-inflammatory dichotomy of PRP, that's a real oversimplification. You know, this leukocyte-rich versus poor kind of implies pro-inflammatory versus anti-inflammatory. Well, in fact, PRP, how it works may be context-dependent. Some good data now to suggest that PRP can inhibit inflammation in a pro-inflammatory environment, but in contrast, PRP may, in fact, be pro-inflammatory in the absence of inflammation. So again, this is really complex. And the more I study this, the less I know. Apart from all the goodies from platelets and the alpha granules and dense granules, there are a number of important signaling molecules in the plasma portion that play a role as well. So tendinopathy. Tremendous variability in the report of clinical outcomes. And you can say this about most orthobiologics in our field here. A couple of systematic reviews to kind of set the stage. This is more recent to give you a little sense. One from Italy here. 33 randomized trials. So, you know, well-done trials. And you see all the different types of tendinopathy that were evaluated here, which is a tremendous variability, you know, anatomically, biologically, biomechanically. But they've concluded that the quality of evidence was great as low or very low. And, in fact, they concluded that in the majority of comparisons, the effect size was comparable just to the control group. So no real effect there. That doesn't really support it here. The, you know, the generally accepted dogma for tendin has been, using leukocyte-rich, you know, this concept of kind of turn on the biology, make a chronic process acute. This goes back to Jane Fence-Patrick from Perth, Australia, where there's a systematic review where she looked at 18 studies. This was published about seven years ago. And reported a strongly positive effect for leukocyte-rich PRP systems. That's where a lot of the concept of using leukocyte-rich came from. And she found no real difference in some of the control treatments, even including steroids. They concluded that there's good evidence to support the use of a single injection of leukocyte-rich formulations. And that's kind of held largely to this day. But a lot of variability. So I think we're talking about tendon here. If we focus on the rotator cuff, again, tremendous variability in outcomes. If you look at the use of PRP for rotator cuff tendinopathy, not a lot of support. Briefly, I picked four kind of well-done studies, higher-level randomized trials. One from Turkey, a placebo-controlled study, PRP versus saline, no real difference. Andy Carr in the UK has done a nice job. He took a patient in the OR, did a subacromial decompression, and then randomized and received PRP or not. And then he did a tendon biopsy three months later. In fact, he found increased apoptosis and really adverse effects in the tendon in the PRP-treated group. So that doesn't support it. This group from Switzerland, similarly a randomized double-blind trial, PRP versus saline, pretty straightforward. Subacromial impingement patients, at 19 months, they saw more adverse effects with stiffness in the PRP-treated group. That doesn't really support it. The last group from China, just last year, another systematic review, PRP versus steroids. Short-term, you know, steroids work. We all know that. But the long-term, no real difference in outcome between the two groups. So again, not really supportive. So my read of literature right now, there's not a lot of data to support the use of PRP just for rotator cuff tendinopathy for sort of non-operative treatment. I'll contrast that with carfeparin a little bit here. If you look at some systematic reviews to kind of summarize some of this, Pietro Randelli's group in Italy. Again, look at the randomized trials. So we look at just the line there, conservative treatment. That's, you know, just your non-op treatment. High heterogeneity, no clear consensus. What they did find is surgical treatment, and I'll talk about that in a moment here, PRP can benefit healing, structural healing, although often doesn't translate to clinical improvement. But in the non-operative conservative treatment, didn't seem to do much. Similarly, nice work from Ewen Hurley in Dublin, Ireland. Another systematic review. Five trials. Again, looking at PRP for cuff tendinopathy. Two studies, PRP was superior to control. One study, no difference. And two studies, PRP is inferior. So this is what we're left with if you look at literature. Depends on what study you look at on a given day, right? So they can conclude that PRP doesn't seem to be beneficial there. This is in the rotator cuff. So if I summarize this, certainly wide variability. And that's because there's different tendons treated. This is just for tendinopathy broadly here, not just going by itself. Let me go backwards. What's the odds that I can go backwards? I'll figure it out. Except for this thing is funny. Here we go. Anyway, let's go. Got to move this little arrow thingy here. So there's variability in the PRP formulations. Another important factor is other concomitant treatments, the rehab protocol. So these things aren't done in isolation. So bottom line, you know, there probably is some support in literature for using a leukocyte-rich system, PRP, for tendinopathy broadly. Again, we've seen for cuff, not much. Maybe for other tendons, I'm going to only focus on so much right here. But again, an area that really needs further work and further development. Just briefly some of these other autologous blood formulations. You've heard of ACS, the Autologous Conditioning Serum. Orthokine in the overseas, Regenikine in this country. A little different process. This is autologous blood. The blood is heated and incubated overnight. It's little chromium sulfate etched glass beads. What does that mean? Essentially the blood is incubated with these glass beads. That induces this process where essentially monocytes will produce R1 receptor antagonists. That is a potent anti-inflammatory cytokines, what this process looks like. But this is kind of a manipulation. This is not currently FDA approved. There is one study from Serbia using this Autologous Conditioning Serum. So again, supraspinatus tendinopathy, non-operative treatment. They compared it to, actually they did four injections weekly of this material versus three weekly steroids. I don't think you and I would do a steroid once a week for three weeks here. Both groups improved in four weeks. At six months, those patients with the Autologous Conditioning Serum did better, as you might expect. So there's a little data there. Another, the Autologous Protein Solution. This has been developed by Zimmer, with whom I have no relationship. This has been looked at in osteoarthritis, not yet to my knowledge intended. But just to give you a little sense of other products out there, or processes. A little different process here, where blood goes through two steps. First, a cell separator that separates the cellular components, and then a concentrator where it's filtered through polyacrylamide beads. At the end of the day, it concentrates, again, IL-1 receptor antagonists, kind of like the Autologous Conditioning Serum. So it's been looked at in osteoarthritis. Alpha-2-macroglobulin is another one. So MMPs, matrix metalloproteases, are critical factors that regulate the matrix in many soft tissues. And so the balance of MMPs and their inhibitors is critically important. Well, Alpha-2-macroglobulin can be derived from blood. And it's a broad-spectrum inhibitor of MMPs. And there are some techniques now to use to concentrate that from autologous blood. I've not used those in my own practice. This is just a laboratory study we had done some years ago. Looking at it, though, at A2M, this is a rat-rotated cuff repair model, where we did a cuff repair, and then we either treated with Alpha-2-macroglobulin or not. And we do see some improvements here. Histologically, you see the fiber cartilage on the histology slide there. We found changes in collagen degradation. So the graph at the bottom there demonstrates collagen fragmentation has improved. So this material modulating MMP activity after cuff repair may offer a novel biologic pathway. But, again, an area just to kind of whet your appetite, but that needs further data and further. So my current recommendation for tendinopathy, again, some data is promising, but certainly, like many things in this area, needs further investigation. If you're going to use this, you typically or it seems reasonable to use a leukocyte-rich formulation. Typically do an ultrasound-guided injection. Some data suggests that local anesthetics may adversely affect these materials. So if you're going to use an anesthetic, I'd just do it in the skin. I wouldn't combine it. Usually do a single injection. You know, will repeat injections improve outcomes? It may well. I'm not going to get into cost issues and logistic issues, but it's going to be repeated. Post-injection rehab, really a black box. A lot of recommendations are really empirical. You know, there is very little basic science or clinical data to support the common recommendation to avoid non-steroidals. And inflammation is complex. And if you look at the data, very little data to support that recommendation, quite honestly. My current recommendation is light activity for three days, followed by a gradual progression. But understanding this is pretty arbitrary. But, you know, as a clinician, you've got a patient in front of you. You've got to tell them something. So this seems kind of reasonable and we've kind of usually done. But, again, we need more data. You know, we know the eccentric exercise protocol is the standard for tendinopathy. We certainly need further data in this area. So what about cuff repair? That was so far was kind of tendinopathy, non-op treatment. Well, looking at PRP for cuff repair, meta-analyses do suggest improved structural healing. And to go through, to summarize briefly, Thomas Vanks-Ness from USC. This was a meta-analysis published some years ago. The re-tear rate was lower in those cuff repairs augmented with PRP. A group from China. Similarly, a systematic review of 10 randomized trials. Again, similarly, PRP reduced the re-tear rate compared to surgery alone. Importantly, the bottom line there, platelet-rich fibrin, which is a different preparation, did not affect tear rates. And we'll kind of emphasize that again right here. Ewan Hurley's work from Dublin, Ireland. Ewan Hurley. PRP versus a platelet-rich fibrin. Those patients, this is cuff repairs augmented with PRP. Better healing rates with PRP. This is based on either ultrasound or MR. So a structural imaging. But in contrast, again, that platelet-rich fibrin matrix did not have an effect. This PRFM, platelet-rich fibrin matrix, essentially taking PRP, adding calcium chloride back in the prep, do a second spin. And it makes it, kind of clots it, almost like has the consistency, almost like chewing gum. You can put a suture through it. And the goal was to kind of trap platelets, but as you see, the data doesn't support its use. And lastly, this group, just last year from Athens, Greece, PRP again superior. So bottom line, PRP doesn't seem to be beneficial. It does seem to be some data that it can improve structure healing following cuff repair. Back to this platelet-rich fibrin matrix, we had a study, this is my patients and a couple of Russ Warren's at HSS we published some years ago, just a simple randomized trial, patients undergoing cuff repair. And we just had the cuff repair versus 39 where we added the platelet-rich fibrin matrix. Essentially, we found no difference in healing based on ultrasound, no difference in patient part outcomes. We used Doppler to look at vascularity, no difference, no difference in strength. And in fact, with the logistic regression, suggested the patients receiving this platelet-rich fibrin matrix had worse outcomes. So again, we have stopped using it. But I put this in that picture of the upper right that shows what this material looks like. You can actually kind of put a suture through it. We can attach it to the repair site, but it doesn't seem to do much. So what about cell therapy? Briefly, to kind of set the stage, because this is so much confusion in this area, what is a stem cell? This goes back to Arnold Kaplan. It actually goes back to probably Friedenstein and Owen in the early 70s. But a lot of us credit the work in orthopedics to Arnold Kaplan, who passed away unfortunately recently. And we know the basic definition is where a progeny becomes committed to a specific phenotype. But think about what a stem cell really is. These are the universal criteria, and I'll say it up front here. Cells we use do not fulfill these criteria. These, of course, need to be unspecialized cells. Importantly, the concept of self-renewal. Cells divide asymmetrically. So one cell can go on to become a different type of cell, but one cell stays a stem cell. If that didn't happen, you would deplete your stem cell pool. This is a very unique feature of a true stem cell. And then, again, the multipotent differentiation capacity. But the bottom line is currently utilized cell sources contain few, if any, stem cells. Now, you can talk about other, you know, there are progenitor cell populations, but I wouldn't use that term, stem cell. Arnold Kaplan, in kind of another classic paper in 2017, became recognized that the biologic effect of cells are due to a Perrican effect. That they produce a number of anti-inflammatory and immune modulating proteins that modify the local environment. And he, that's when he suggested that we call an MSC, a medicinal signaling cell, in recognition of the fact that these cells produce these signaling molecules. And, in fact, there's very little evidence to support or suggest these cells even engraft into the tissues we inject them. Rather, they just produce these various signaling molecules. I submit to you, we have essentially no ability to use, quote, unquote, stem cells. And patients ask about us all the time. Again, the number of true stem cells by any criteria, cellular, molecular, functional is vanishingly small in our current formulations. If you go back to an MSC, and the S is stromal, not stem. So, the classic definition is based on culture expanded cells. That's very different than the cell population that you and I use from bone marrow or adipose, or, you know, you do lipogems or something like that. These minimally manipulated preparations that we use here, and you hear Dr. Weber talk about the importance of this, you know, minimal manipulation. That needs to be distinguished from sorted culture expanded cells. Again, those are very, very different. And the term MSC should only be used to refer to culture expanded cells. And you and I don't use those. So, that's, I think, is important points for us here. And a lot of us just know them in culture, but I think normal culture is important. And so, what can we, to kind of focus it back at the clinical level, what can we as clinicians use? Well, we can use cells derived from bone marrow. We can use cells from peripheral blood, adipose tissue, of course. Distinguish the microfragmented fat. That's, you know, the minimal processing, minimal manipulation. That's the lipogems. That should be distinguished from the stromal vascular fraction. As you heard, the stromal vascular fraction, that requires enzymatic digestion. Not currently allowed, that level of manipulation. That needs to be done only under an IND or in an FDA trial. All these perinatal products have been mentioned here that exist. In fact, these perinatal fluids, amniotic bloods or amniotic fluids, placental derived materials, umbilical cord bloods, they do in fact contain immune modulating proteins. But virtually no viable cells, unlike zero cells that would qualify a stem cell by any criteria. And as you heard, those are essentially off the market now, these perinatal formulations. So, I still see individuals, patients that are receiving these here and there. So, be careful. Talking about cells though, there's a little bit of data out there to suggest the cells may in fact be structure modifying. You know, I tell my patients, many treatments are symptom modifying. They may improve symptoms. Very little data they will really regenerate tissue. But there's a little early data out there that kind of whets your appetite. So, this group from Malaysia, this is a small group of patients, just three cases, use peripheral blood derived cells and chronic Achilles tendinopathy. Both an imaging study using MR, changes in tendon thickness, changes structurally in the tendons. Similarly, this group from Italy, adipose derived cells. Again, comparing this to PRP, they found some structural changes. And lastly, Nicola Mefoulian in London, this is bone marrow derived cells where they're treating patients with patellar tendinopathy with bone marrow cells versus PRP. And with the cells, they found improvements in tendon structure on MRI. So, what I put on this slide is three different cell populations. Peripheral blood stem cells, first one, adipose derived, second, and bone marrow. So, all different. All these studies, again, small patient numbers, but demonstrate some evidence that you can maybe impact structure. So, it's an area that certainly just needs further evaluation. If you go back to systematic reviews, this is one from Denmark, level of evidence is just four. You see a number of different tendons that are treated here with cells, high risk of bias. And they conclude that evidence based recommendations for the use of stem cell therapy, I'm not sure we should use those words, for tendon disorders cannot be made at this time. Now, in contrast, another systematic review is from Iran, actually. Again, a mix of different tendons, which also brings in such a variability, where they suggested or concluded that cell therapy does show some promising results, seems to be safe. So, again, you're kind of left with a mixed message, but I think we need further data in this area here. On rotator cuff repair, there is some data that cell therapy can augment healing. Probably one of the first studies, 10 years ago now, Philippe Pruner grew out a series of 90 patients undergoing cuff repair, half of whom received bone marrow derived cells. And a 10 year follow up, he found a higher rate of intact repairs. And in fact, the cuff integrity was correlated with cell number. Grew from Korea, had 70 patients, half of whom received adipose derived cells. And similarly, the re-tear rate, or the healing rate, was higher than those receiving cells. And then the Rush Group, with Nick Verma and Brian Cole, this is 91 patients, half of whom received bone marrow cells. Also, improvement structurally in healing based on imaging, although that did not translate to changes in your clinical outcomes, as far as your patient-reported outcomes, which is often the case. Looking at the lipogems here, Pietra Randelli's study using this microfragmented adipose tissue. Again, this is mechanical emulsification. It's a randomized trial, 22 patients in each group. Again, simple cuff repair, with or without the lipogems. They found that there wasn't an improvement at six months. You look at the graph there, the groups deviate at six months. But no real differences beyond that time point. And no differences as far as re-rupture rate based on MR. They concluded that, you know, using this microfragmented fat may improve your short-term clinical results, but didn't have much of an effect at that one-year point. So, again, bottom line, cell therapy approaches seem to have some promise for improving structural healing, but certainly an area that needs further data. And lastly, to finish up, just to give you a sense on tendon, there are a number of metabolic factors that are associated with tendinopathy and that affect tendon healing. Just to briefly give you a 30,000-foot view, we know that hypercholesterolemia has an adverse effect. There's data out there. Smoking, of course, dose-dependent relationship between smoking and healing. Diabetes, we know. Osteoporosis, interestingly, higher failure rates reported with osteoporosis, and not just due to poor fixation of our devices. Vitamin D deficiency, there is data demonstrating the lower serum levels of vitamin D is related to higher fatty degenerations, and we know vitamin D has mirrored effects. Renal disease, of course. Fluoroclonal antibiotics, levofloxacin, things like that, we know have an adverse effect on tendon matrix. And lastly, thyroid. I put this up because all these, you know, just keep this in mind. Some are modifiable, some are not modifiable. Lastly, some currently available drugs that maybe we can exploit for biologic augmentation. Different pathway. We already talked about PRP in cells, or maybe this is biologics as well. Maybe we should use parathyroid hormone, Forteo. Preclinical data suggests that PTH can improve tendon healing. Some animal work from our lab and others. There's a clinical study. The patient's going to go in cuff repair with daily injections of parathyroid hormone had lower re-tear rates. So now it's something to consider. It's costly and often not approved by insurance. Statin drugs. Statin drugs seem to have a lower risk of developing rotator cuff disease based on large insurance database studies. So if the patient's on a statin, maybe leave them on the statin. And lastly, vitamin D. As I mentioned, we know it affects osteoblastic activity, affects muscle. There's some data out there. Preclinical studies. There's clinical studies demonstrate the lower levels of vitamin D. Again, higher levels of fatty degeneration. And so that's a modifiable risk factor. And, you know, maybe consider post-operative supplementation. So lastly, to summarize here, area that has great promise, needs further work. I think we need to identify biomarkers to characterize the quality and the activity of a given formulation. You know, what's the purity, the potency, the activity of what I'm putting into my patient, and correlate that with the outcomes. We need linked clinical registry so I can correlate what I'm putting in the patient with the clinical imaging outcomes. Ultimately, changing the regulatory environment, allowing some, quote, unquote, manipulation may advance this field. The ability to maybe to use enzymes for digesting adipose tissue, cell sorting and culture expansion. I think importantly, methods to select the desired cells. And more importantly, eliminate competing cells. You culture cells, a certain cell is going to take over the culture that may or may not be the cell that we want. Nothing lends itself to this whole area of precision medicine as much as orthobiologic. You know, the concept of the right patient, right drug, right dose, right route, back to, you know, what are we trying to treat, what's the biologic target, one size does not fit all. And on the horizon, again, a whole other lecture, you can talk about exosomes. And I think methods to simulate the intrinsic progenitor cells that exist in many tissues will be an area that we'll continue to study. And importantly, the role and interaction between local immune cells and intrinsic progenitor cells, and how those interact with orthobiology that we put into our patient. Thank you. All right, next, we're going to have Jason talk about the other side of the fence here. Oh, good. All right, well, sort of. I'm going to do the two for two, so that's good. You can advance from here. Oh, great, thank you. Good morning, everyone. So, we have 30 minutes left to speed through osteoarthritis and articular cartilage, lots to talk about, some of which is in the United States, some on the world stage. But to keep us all up to date, so this thing isn't working, let me just see. I used the little thing at the bottom. This one? The left bottom. Okay, got it. So, when you look at the field of biologics, and especially osteoarthritis, it's really important to think about what we're trying to do. It's exactly what Scott said. It's like we have to have an understanding of, as a physician, what we're trying to achieve in this patient. There are two really big areas that we can improve patient symptoms, at least, is number one, decreasing inflammation and pain associated with osteoarthritis. And the other is the attempt to increase cartilage thickness or chondral defect restoration. It's important to draw the line there, because these technologies can't do some things. And so, we'll start with osteoarthritis and symptoms. And see the list there, and the first is platelet-rich plasma. I put this slide, because it's a good summary slide of the available evidence that is out there. But I fully agree with Scott that this isn't going to be enough of a demarcation of the different formulations of osteoarthritis going forward. So, it's good to get us where we are, and we need to go forward from here. This is an analysis, a systematic review that we did previously just to understand the power of PRP and its ability to improve the symptoms of osteoarthritis. And this is in comparison to high uronic acid. And the summary is that PRP across the board, when you looked at this in the level one trials only, showed a significant improvement in comparison to the results of high uronic acid. So, I think that conclusion is pretty easy to make. The more trickier conclusion is what type of PRP should you use? The data tended, and this is the graph all the way to the right, showed that most of the world's literature showed that the leukocyte-poor preparation did better than the leukocyte-rich. But we want to keep going here with our understanding of this. And many of us in the room, Scott and I, are involved with this biorepository network, and we're starting to get some good information about studying lots of patients with osteoarthritis. And our conclusions then, you see, are going to change as we get more and more information. So, I just, again, wanted to whet your appetite on some early data. And so, the way we're doing this is we're taking the patients and we're dividing them into responders versus non-responders to understand why did some people get an effect with PRP and some did not. And here's some early data. But it shows maybe just kind of opposite what I was showing on the other slides is that be careful what we're calling leukocytes because patients with higher lymphocyte counts responded more than the lower lymphocytes. And so, again, that's in the leukocyte category. So, that's not necessarily a leukocyte we want to deplete from our PRP preparations. One of the other clear data that's starting to emerge, and many labs are seeing this, and that is that the platelet counts do matter. And the higher platelet counts tend to be correlated with more of a response to decrease the symptoms of arthritis compared to formulations processing that has a less platelet concentration. So, platelets do matter. So, where are we going with this? This is the old slide. And the new slide really is that we need to go in the direction of dosing. This is something that has been started. Many companies are working on this process to figure out how we can deliver a dose. Makes sense to us as physicians, right, if we're going to take ibuprofen that we know it's 200 milligrams. But the whole biologics, we don't have that clarity. So, we need to develop. And this is one of Scott's slides from a talk later on today. And it just shows that this is being done, right. And here is a study using an absolute count of 10 billion platelets. That's where the future is going, right. We're understanding what we're putting into the patient, giving doses, and then we're going to be able to study that. And I hope that produces a lot of clarity. Because right now, what we have is this. We have JAMA, and we have these articles coming out. And the big conclusions is these findings from this paper do not support the use of PRP for the management of osteoarthritis. Holy Toledo, what are we doing? We're confusing everyone here. That is not a logical conclusion. When you look at the world's literature, that is the conclusion of this paper. This paper's processing system made a PRP that's very low in platelets. It didn't work. That's a good conclusion that could be from this paper. But you see, we're confusing everyone. We're confusing our patients because it's not overarching. But we need to be careful of this. This is what our data is showing. This has a much less chance of response because of the low platelet count. So be careful with the system that you're using. Well, where are we going also is to say that PRP was a really good start. But biologists say, well, boy, oh, boy, look at all this stuff on our blood. Why are we spending so much time on PRP when we could be mining other biologic molecules within our blood, and that can get us possibly even further down the road? I'm going to give you some concrete examples of this. This includes the new generation plasma filters that you see on the right. These are available. These are FDA approved to be able to use as of now. And I just kind of want to show you where we're going, right? So then this is an evaluation of the market filters and the different porosities. And the porosities and the size of the pores are showing how well we can trap small biologic molecules that may be beneficial for us in our art of medicine and treating the symptoms of osteoarthritis. Scott brought up this one. This is a very much emerging one. If you look at all the randomized trials of A2M, you're not going to find them. But it is a very biologically important molecule in our blood. So then can we use that in osteoarthritis? And those of us who have used this in our clinical practices, please forgive anecdotal comments, but this has power behind it. And those patients that are struggling with recurrent diffusions, nothing, surgery, nothing worked, this has been a big part of our armamentarium. But again, data is lacking. So I want to be very clear on that, but very also clear from a scientific perspective, the power behind its anti-inflammatory, anti-enzymatic properties of A2M. So if you use these filters, you could see that you could really increase the amount of A2M in the solution. So this is, again, it's a low-cost way from the platelet-poor plasma where the product we used to throw away, now we are harnessing the potential of the waste products of PRP, believe it or not. And so this is platelet-poor plasma, and you see how we can really increase the amount of A2M. So studies galore need to be done here. IL-1RA, this is another thing that Scott talked about. This has been popular in Europe. And the question is, well, what do we need to do to harness this potential? Well, there's a couple of things. Number one, we need to be able to concentrate it within our PRP and our serum. And so now we have some tools to be able to do that. But there's one other important thing, and that is it doesn't really matter how much IL-1RA you have unless it's in a ratio that's much greater than IL-1, right? It's the antagonist. So we always must talk about a ratio of IL-1RA versus IL-1. Otherwise, it doesn't really make sense, and we don't even know what to do with the data. And if you look at the literature, the literature says that this ratio should be somewhere between 100 to 1. So if you look at the current, again, filter systems, we see that these can achieve that ratio of 100 to 1, and so therefore can give us, again, maybe, again, there's no data to show that these filters and their power of decreasing the symptoms of arthritis. But this is the science behind it, right? So this is the starting block. This is where we are in developing new technology. So it is something, and it's something that we can use. And so then I encourage all of us to begin the clinical trials because we can use these type of filters in modern day. Soluble TNF, right? So this is the other part of the biologic equation of inflammation, right? We know IL-1 is a potent inflammatory meteor, and so is TNF. So can we do the same thing? And the answer is yes. So we can trap these soluble receptors within the plasma, and this gives us more of the potential of anti-inflammatory therapy. Again, just proving the science behind this first, and the clinical trials are going to come next. But you see, this is a tough equation because the size of these soluble receptors are really small. That's why the filter technology has had to improve over these last couple of years, and I think we're finally getting there. Platelet-derived growth factor BB, this was something Arnie's, one of Arnie's babies here of understanding how we can release these local MSCs from their perivascular nature. And some pretty good evidence, basic science-wise, to suggest this is the thing we can use, platelet-derived growth factor. And what I wanted to show again is that we can concentrate this both from the PRP fractions, if this is what we want, or from the platelet-poor plasma. And so this is harvesting techniques of these molecules that we are becoming better and better at, and you see this is exciting new territory. And stay tuned for clinical results because that's the thing that we don't have from these systems. Let's switch gears to the adipose preparation. As everyone has said here today, this isn't cell therapy, right? This is, we're not breaking down the fat tissue into the cell, the cells. This is tissue therapy. So this is breaking down the adipose tissue into bioactive fragments. That's the difference. Plastic surgery technique is to the left. Orthopedic surgery technique is to the right. There's multiple ways that you can do this. And then bottom line is I want to talk about the FDA-approved system to the right, the micronized fat system, and just show you, again, the science behind it. Because if we're going to consider using in these patients, we should be able to tell them the data that's behind them and the reason why we think that this is appropriate therapy for them. So this is the basic science that was done. So this was lipopolysaccharide, as we all know, important inflammatory mediator. And when this was placed in the laboratory with cells, it creates a dramatic reaction. We know that in medicine. But what happens if you put the micronized fat on there at the same time, and you see it just quenches the inflammatory reaction? It prevents it from occurring. And this is the basic science, then, proof of its anti-inflammatory capacity. If we look at this from the meta-analysis and systematic review, we see that there's lots of studies that have been done with micronized fat. And if you look at how well they decrease pain, you see it's just across the board with the plots. It's all consistent. So there's power behind it. And there's some power now of comparing PRP. And we don't have time to go over a lot of that today. But there's power behind this. So this is just something that's in our group of biologics that we can use to change the symptoms of osteoarthritis. And again, with clarity, no evidence to suggest that there's some regenerative effect of either PRP or micronized fat to regrow cartilage. There's really no data to suggest that. Bone marrow acid, you also see that bone marrow cells are something that we can use. And you notice that there's no slides that we have discussed about decreasing the symptoms of osteoarthritis. No good evidence to suggest that we should be using the bone marrow aspiration. That said, there's new techniques and new ways of treating the sister part of what's happening with osteoarthritis. And this is the reaction within the bone. This doesn't happen with everyone with osteoarthritis, but is the modern-day method of looking at a patient with osteoarthritis and customizing treatment for them. And so then the old days, hey, we would just get an X-ray. And then, hey, you can have some types of injections in your joint. But what if this was occurring? Then, of course, none of those things would work. And we wouldn't know that they had this bone marrow reaction insufficiency fractures because we didn't get an MRI. So now things are progressing in our method of evaluating patients with osteoarthritis and their candidacy for biologics. This makes it more powerful because we're targeting them. And so what has been used is bone marrow concentrate and interosseous injections. And new techniques have been described about how we can get some biologic potential of really venting the bone marrow and stimulating bony remodeling. And this is just one of those techniques. But bottom line is that this has been a powerful entity. Now again, new data is coming out. I'll just show you a little bit of our initial data. But look at this. This is pre-collapse, right? This is this circular lesion that we know is right before this whole thing is going to collapse. So the question is, can we save it? And again, here is our data. The numbers now have doubled from 7 to 14. So it's not overwhelming data. But again, it's just where are we at, right? We just want to be up front of where we're at in biologics. But we can make a difference, right? And if you look at the volume of bone marrow change, bone marrow so-called edema or T2 signal, you see that these interosseous treatments can markedly decrease that bone marrow abnormal volume. So there's something here, more data required. So what about cartilage restoration? So this is what we really want to do, right? This is the next generation. Some of these techniques are available in the United States. I'll be clear of which ones are and which ones are not. And then I also, though, want to... This is an international conference, and I want to make sure that we are giving representative data from across the globe, not just concentrate on the United States. One of the things that fits in the biologic category is juvenile chondrocyte. And you may say, well, how come Macy's not a part of this menu? And Steve brought up a really good point. It's a really good technique. But that's adult chondrocytes, right? And then so then is that real biologic therapy? Well, maybe not meeting the definition of what we're trying to do in biologics because it's adult cells. And then you would say, okay, well, juvenile, fine. Show me the proof then that those are different than adult cells. And there's plenty of data to suggest that these cells are very different in their makeup and their cell products in comparison to adult chondrocytes. And that's one of the reasons why, you know, they're on the market and there's some excitement about that. So again, lots of data to show that they produce more matrix of cartilage than their adult brother in there. And then this is a part of the study where we looked at the MSCs and what they're producing and genes that are active in comparison to these juvenile chondrocytes. And we see that there's a lot in correlation. We're seeing there's more stemness in the juvenile cells in comparison to the adults. And they're closer to the MSC side of the fence, right? They're kind of an intermediate type of cell. So it's something that's available. The good news, in contrast to MACI, this is a single procedure, right? So you can then just order these cells. The techniques are now... this is all done arthroscopically. So then that is good with respect to the financial part of it, as well as a single surgery rather than two surgeries for the patient. Technique... I'm just going to gloss through this pretty quickly. But again, there's these arthroscopic techniques where it involves a couple of things. Number one, taking out the saline. Number two, withdrawing the soft tissues using a cannula. So you see that in the background, the blue. That's to develop working space. And then the fiber and glue application. And this is the technique of applying, again, the juvenile chondrocytes and then putting them in a little cocoon. And that's the surgical technique of that. Well, this is the anecdotal here, patient of one. I just want to show you the regenerative capacity of these cells. It's really been... when we're doing our MRI review, it's really been fascinating to see the regenerative capacity of these cells. Here's what I really want to show, the data. Right? The outcome data has also been really good. And so then this is coming out now, the data, and the number is much higher than 58, which is great. So this just continues, no matter how you look at it, to be a viable technology. More data coming soon. Okay. Well, what about the progenitor cells? Here is the thing that we have always been trying... this is our fountain of youth, right? This is the original thought of stem cells, that we can rebuild your cartilage, etc. Well, of course, we're not there. But is there some data worldwide that suggests that we can have an increase in the thickness of our cartilage? And the answer is yes, across the globe. Here is a meta-analysis of 15 randomized controlled trials of MSCs used for osteoarthritis. And we see that 10 out of the 15 randomized controlled trials around the globe did lead to significant increase in cartilage thickness. And this is with functional MRI scanning, right? So this is T2, Degemeric, and other ways of measuring cartilage physiologically with MRIs. Now, I do want to back up, if I can. I'm not sure what button to push. But I did want to say, hey, I won't back up, but I'll say this. What these studies used are dose cells, laboratory-prepared cells. This is not bone marrow aspirate. This is not breaking down our fat molecules, right? These are using cells from the patient that are expanded, so a little different than the things that we're doing in the United States. So be careful not to make the mistake of saying that a lot of our techniques here have been shown to increase cartilage thickness, just for clarity there. This is a meta-analysis of 19 randomized controlled trials. And what they did is they looked at, well, which cell source that you take to the laboratory has been most successful with the regeneration of some cartilage thickness? And the answer is the adipose-derived cells. And this is actually really important for a number of reasons, mostly for the scientists in the room. But the thing at the bottom is also really important, and that is the dose. Because there is a dose threshold, and I'm going to show you some different techniques the bottom line is we think that there is going to be a dose that is going to be necessary to be able to give us this effect. And somewhere right now, that's harboring around 50 million cells. Well, why is that important in the United States? And the answer is there's a couple of companies now that are ready for their phase two clinical trials on this. And then the question is, well, how are we going to put these trials together? What are we going to choose as the dose to start? And you see this worldwide data provides us the source of data to begin planning these clinical trials. Why is it important for adipose tissue? Real quickly, it's because of numbers. When you expand cells, you can only expand them so much. Because if you do too much, they're going to lose their biologic activity. So starting with a greater number of cells at time zero is really important. And it's the reason the worldwide literature has really swung to the adipose-derived cells. I want to... Well, that did it on its own. And again, have... There we go. I just wanted to show you this. It's only because it's just a reasonable trial. It's just a case series of 27 folks with advanced osteoarthritis. This is from Australia, okay? But I wanted to show it to you because of two things. Number one, there's the MRIs. These are what they're looking at and measuring as far as the cartilage thickness. So you can draw your own conclusions if this is relevant. But this is something. This is where the field is going. Second, this is using optimization of these patients with surgery. And so then this is really making sure that their stability of the cartilage, the meniscus, the inflammatory burden of the synovium, it's all done to prep and to prepare the patients for their cell therapy part of it. The second part of it, many of these trials that I'm gonna show you with the best evidence are autologous trials, right? Using the patient's own cells. And that's what's going to be happening first, kind of, in the United States. And I'll clarify. But using the patient's own cells, sending it to a company, then by a laboratory, getting a dose of cells in a vial, and then being able to inject that. That is the next stage of events in the United States, which is already going in other countries. So here are the randomized controlled trials. These are three examples of high-level trials. Level 1, where they showed, again, decreasing pain, improved function, and improved cartilage thickness. Kind of a little bit of how it's done from the MRI analysis perspective. So there's quite a lot of literature out there. Obviously none from the United States. But we have the companies on board to begin this process and the trials. So if you feel that you want to do that, your site can be a contributor of a trial for these companies. I'm not gonna spend much time on this. We're trying to do this in the United States way, even though this is still even a little bit controversial with regards to the FDA. So we have to do this under a clinical trial. But the bottom line is, we're preparing the cells. But we're not counting them. So this is the same technique. I'm not gonna bore you with the same technique I showed you with the juvenile chondrocytes. But if I can keep this going, unsuccessfully, I'm just gonna pass through this. There we go. So per the FDA, we cannot have these cells down to the cellular level. And AKA, we cannot count them. So we've done lots of studies with fat. And we can infer that these cell doses are around 8 million. But we don't really know. So then the question for all of us is, is this sort of technology gonna be enough? And I'm personally doubting it. Because 8 million cells here, that's nothing in comparison to the 50 million cells, which around the globe has shown most of the effect. Yeah, we have some improvements. This is a randomized controlled trial compared to the micro-drilling with the pain relief. But the most important part is the structural part of it, where we're really seeing that we could have better restoration of that cartilage in a physiologic way in comparison to its neighbor in comparison to the micro-drilling, which we know is not a lasting cartilage solution. So then this is maybe an incremental thing. And then our big question is gonna be, if we use a big dose of cells, can we even do much better than this? One I really tell you about a couple of things happening in the United States. So everyone is up to date with the United States technology. We claim this is a technology out of Mayo Clinic, where this is the first, certainly, in the United States to use allograft cells, right? This is allograft adipose derived cells. And it's a co-culture technique of using some of the patient's own cells. So it's something done all the time in the laboratory. And it's really cool to see that this technology is going forward. Here's their initial trial. This still, of course, has ways to go in this phase 2 and 3 trials. But nonetheless, their initial data of trying this co-culture technique was very successful. And so then this is going through the FDA process. And if you are interested in this technology, then contact the Mayo Clinic. Dan Saris is running these trials. One thing that's in a lot of our centers is this trial. So this is phase 3 FDA trial. And they are actively looking for new centers. And our center is just going to be starting this as well on their phase 3 clinical trial. Cardostem is a technology from Asia. And what this requires is two things. Number one, wow, brand new leap of faith of using 50 million cells. There's that number again. But it is allogenic umbilical cord cells. Holy cow. This is a big change for the United States and to be really looking at this technology. So I think that that is really a cool next step. We're getting there. We're getting into the world's technology. That is here in the United States under review. And if you want to participate in this trial, you can contact the company. The part of it that shakes a couple of us in the audience is that this is kind of wide bore micro-drilling. This is not holding back. But this is creating big holes in the subchondral bone because this technology requires cells to migrate from the subchondral space. And at the same time, also, it probably decompresses areas that in certain patients with osteoarthritis cause pain. So however you look at it, it is a big deal. We're really messing with the subchondral bone. But boy, look at the data. The data is the one that we should look at. So maybe we have to reframe our thoughts on the subchondral bone when we use the cell therapy. This is something that I think Steve brought up, which is the Agile C. This is an FDA approved in the United States. This is usable. And this is kind of a biphasic. It's coral. It's aragonite. But it's interesting because this is cell free. This is the reason. It still took a long time to get through the FDA. But it was the reason probably it did get through the FDA is there's no cells that are associated with this. So this is drilled into the subchondral bone and placed. And again, because it's biphasic, there's part of this that tends to reconstitute bone and part of this that tends to reconstitute the articular surface. So again, available in the United States, not under trial. You can use this as surgeons. Data is pretty impressive. From their initial trials, a lot of this are kind of, quote, company trials, but a very good investigator. So I do not want to downplay the data. The data was pretty exceptional. I think the question is, and maybe we can have the panel respond or you guys respond, and that is, this seems to be a really good solution for isolated treatment of chondral defects. The FDA says that we can use this also for the treatment of, let's just call it, regional arthritis. But is this really going to do that? And you see the upper picture there. We have two holes with a bridge of arthritis in between. Is that going to really refill that? I haven't seen a whole lot of data. I just want to be transparent about that, be careful, in that we think that this can just resurface our osteoarthritis. But this belongs in our thought process of ways that we could treat patients with arthritis. And again, because they have data to support this. The data has been impressive. And the data has been impressive with regards to their MRI fill. And so then, if you look at how much cartilage fill that they have with this, this is impressive amount of it. So again, I think there's enough data to suggest that this is a very reasonable thing to consider. But again, where's the line between chondral defects and osteoarthritis and the ability for this particular implant to bridge that? I'm not sure on that one. So that's it, in summary, that these new techniques are, A, all involving surgeons, and all involving removing calcified cartilage layer, optimizing the environment. I think, to be honest with you, there's a really good strategy. That's where, personally, anecdotally, I've had the most results myself. And just injecting cells has just not been the same. I'll just say that with the trials. The other thing is that we need dosing, right? And that's coming. And again, I know that everyone feels that the United States is lagging behind this. But I wanted to tell you, again, it's coming here, right? That there are these technologies, and they are an FDA trial. So this is, at least, good that we're going to be able to use these somewhat soon. And we could use them now under FDA trials. So feel free that if you have something that you feel would fit into your practice, you can contact the companies that are undergoing their FDA trials. Because they're always looking for additional centers. So thank you guys very much. That's all I want to say this morning. And I don't know if we have any time left. But if there is, let's open up to questions. We're at time. OK. I think all of us can stick around down the podium here. If you have questions, I don't want to keep you from your next talk if you've got places to go. But thank you, everybody, for attending, especially at dark 30 in the morning on Saturday. And we'll hang around for a little bit to answer any questions. Thank you very much. Thank you.

orthobiologics

Steve Weber

FDA regulations

biologics

orthopedic treatments

HCTPs

361 products

351 products

homologous use

minimally manipulated

regulatory compliance

ethical use