Thank you. I've got an 11 o'clock flight to get back to New York. I'm going to do an ECL, PCL, MCL, route repair, you know, starting at, hopefully by my, so my, you know, they should land at noon. I'm praying the flight's on time. Yeah, I was getting nervous about doing my ICL. I think that's, that's far worse. It's like, if there was a flight. There's a lot of ways for that to go safely. Yeah, I know. Dare travel is never... Here he is. This is the clicker, I'll give it to you. Okay. I can't get you. You're here. You made it. That's your site key. If you're off set bullets, the big cheese wasn't here. Okay, I'm sorry. I went back to one side of the camera. All right, if we can get everybody in that wants to be in. There's one. Well, thanks everybody for coming. This is the ICL on biologics. And I'm proud to have a great group of people, present company accepted to talk about biologics in orthopedics in 2025. So without ado, our first speaker, Scott Rodeo, that all of you know well, that's gonna talk about cell therapy and rotator cuff repair. All right, good morning. I'll try to move through this. I thought I'd put in some introductory type of material here on kind of cell therapy and we'll focus a bit on tendon here. So the disclosures, it supports our laboratory research here. So I always think it's good to start this whole biologics here almost kind of sets the stage. And what are the targets we're trying to treat? And I kind of listed all the different processes here that we could potentially affect with biologics. Cell proliferation, matrix synthesis, cell migration, angiogenesis, matrix remodeling, inflammatory mediators, major stenosis set for mediators. And these are all important, all relevant, but they're all really different. Maybe in fact, we just want to stimulate the intrinsic stem cell niche. So just that's kind of maybe frames the discussion that we started here. At the same time, in addition to identifying the biologic target, we needed to find the composition and biologic activity of our different biologic treatments, whether it's PRP or cells from various sources here. Only then can we match the desired biologic agent with the biologic target that we're trying to treat. Certainly one size did not fit all. I know the same biologic preparation PRP or cells wouldn't be expected to have the same effect on diverse tissue types. Obviously acute versus chronic processes, very different biology, gender, age, all those things are probably important here. So I'm gonna focus a little bit here on nutrient cells and in rotator cuff in particular, and some general thoughts about tendon, but we'll kind of focus on the rotator cuff. Obviously, cuff pathology has always thought to be sort of a degenerative pathology, but in fact, we're learning that in the setting of tendinopathy, there are immunocompetent cells and activated stromal fibroblasts in tendon. But the point here is it's often a non-resolved or chronic inflammatory process. And I mentioned this, I think that's some of the processes biologically we're trying to affect with our orthobiologics is the underlying inflammatory environment and chronic unresolved inflammation here. So, very complex biology here. At the same time, we know if we repair a tendon, a bone, that healing is a slow process. And we don't recapitulate that normal insertion site. So it leads us to, can we use cell therapy to improve healing? So you and I as clinicians have this there, and we go ahead and do a repair, and we'd love to have it do this, and then you form the normal insertion site, which is actually a highly complex tissue. But in fact, instead we get this fibrovascular, it's kind of scar tissue. They have probably inferior material properties and likely an important reason why we have these rates of re-tears or failed healing. So this leads to cell therapy approaches. I put this in to remind us all about the aggressive marketing, the indiscriminate use of unproven and often unapproved therapies that's out there. We all see these advertisements, but our patients come to us, of course, having seen these type of things here. And the point is that we clearly, us in the room, if you're interested in this area, we need a rigorous, evidence-based approach. And I try to write an editorial each year in our sports journal in this area, kind of bring it up to date with the current status and where we are and the need to really have a responsible approach here. So why might we use cell therapy, and particularly in soft tissue repair and rotator cuff in particular? Well, we know cells produce a number of important signaling molecules, cytokines, anti-inflammatory mediators, immune modulating factors. And these signaling factors do in fact stimulate important biologic activity, seeing here, matrix synthesis and remodeling and adrenogenesis. So again, back to those biologic targets we mentioned at the beginning. We know the cells play work via paracrine mechanism. The secretive molecules from the cells affect the local environment, may affect both local and maybe even distant cells in the environment there. Importantly, there's very little data to suggest that the cells we put in actually engraft into the healing tissue and we'll make that point again in a moment here, I think. So just to set the stage, what can we use as clinicians? Well, obviously we can use cells from bone marrow. We can use actually cells from peripheral blood. We can do a lipoaspirin and use microfragmented fat. I have no relationship with any of these companies if you see anything here. So this MFAT, microfragmented fat, should be distinguished from the stromal vascular fraction. The stromal vascular fraction requires enzymatic digestion, not allowed by the FDA now. It can only be done under an investigation of a new drug, IND, or maybe an IDE if you have a device to do this. But it can only be done in a trial. And certainly adipose-derived stem cells requires culturing. So we're left with this microfragmented fat. These perinatal products derived from amniotic fluid, amniotic membrane, buccal cord bloods, placenta, all these different materials, they're out there. In fact, they do contain some immune-modulating proteins, but essentially almost zero viable cells and probably truly zero that qualify as a stem cell by any leap of the imagination. All these preparations, these perinatal formulations, since the end of the FDA discretionary period, May of 2021, these are essentially off the market. These can only be used now under an IND or a formal clinical trial. So for you and I, most of us, we can't use these. And they are still being used. I see patients and athletes that have been treated with these things, so be careful here. Just to set the stage, you're worried it's all about stem cells. Well, what really is a stem cell? Are there any stem cells that you and I can truly use? Think about the basic stem cell criteria very, very simply. Obviously, unspecialized cells, but even more importantly, the concept of self-renewal. A true stem cell undergoes asymmetric cell division. That's an important concept here, where one copy of the cell can go on and differentiate, but one copy stays in the daughter cell. If that didn't happen, you'd deplete your stem cell pool, right? So this asymmetric cell division is a very unique feature that doesn't happen in most of the cells we use. And then, of course, this multipotent differentiation capacity. I would submit to you that the currently used sources that we use now, very few of any stem cells by any formal cellular or molecular criteria. This whole concept of the progenitor cell probably goes back to Friedenstein and Owen in the 1970s, but a lot of us, of course, credited to Arnold Kaplan with his seminal 1991 paper where he defined this progeny. Some nice work with Scott Bruder, who's here, and Scott did some nice work over the years with Arnold Kaplan. This is the concept back in the 1990s here, where this progeny can differentiate into various specific cell types. In more recent years, actually this is kind of a well-cited 2017 paper, but really it's 2010, I think, that Arnold kind of started to teach us all that the biological cells, effective cells, seem to do more to the production of these anti-inflammatory and immune modulating factors rather than the cells themselves dividing and differentiating. So he suggested that MSCs should be used to define a medicinal signaling cell in recognition of this fact that cells act in this parakeet fashion here. So cell therapy for soft tissue repair, our topic here. Great area that has great potential, but I would submit to you a lot of unknowns. I want to make a couple more points to kind of set the stage when you think about cells. It's such a hot topic and a growing area. The minimally manipulated cell preparation that we use need to be distinguished from cells, from sorted, culture-expanded cells. The term stem cell, I submit to you, should not even be used when discussing current techniques of cell-based therapy. George Musler, some years ago, coined the term connective tissue degenerate cells. This is a population of cells that exist in many tissues and do, in fact, have some ability to differentiate, but they have a more limited repertoire. You wouldn't call them a true stem cell. They don't undergo asymmetric cell division. You can measure connective tissue degenerate cells by measuring colony forming units and cultures. This is probably a better term for us to use. But I submit to you, we have almost no ability to use a true stem cell by any criteria here. Again, it's a classic definition. The S is stromal cell, MSC is stromal cell. It goes back to the classic definition of 2006. That is based on culture-expanded cell. That's very different than the cell populations that we use in our operating room and in our clinics from freshly harvested tissues. So a term minimally-stationed really can only be used to refer to culture-expanded populations of cells that meet these criteria from the International Society for Cell Therapy. It's a Gomenici paper in 2006. As I also mentioned, there's very little evidence to suggest that the cells that we inject engraft. Again, back to the current understanding of how the cells work via this paracrine mechanism by producing various signaling factors. You know, this multi-lineage pathway that we all have been looking after, you know, 25 years. We don't even know if that happens in vivo. It's all largely based on in vitro work. So we don't really know if it even happens in the body, quite honestly. And our regulatory environment, of course, prohibits cell sorting and culture expansion. So, again, back to the importance of distinguishing these cell populations from freshly harvested tissue that are different than culture-expanded cell populations. We can't do so-called manipulation. We can't do cell sorting or culture expansion. And these culture-expanded populations, they're fundamentally very different than the starting population of cells that we start with. So we harvest bone marrow or adipose. That's your starting population. You go and expand those in culture, certain cells will take over the culture. Some cells die, so they're very, very different populations here. You know, our cell populations are very poorly characterized. We still need better markers of purity, potency, biologic activity. All of this, you know, that foregoing kind of suggests that soft tissue healing and tissue regeneration via cell therapy, probably a little bit unpredictable. I think it needs more work, more questions and answers here. So, now, focusing more on the clinical side, there is some data on rotator cuff. We'll go back to a well-cited paper from Philippe Pernigou 10 years, 11 years ago now, using bone marrow aspirate to augment rotator cuff repairs here. 90 patients. Essentially, he found distinctly improved rates. At six months, healing rates like 87% versus 2 3rds. At, or anyway, at 10 years, 10 years falls to the important data. Intact cuffs in 87% versus about half in those patients treated without cells, just a standard repair there. And cuff integrity was better over the long term in those patients who received a higher number of cells. He used colony forming units to define the number of cells. Note that that number of MSCs, 51,000, that's very, very small. But he had some positive data. Similar study, 70 patients, a group in Korea, using adipose-derived cells, half of whom received adipose-derived cells. Again, the failure rate is about half, 28% in conventional repair versus 14% in those who received the cells. Now, sometimes these don't correlate or translate into clinical differences. We often see the mismatch. But clearly, some structural changes here. And then, Brian Kwon, the group at Rush, kind of similar trial. Last year, 91 patients. Again, pretty standard cuff repair, concentrated bone marrow aspirate injected there. The number of cells, they averaged about 44,000. So again, our trials try to put in 10 million cells or five million cells. But they found a lower retail rate as well, 57% versus 18%. But it didn't translate to a difference in their clinical outcomes as far as patient-reported outcome measures, no difference in overall failure rate. So they concluded, in fact, the cell-augmented cuff repair may improve structural healing, but didn't change your clinical outcomes. I would submit to you a longer-term follow-up. That may change. We all agree we'd rather have a heel tendon than not. Have a lipogems, Pietro Randelli in Italy. Small study using the autologous microfragmented fat in the lipogems process. 44 patients. Single-row repair, quite simply, 22 patients had a repair, 22 had the cells, the adipose, injected at the time of surgery. What they found is a difference only at six months in favor of the treatment. And just based on the constant score, you see in the graph at the bottom. So at six months, the groups differed. But later on, there's no differences. No differences in the rupture rate based on MRs. They concluded that intraoperative injection of autologous microfab may give you some short-term benefit, but no real long-term outcomes. So partial tears are a challenge for all of us. And there's an ongoing trial using adipose-derived cells, deviating the stromal vascular fraction. This company in Generon, which you might know the relationship, that small study they published here. These are uncultured cells, but the stromal vascular fraction, 16 patients. 11 received the cells here. So you can see the number of cells injected. This is 11 million. So contrast that with those other studies where we measured cells based on colony-forming units. So they did find this small trial. Better outcome scores as far as the AACS score in those patients treated with cells. This is a non-operative, just single injection, partial thickness cuff tears. The green line is those patients treated with cells. So they have an ongoing trial. So it's a small, early data here. They have a randomized trial going on now. So we'll await further data there. Gus Mazzocca of Harvard now, who's popularized looking at Bursa as a source of degenerative cells. And if you just compare Bursa with concentrated bone-raspid there, this is looking at colony-forming units. Pretty high number in the Bursa. It's kind of showed you can measure colony-forming units by you plate the cells, culture them, then you stand with crystal violet. He's just shown measuring the colony-forming units and based on some standard cell surface markers, CD7390105, which are a place to start. Necessary, but not sufficient. But another way to define these cells. And then a small animal model, mouse model, wrote through the cuff repair, Bursal cell, just even improved healing. So some early data, and Gus continues to work in this area here. This I just saw last week. This is just our sports medicine journal last month. A group from Korea taking autologous skin cells. They took a skin biopsy, cultured the cells over four weeks, and then did a cuff repair and injected the cells at the tendon bone interface. And they found the re-tear rate was lower based on MR, five and a half percent versus 24%. So again, a structural change. But like the other score, the other studies, didn't really translate to a difference in your patient-reported outcome measures, listed there, your ASCS and constant score. No difference between the groups in these clinical outcomes. But again, some structural changes. When you use cells, the other question comes up is, should we have a carrier vehicle? And this was also a recent paper in that same group in Korea, looking at, this is in a Rambam model. But using bone marrow aspirate, I've always thought we should have some type of carrier vehicle. And they looked at something called polydeoxyribonucleides, one of these nucleotides, versus atelocollagen as carrier vehicles. And simply, rabbit study, cuff detachment, they did a late repair and had different groups. You see here, bone marrow aspirate alone or with the different carriers. What they found essentially is, if you use bone marrow with this atelocollagen, atelocollagen is just collagen removing the telopeptide, so it makes it less immunogenic. If you use that collagen carrier, they have better results there. Better gene expression histologically. See at the bottom, biomechanically it was better. And in fact, just bone marrow by itself did have an effect. You can always wonder if it stays there, does it just disperse and leak away? And so think about carrier vehicles in some words. Just briefly, some clinical trials ongoing. Each assess, this is one using stromal vascular fraction. This is under an ID, investigation of device exemptions. We could use enzymes to digest the fat here. On double-blind trial, hard to enroll patients because everybody, they have to undergo the lipoaspirin, only half of them get the cells back. In the future, I'd be smarter and do a two-to-one randomization because everybody's like, no, no, I want the cells, I don't want to be in the trial. Hard to enroll patients. So we do a standard lipoaspirin and then just inject the cells at the repair site and we use MR and ultrasound. This is ongoing now. We put them in the repair site and in the muscle. Another similar trial that I have finished just in FDA is a phase one trial. This is using umbilical vein cells to modify with a particular gene. This is 20 patients, actually 21 we enrolled. This is a safety study. These cells derive from human umbilical vein and they're transfected to a particular gene. It's E4RF, what is that? Essentially, it confers cells with sort of anti-inflammatory properties. It makes them stable in culture. This is worked out by a company called Angiocrine who they funded the research. I have no other relationship with them, but so we use these cells. Here we put 7.5 million cells at the tendon bone attachment site and then 7.5 in the muscle is just injecting the cells to the tendon and the muscle. Like since I finished the repair, put a spinal needle into the sites, close the portals and then inject the cells. And here we used a, I thought I'd show up, we used a thrombin and plasminogen carrier. I think you need, again, a carrier vehicle to localize the cells here, so. So bottom line, cell therapy, augmentation, a curve repair, I think promising, but further study is certainly needed. Lastly, some future approaches. I think the ability to stimulate the intrinsic stem cell niche has tremendous potential. We know these cells exist, so-called pericytes in the walls of capillaries. Classic study by Marion Young, 2007, kind of identified these progenitor cells in tendon and in more recent years, Charles Chan and Michael Longacre at Stanford have looked at these skeletal stem cells. We wrote a little recent review on this as well. But suffice it to say that these quericin cells, they're there. If we can learn how to stimulate these cells, that might be a whole new avenue here. Obviously, exosome, you've heard a lot about it. Just a brief mention here, these bilipid membrane particles, these blobs that come from cells. Essentially, exosomes contain the goody of the cell, the cargo of all the different cytokines, microRNAs, and other factors in the cell. But the goal, the value of exosomes would be you get the beneficial effect of cells without all the issues that go with cell culturing, manufacturing, and things like that. But the challenge is, of course, the lack of standardized procedures, manufacturing, quality control, determining purity, potency, quality, all those things need to be worked out. There's some ongoing clinical trials, but understand that there are no approved exosome therapies in this country at this time. I get this about every two weeks, I get this email, and maybe you get this thing. These blood cells and exosomes. It's the world that we live in, obviously. Where's our field headed? I think ongoing study of the role of immune cells is an area that we're working in and others as well. Immune cells have a fundamental role in tissue repair, looking at, in particular, macrophage subpopulations. It's complex. I think we know that these orthobiologics do have profound effects on local immune cell function. I think using single-cell analysis now to really characterize the cells we put in our patients. The biggest issue with this area of heterogeneity is really always knowing what we're putting in our patients, cell types, cell numbers, and certainly the transcriptional state of our cells. And so maybe in the future, gene editing techniques and things like that. This area of induced pluripotent cells is sort of making a comeback. Trials in Japan, this goes back to the 2012 Nobel Prize for Yamanaka genes. For genes, we can take a mature cell, blood cell or skin cell, transfect and make it into tantamount embryonic stem cell. Classic work, famous paper in 2006. Now there's some resurgence of interest in this area of some trials going on, particularly in Japan. How might we move this field forward? I think we need to identify biomarkers to characterize what we're putting in our patients, whether it's blood product, cells in bone marrow, adipose, whatever it is. Maybe changing the regulatory environment that allow us to, quote unquote, manipulate these materials will help. Maybe eventually we can use enzymes to digest adipose tissue, do cell thwarting or culture expansion. I think importantly, we need methods to select the cells we want and eliminate those we don't want. That takes some understanding of what cells those are. No area lends itself to this whole area of precision medicine better than probably regenerative medicine, managing the right patient, right drug, right time. I think on the horizon, again, exosomes, methods to stimulate the intrinsic stem cell niche and understand the role of immune cells. Lastly, my current approach is some thoughts for you as a clinician, optimizing tendon healing. So I think we should encourage patients to stop smoking. Think about serum cholesterol. Hyperclostidemia has an adverse effect on healing. Diabetes, we know, has an adverse effect. Vitamin D. Use vitamin D supplementation. That's easy and fairly cheap to do. Glucose control is important. Statins may have a positive role in tendon healing. If the patient's on statins, maybe we can leave them on it. NSAIDs, controversial. I do try to minimize them, at least for my bigger tears, older patients, things like that. Using PRP, the existing data policy suggests a leukocyte-rich form. If you play what you want, it's higher click. You'll play a number maybe more important than leukocytes. Again, a whole other discussion for another day. We've seen that there's some problems with cell. We need more work as far as in both bone marrow and adipose tissue here. PTH, parathyroid hormone. You know, healing of the cuff comes from bone growing into the tendon. You can make a case for using PTH. There's some animal work from our lab and others. Problem is getting it approved. I've tried. Usually time being sure it approves after like four months post-op, so hard to do. And then I'll stop there. Thank you. Any questions? There he is. Yeah. Take a seat around. Yeah. Thanks, Scott. As always, great talk. Next is going to be Ken Zasloff, who's going to talk to us a little bit about PRP. Thanks for all getting up so early. This is a big crowd for a 7 AM meeting. Thank you. So I'm here from Lenox Hill Hospital in New York. We're going to talk about PRP for the treatment of NeoA. I don't have any specific disclosures related to PRP at the moment. So PRP is more than just platelets, as we know. There's at least 1,500 unique proteins. The person who gave me this slide years ago is sitting in the front row. But I want you to see, when we separate out these things, we have a platelet-poor plasma, which we used to think we should throw away. We'll talk a little bit about the benefits that might be in there. And then what we're talking about is mostly in this buffy coat. And then the red cells are at the bottom. And we have a lot of anti-inflammatory factors and a lot of anabolic factors. So why is there a benefit effect? Why do we think, scientifically, based on in vitro and animal studies, that this would work? And it's clear that, for many, many studies, we've shown anabolic benefits, stimulating cell proliferation, stimulating the production of better cartilage matrix, even causing synovia sites to stimulate more hyaluronic acid. That's all been shown by Lisa Fortier. And then there's been many, many studies that have shown the anti-inflammatory cytokines, specifically IL-1RA and STNF-alpha receptor and interferon, all of which can decrease the effect of the cytokines that are being elicited that are inflammatory in osteoarthritis. There's a lot of clinical evidence. There was prospective studies that were done in the early 2000s that clearly showed potential benefits. And now we have level one evidence, of course, with randomized control trials. And really, we've had at least over 40 systematic reviews looking at these various trials. And here's one, for instance, with 14 randomized control trials, over 1,400 patients, comparing PRP both to saline placebo, HA, and corticosteroids. And at 3, 6, and 12 months, at all time periods, PRP clinically had a better effect on the PROMs than all the other treatments. And then at the various subtypes, different other treatments were second and third. And the conclusion of this study was that intraarticular PRP is more efficacious in the treatment of NeoA than all these other treatments. And then here's a much bigger level one evidence, systematic review, done with over 30 randomized control trials from throughout the world with over 3,400 patients, again, looking at both WOMAC and VASc scores versus placebo, corticosteroid, HA. And in every one of these time points, 3, 6, and 12 months, PRP performed better. And then at the different time points, obviously, early cortisone was better as a second, and later on, HA was better. But notice that at the 12-month mark, the second best was placebo. And we've learned this from Dr. Cole's study, that placebo is an incredibly effective, or saline placebo can be an incredibly effective treatment as well, which is why it's very hard for so many cell studies to beat that placebo. The AOS technology review, the AOS, you know, is always extremely cautious about biologics. We've come a long way in the last few years with Jason being the chairman of their department and their subgroup on biologics. But even back in 2021, they showed that there were eight high-quality studies versus placebo, over 18 versus HA, and even a few over NSAIDs. And that all of these showed statistically improved treatment with PRP, but they felt that the populations were not big enough yet to recommend, and they felt larger studies were really needed. So we've also got consensus statements from our peers. The NFL Physicians Organization put out a clear statement that leukocyte-poor platelet-rich plasma, in their mind, should be recommended for NeoA based on the number of studies they reviewed. And then the ESCA Orbit series had a very large RAND-type consensus, which gave a group, sorry, a grade of A for leukocyte-poor PRP for NeoA. But all of these studies really just looked at, did you use PRP or not? And as you know, there's quite a heterogeneity. Not only does what your PRP have in it vary by person, it varies by time of day in the same person. It varies by the diet you may have had. It varies by the amount of exercise. So we really need to more accurately look at what we're injecting if we want these studies to have more meaning, especially to move towards what Scott mentioned, which is more personalized treatment. So the most basic discussion should at least be to know how many platelets you're injecting, how many white cells, how many monocytes, maybe even within the white cell population. These things may be, we feel, important, so we at least have to be measuring them. So those of us in the Biologic Association and many more people now around the country are starting to at least run tabletop hemoanalyzers at the time of our PRP injection. So we look at the whole blood and we take a very small sample. You can take just a few microliters and you can run these things on these tabletop things immediately within minutes, see how many platelets you have, both in the whole blood as well as in the PRP injectate. And then you can more appropriately define it. So why is this important? This was a well-done prospective randomized study that got a lot of hype in the press and was published in JAMA, which showed no statistical difference between the use of PRP and saline placebo. And you just saw all these studies that I showed that showed a difference. So why was this very well-run study from a good group of researchers so ineffective? And we think it's because if you look at the machine they were using, it's a machine that basically gets 1.6 to 2x max concentration. And if you looked at the number of platelets, they were not really actually characterizing that. And so we think that's why these patients failed. The machines we're using now are getting anywhere from three to 10x. And we'll talk about what that means. We're really less interested in the concentration than we are in the actual number of platelets. So there are more detailed studies now that have come out. The KSSTA study by Chu et al showed that if you do characterize your PRP and you take a 50cc blood drawer, do a two-spin technique, and end up with over four billion platelets and inject that in a five cc injection, then you look at the number of platelets in your CVC and you multiply it by the number of cc's and then by a billion, and then you're gonna get the number of actual platelets, which in this case, 4.2 billion. And he not only had significant benefit at six and 12 months, but as far out to 60 months, five years. Second big study that's now been quoted a lot is by Bancel et al. And they looked at taking, this was in science, sorry, nature, and randomized 75 patients into a PRP group and a monobase group, 60cc blood drawer, and they ended up with 10 billion platelets and eight cc's on a regular basis. And he would inject this in, and they noticed statistically significant MCID at one year, as well as lower levels of IL-6 and TNF-alpha in the PRP group as quickly as one month. So when you're starting to get doses like this, we might start to see better benefits and longer acting benefits. People often ask me, can we proactively improve our PRP? There's been a few studies looking at this. There's one in arthroscopy in 2019 showing that exercise, both strength training as well as aerobic exercise for 20 minutes or more can increase your platelet, the amount of platelets available at any moment in time in your body. So 20 minutes of vigorous exercise seems to have some statistically significant benefit. There's a lot of other studies showing us things, but these are very low evidence studies with very small populations. So we really can't promise you that these make a difference. Certainly eating a more Mediterranean diet and good vegetables versus a fatty diet, probably in my mind, you know, Jason always shows pictures. If you have a patient who had a big fatty meal at lunch and then comes in, it's a very not good looking PRP. And we probably don't wanna be injecting fat, which of course can be somewhat inflammatory. So, but all of these are really low evidence. So right now, as Scott said, I do tend to tell patients to not take NSAIDs for a few days before and for a week after. Again, not great evidence for that yet. We tend to certainly tell them to avoid smoking if they can and caffeine the day of the injection. But again, these are all low level studies and more work to be done. The whole dogma that we have that leukocyte rich is better for tendons and leukocyte poor is better for Neo A is also now coming under question. There's a number of things that we've seen over time. The first is that there were a number of studies on what we call autologous protein serum, where we're doing the double spin technique with glass beads, very similar to the orthokine work that was done in Germany by Peter Welling. And all of those end up with a very leukocyte rich PRP and yet they're very successful. And probably because the leukocytes that are really more predominant are the monocytes. So if you could move the monocytes from M1 to M2, that may be more importantly than the actual number of total neutrophils. And Tom Buchheit, who was at Duke till recently, when he just recently left to set up practice somewhere else, had a very interesting feeling. He said, I believe don't fear the leukocyte. When you look at injury models, there's always an inflammatory reaction immediately after injury, which is then the precursor for the anabolic reaction that comes next for healing. So it may be this is why that white cells may not be bad. These are all theories at this moment. But certainly there's been a number of randomized control trials now. One important one out of the Rizzoli Institute that showed that when you do a randomized control trial of leukocyte rich versus leukocyte poor PRP, both of them give good PROM results and no statistical difference between the two. So that may not be the main issue, the number of white cells. As Scott said, it may be more about the platelet dose. And then as we do more studies, we may find, as Jason will talk about, even more important cytokines that are the actual factor that make the difference. So what about randomized control trials comparing PRP to PRP plus HA? That's another thing that's starting to come out now. There are at least two good studies that do show statistical significant benefit in PROMs and longer lasting for up to a year when you combine it with HA. But there's also a study or two that shows no statistical difference. So more work needs to be done. It may be that the HA acts as a scaffold to help hold the PRP in place. It may be something to do with activation. We don't really know. Or it may just be that it decreases the immediate inflammatory pain that you feel. I don't know, but anyway, these are things we still have to study more. And many of us now are adding HA to some of our injections. What about platelet-poor plasma? So this is what we used to just throw away thinking it had nothing. But in fact, there are a number of very important proteins that are in platelet-poor plasma that do have potential anti-inflammatory and pro-anabolic effects. This is a slide which I got from Jason actually shows the number of proteins that we can concentrate with different generation one and two filters. And there's a number of companies now that have manual filters to allow you to concentrate the PPP and then inject that at the same time as the PRP. We'll look at a few of the important molecules. One of the most commonly studied and quoted one is alpha-2-microglobulin or A2M. It's a very potent protease inhibitor. So it helps to stop the MMPs from destroying cartilage or degrading the articular cartilage matrix. It also has anti-inflammatory effects. And if you look at these filters, you can see that we can statistically really improve the amount of A2M in the injectate after concentration. And in fact, there's over five times the amount of A2M in PPP than there is in PRP. And you could get to a ratio of anywhere from 100 to one, which is what has been shown to make a clinical effective difference. Sorry, let me get back to here. The next one is IL-1RA. We know how important this is in BMAC. We also know that the orthokine work that's been done by Peter Welling has shown that with his double spin and glass bead technique he gets a significant increase in IL-1RA. And this is extremely strong anti-inflammatory effect. And we can also get this from our PPP. And it's again shown what I mentioned a moment ago, that you need a ratio of at least 100 to one between IL-1RA and the IL-1 protein. And we can get that with these filters. In fact, some of the glass beads and polyacrylamide beads, things that are available in Europe, can get up to 1,000 to one ratio. And that can make a big effect on our anti-inflammatory benefit. And last is STNF receptor concentration can also be increased in the PPP. And this is another strong anti-inflammatory against TNF alpha. So what are the open questions that are remaining? We have a lot of work still to do. What makes some patients responders? I mean, every study you look at probably has 20 to 25% non-responders. And then everyone else seems to respond fairly well. And this is to all the various things we've discussed today and we'll discuss a little later with Jason. So what cytokines and factors in the PRP are essential? Which ones elicit the response? We're starting to get some early literature on this from both Scott, Jason, and Bert Mandelbaum. But it's very, very small populations. But we'll talk about in a moment our collaborative that's working on this particular issue. Also, how can we augment the patient's own PRP or blood to have these essential factors once we know what they are? And then what is the actual concomitant benefit of HA and PPP? And should we all be using all three of these as a triumvirate or a trilogy, as Bert calls it, when he injects some of his patients? So the Biologic Association, and you've got three of the past presidents here speaking to you today. We've been working on a project with J.T. Tokash at the head at the Mayo Clinic and all of these six important institutions. And now the military has been added as a seventh institution. And we're looking for patterns of factors that lead to success. So every time we inject the PRP, the patients who are willing to be in the study will fill out PROMs at six weeks, six months, 12 months, and 24 months. And we will also injectate a bit of their PRP and a bit of their whole blood, as well as synovial fluid, if they had an effusion at the time. And we're freezing these. And we ultimately just finished setting up this incredible registry and biorepository where we can share samples. And we'll all be sending these samples to, I think, Cedars at first to look at the same group of cytokines and factors and figure out what was in the responders and what was not there in the non-responders and maybe be able to give you more data in the future. So in conclusion, we have excellent preclinical and in vitro mechanism of action data. We have a decade of mounting prospective data and level one studies. We have acceptance by our peer groups and consensus statements, all of which support the fact that PRP is effective in symptom relief and pain relief in OA. Not a lot of data yet that shows any regeneration. But we feel that further quantification and qualification will fine tune on injections with PRP and PPP and ultimately help us get to that point that Scott talked about, which is true individualized treatment or personalized treatment for our patients. Thank you very much. Next up is Jason Drago. Good morning, everyone. Thank you for waking up early here on a Friday. So talk a little bit about new things in cartilage restorations. There's lots to talk about. But I really maybe wanted to start by taking a step back a little bit, because I think the more the literature is going on, the more biologics that's going forward, the more the understanding is there's no perfect cartilage resurfacing strategy. And part of that strategy is maybe this 30,000-foot view when you have your patient there of saying, time out, take a step back, and asking yourself the question as a surgeon, how did this cartilage defecate there in the first place? What can I do as a surgeon not only to resurface, but to change the environment that might be off from the very beginning? And this is the strategy that you can look at it from easy examples or patellofemoral joint, where if you look at the trials coming forward, you see that most of them are reporting their cartilage resurfacing in conjunction with a change of environmental type of procedure. And this could be soft tissues, lateral retinacular lengthening, change of volume. This can be tibial tubercle osteotomy on the previous slide. This can be joint optimization even in our compartments, or medial and lateral compartments. Interesting paper blurring the paradigm here of how we can change things from South America, where they had arthritic pain patients' medial compartment, and all they did is a medial capsular release on those patients that are really tough to get a scope in. And with that and just that, they changed their pain relief substantially. So there's maybe something to this strategy before or concurrently when we are discussing and thinking about our cartilage resurfacing. And obviously, hto is a big strategy, obviously, as well. So let's go over some of the techniques, starting with really what we're going to spend today on, because we can't really go into the osteochondral defects. There's just too much to talk about. But isolated cartilage defects, so this is a patient that we all have. And then the question is, what are our choices? And I put this slide in for, again, perspective of where we're at. Most would say that MACI is not a biologic. And the reason why is because it's adult chondrocytes. And MACI certainly is not the only technique that uses adult chondrocytes. There's a ton of them. But it sets the tone. And if you look at this from a worldwide perspective, it's really the standard of this, just because it's used in so many countries around the globe. So it's important for us, when we're judging our techniques, to say, well, what is the standard? And what is the data? And here's 10 years' data from down below the equator in Australia. And you see that for 10 years, they have really very little degradation of their results and good outcomes, pretty consistently with MACI. OK, sets the tone. Then, new modern MACI, we don't have a lot of data yet. So this is the part of understanding of where we're going from here. You took a real good open technique. Can you do the same thing with arthroscopic MACI? Brand new to the world. The data is not there yet. But that's where this whole ship is going. So speaking of that, then there are other techniques that are fundamentally different, yet similar. And this is the use of the juvenile chondrocytes. And the reason why these grouping of procedures are in biologics is because the cells are fundamentally different. If you look at the mature chondrocyte at the bottom, this is one step back, with much more immatureness of the cells than adult chondrocytes. And maybe many of you say, oh, yeah, right. Yeah, whatever. True. Lots of data. Lots of data we've done in the basic science laboratory to show that these cells are fundamentally different. There's different genes that are turned on, different gene products. And so this is a very different cell population with a lot more metabolic power to be able to produce the extracellular matrix and the cartilage. So it's fundamentally different. The fundamental difference also is that now this is a single-stage arthroscopic technique. And so then that's changed. Now MACI is going along that same way. But this is a somewhat easier technique to do because you're not putting in a membrane and stabilizing a membrane. You're just putting in the particulate pieces. So here's an example of the technique. It's a little bit different arthroscopic setup. And this is also changing with new arthroscopic tools that we have. But bottom line is one of the principles of this, along with all of the other biologics of cartilage resurfacing, is removing the calcified cartilage layer first. And that's the thing that's way back from microfracture. That's what we learned. That was the positive part of microfracture. And so now we're doing it with all these other techniques. And you see it just takes a little bit of work to get these particles in the plane of your cartilage and then putting the fiber and glue cocoon over the top. These same techniques have been developed for the patellofemoral joint. It's just different, right? And kind of spackling on the ceiling, pretty similar strategy to this. And again, this is with the saline removed. But again, all strategies that are doable doable from an arthroscopic perspective. And then we look at the follow-up data. So there's a couple of places in the United States that are doing this. Number one, we routinely see MRIs that look like this. So it's actually pretty impressive to see the restorative capacity on MRI review. Our outcomes data, now that we're having five-year and eight-year outcomes data, all showing very similar. They're showing that it is about the same as the standard, the same as the MACI, right? The data is pretty much mirroring it. So the question for this group is going to be, can it sustain for the 10-year as MACI withstood, right? So that's the part of the data that we need. Beth Schubenstein has some great data. And again, these are hard resurfacing projects, right, to be done at the patellofemoral joint, especially of the patella. And so she's also used this with, again, good MRI evaluation afterwards and pretty reasonable results with a tough study population. So that's where the juvenile technology going to take a two-stage procedure and to make it one, probably the most important change. And longer-term follow-up, though, is necessary before we really switch gears. Well, I wanted to talk about the world stage because the world stage is quickly coming to the United States. I don't know about quickly, but it is coming to the United States. I want to explain it a little bit. I want to explain that the, quote, cell trials, right, that are worldwide have been uniformly positive as far as improving pain, improving activity levels, right? And this review of these high-level trials are also showing that 10 out of the 15 of the randomized trials actually increased cartilage thickness. And that's the difference, right? And that's where we're trying to go with regards to osteoarthritis. But I wanted to produce some clarity in a couple of different areas. Number one, we've been talking this morning about BMAC. We've been talking about lipogems and micronized fat injections. Those are not part of this presentation because they really don't have cartilage regenerative capacity, right? So we don't want to be fooled. We don't want to be fooled with corporate America saying we also have amniotic products, which are coming back through the FDA process. And we don't want to be fooled that they have these regenerative parts to it because that's not what we're talking about, and that's not what these trials do. But what these trials do is have culture-expanded cells, right? So a known dose of cells, and that has been showing to be increasingly successful in the trilogy of taking all three things, right, including improving the cartilage environment. I also wanted to talk about it because there are a couple of companies. And, Scott Brood, are you still here? I can't. There you are. And you may want to make some comments at the end on this, but we all have patients that are in a real tough scenario, and some of them can barely walk. OA has been designated as a severe disease, right? And so then that's an important part of this. But there are some companies that are beginning to, through FDA registration, allow these federal right-to-try trials, okay? And these are state-specific. Not all states have these federal right-to-try. This comes from cancer therapy, life-threatening therapies, where the patients have this right-to-try, and the law protects that. This is being done also with those companies that are going through the FDA process, so there's nothing shady about this, but there's a lot of paperwork, et cetera. So if you have those patients, there are a couple of companies now that, through that process, you can have cultured cells and give them to the patients under this, but it's very strictly regulated with paperwork. It's not regulated by the FDA, but you have to show the FDA the paperwork, so very specific. But I just want everyone to know, right? It's coming in the United States here soon. We heard a lot from Scott about the trials, and then there is a little bit of more of a hedge of using these adipose cells, right? And that's kind of the world's summary statement, is that there's more trials worldwide using adipose-derived cells. And that's kind of what this article is saying, that there is going to be, just like PRP and what Ken said, there's going to be a dose of PRP that we'll be able to say within a couple of years. There's going to be a dose of cell therapy that we'll be able to say within a couple of years. This is the current state of it, around 50 million cells, and the use of the adipose-derived cells. For the scientists in the room, this would make sense. Why? Why is it now becoming more popular for the adipose-derived cells to be part of the literature and the trials than bone marrow cells? And the basic scientists would say that this is a numbers game that's a really important numbers game, because adipose tissue, by its nature, has many more of these bioactive cells. And whether we call them MSCs or stromal cells, they're more in per cc of fat than in per cc of bone marrow. And so if your starting number is higher, you have to have less passages to get to your number. And these cells don't like passaging. They don't like being in culture. They change, and they lose part of their regenerative capacity doing that. So if you're taking a few cells and you're trying to make 50 million, it's a much longer process which changes the cells more. If you start with a greater population, then you have to do less in the laboratory to get to your number. So that's kind of one of the fundamental reasons why adipose tissue is becoming more popular. This is really the proof, the study of the strategy going forward. And again, I want to talk strategy, this and kind of where the world is going with this. And this strategy is a couple of things. Number one, orthopedic surgery and the optimization of the environment, including the first slides that I showed you today, is becoming pretty important in the understanding of getting results. If you have a compartment of the knee and it is rough because there's debris and inflammation, everything going on, how do we expect that we're going to be successful? So optimization, including arthroscopic optimization, that's what this study has done, is fundamentally prepare the joint for the potential of some growth of the cells. And you can see from the MRI in grade four arthritis, it was true with this. Fundamental piece number two is using autologous cells. And for the most part of the world, that's been the biggest thing, is just making sure for safety reasons and maybe biocompatibilities, we don't know everything about allografting, to keeping it more safe. And so all our patients that are traveling, the recommendation at this time is, if you go to another country, make sure you use your own cells for the most part. But then for here, world trials, again, this is kind of an older slide, but it's really showing there is world literature, level one data, to suggest decreased pain, improved function, improved cartilage thickness across the globe. And this is where we are going. Okay, we're not there yet in the United States, but you see, every year, we get a little closer to this goal. In the United States, also through the FDA process, this is Dan Saris' work in Mayo Clinic and the Restore Project, sorry, Reclaim Project. And this one is using a combo of both the patient's mature cartilage and allogenic adipose-derived cells. So this is one of the first in the trials of using non-autologous cells. And their initial study results have been great. They're onto the hip now and doing hip resurfacing. So stay tuned for this. It's not available yet, but their next level trials through the FDA is going to be coming soon. So anyone interested in this should contact Dan Saris, but a very promising, and the science is promising, and I won't get into why, but that mixture of the young cells and the adult cells is a promising tactic going forward. But this is their first in human trials, so pretty reasonable trials from day one. This is definitely coming to the United States, and there's some investigators that are going to be in this trial in the United States in the room here for anyone who has any questions. But this is the first use of kind of a lawful use of allogenic umbilical cord mesenchymal cells with subchondral exploitation of cells as well. So I wanted to describe it in that way because that's the controversy. So believe it or not, using umbilical cells from this company has been done for years, so there's pretty good safety in that. As we look at this from a surgery perspective, I think the controversy is not in the use of those umbilical cells, but it is in drilling the subchondral bone. Now, we already learned our lesson a little bit with microfracture, and here we go again with the use of the quote stem cells or the umbilical cells. So is this going to work? Well, I'll tell you, the initial data is shockingly good, and especially in those patients where we don't have a good option. So I think we have to be careful of two things. Number one, just saying, ah, forget about it. That's crazy strategy because there is good data. It is coming to the United States, and it is going to be an option, right? But we also have to balance it on the other side and saying, well, we've learned a lot about making sure our subchondral bone that we're building our cartilage is healthy, so let's be careful as we're drilling it and making it abnormal from the beginning as one of our goals, right? There's a double edge to this, and we don't know where it's gonna go, FYI. A final, agility C, again, investigators, and these trials are in the audience here. If anyone has any specifics, I'm gonna finish on this. This is a biologic without any cells, right? So this was easier to get through the FDA process because this creates the hospitality of your native cells to create dimensional improvements in both the bone and the cartilage. This is available for FDA-approved use today, and it's really the only one that's been approved not only for the treatment of chondral defects but also osteoarthritis. And if you look at the data, and this is in the comparison to, again, microfracture standard of care treatments, including debridement, you see a marked improvement of that over time. This is also very promising because, again, these are in patients that we don't really have any good options, if you look on the screen there. And so what this is approved for is also resurfacing of arthritis, right? So that's exciting, but I wanna call your attention, if you can see that, to lesion number three and two at the top, right? And it's a trough, and there are points of care, number three and number two, at the ends of the lesion, and this is authorized, right, to kind of regrow cartilage also in the middle of that. And my question is, can it do that? Is there enough power in this technique to be able to do that? And we see really good results of number three and number two, but what about the results in the middle? And I think that's where this technique just needs to see where it has the edges or the boundaries, but otherwise, boy, the data also is just very powerfully good, right? So it's certainly something to consider. The data is there, and the data is there with regards to MRI follow-up, right? As we're looking at how patients do, we're also looking at how their MRI is in the percent fill. So there's something about the hospitality of the agility that really allows these cells to reorganize, and it shows on follow-up imaging. So in summary, things are maybe switching a little bit with the understanding that there is no pixie dust, there's no magic wand, but instead, we have to really do our job as surgeons. We have to optimize the environment. We know we have to get rid of the cartilage, the calcified cartilage there. We're not gonna just be adding on to things like spackling and glue, because it doesn't work. So we already know that. We normalize the forces, and we think through that particular patient in a personalized way of how we can change their environment and then do our biologics, and then choose our cartilage resurfacing technique of choice. Thank you guys very much. Thank you. Thanks, Jason. We're a little behind schedule. I wanna have plenty of time for questions, so I'm gonna fly through my talk. These are my disclosures nothing for sale in terms of my talk This is the take-home message of nothing else So, this is an idea of how much money is involved with this, a couple of take-home slides, and this is getting close to billions of dollars in orthobiologics, so that's sadly what drives this. And biologics are hard to define, and I'm not sure I've got a good handle on it yet, but they're basically, as the FDA says, it's a wide variety of different things, and they can be both synthesized and come from animal sources, so it's a little bit up to talking to the FDA and deciding what they think is a biologic. There are small molecule drugs, there are biologics like cells, like Scott talked about. Biologics right now represent 2% of prescriptions in the United States, but they're expensive. So the jurisdiction for these is also confusing, and Scott mentioned this a little bit. The device branch, or CDRH, looks at a lot of these, especially for... CBIR, the biologics that covers most of these, and some would seem to be drugs what are biologics like insulin that are covered by CDER. And then you can get into combination products which gets even crazier. So these are the definitions. I don't want to get into great detail with these, but basically we're dividing these human cell tissues into two categories. One are the 361 products and these require an IDE or PMA. You can't put these in people legally, period. The 351 products can be regulated any way you want, but these, I misspoke, I'm sorry, the 351 products are the ones that need pre-market review of some type. So to use these in your office or your surgery center or your hospital, there are basic criteria set out by the Congressional Federal Registry for what it is. Obviously we heard already today these have to be minimally manipulated and that's a little hard to define at times. They have to be for homologous use. In other words, what you're putting in has to be similar in structural qualities to what you're injecting it into, although it gets stretched. We were talking yesterday, I think, about how fat cells can be injected in the knee for homologous use, which I think to some of us is a little bit of a stretch. You can't involve a combination of cells or tissues and it can't have a systemic effect. So these things are tough. Minimal manipulation is described more by the FDA rules here. Homologous use, again, I think is confusing, but generally speaking, with the 361 products, we need to understand these aren't formally regulated. They're essentially self-regulated by the manufacturers. So if they self-designate, which they often do, then it's up to the surgeon and patient to decide if what they're telling you is actually true. These are some examples. Busy slide, obviously, but generally speaking the 361 and 351 products are divided and we tend to use both of them. This is an important one because the FDA generally regulates facilities that make biologics. So if you're going to quote-unquote make a biologic in your recovery room, why aren't you going to be forced to regulate your surgery center as a producer of a biologic? Well, this is the same surgical procedure exception, which basically says as long as you're taking it out and putting it back in the same day in the same place, you don't have to regulate yourself as a manufacturer. So there are some odd loopholes to this, to me, that are confusing. For example, we all think of PRP as a biologic, but it's really a blood product and it's not regulated in any way by the FDA. FDA regulates the centrifuges, but they don't regulate any PRP use at all. Amniotic fluid, surprisingly, is secreted body fluid, is not considered a human tissue product, but it's a body fluid. And adipose tissue, as we discussed, is a structural tissue. You can't use it without a study if it's more than minimally manipulated, but it is felt to be a homologous use. So why do we need to be careful? I mean, who cares? And the answer is you can basically get in trouble and or go to jail. FDA feels pretty strongly that illegal use of these biologic products is prosecutable and it's not a good place to be. And you need to understand, I was at FDA for four years. They're worse now, obviously, but even then they weren't staffed to do any kind of enforcement. So the person that turns you in is not going to be the FDA investigator that's searching your website. It's going to be your competitor down the hall that says, I don't think Weber's doing the right thing with these stem cells and I'm going to bust him. So be very well aware that your competition will police you far more effectively than the FDA will. So abuses of stem cells are well documented and Penn and JBJS provided a very detailed outline of illicit stem cell clinics. Kingery and another article from JBJS looked at websites, looked at 896 websites, 95% of them had at least one statement of misinformation. So we need to understand we're not doing our patients any service with this kind of basically false advertising. So we've heard this already at this meeting, don't put the word stem cell on your website. It's an immediate flag. You're going to get in trouble, the guys down the hall will turn you in and you'll get busted, so don't do this. There are only two stem cells that are approved, Cardocell and Macy. And again, we talked to about testimonials a little bit at the meeting, but if you have your website and it says you can come to my office and here's my patient who climbed Mount Everest after your stem cell treatment, you can't do that. You've got to use the typical average result in your website, so be careful of that. So there are several approaches to this. Untitled letters is the first one and then a warning letter after that. These get published, people know about these, we've already talked about enforcement discretion and how that worked with Clawbacks. I'm going to kind of bump through this and part of what you need to understand is you may think that stem cells are the best thing next to sliced bread, but FDA is not telling patients that and you need to be aware of that and if you're going to do these kinds of things, you need to look at the FDA websites to see what they think is going on. This is another good study from DePue Charitable Trust. Unfortunately, the U.S. is not really good at looking at adverse events in general, but they looked at adverse events that were published or documented. They had 334 cases of adverse events using stem cells. Five of them got reported through FDA, so that's a problem. There have been some big fails. So I want to go through this quick and then I'm going to cut off. We understand at AOS that it's challenging to figure out what's legal, what's not legal. The companies bald-faced lie to you. So we spent a lot of work, Jason and the gang, on getting this biologics dashboard going so that you have some resource to figure this out. That's the web link. It's all over the place. It's free. Free is good and you can search this either by type of biologic or to some degree by product name. So this is what happens when you open it up. I just did this as random. I said I want to find out if liposuction obtained SVCs are currently okay to use in my clinic. So I open this up. I get this view. I pick adipose tissue. I pick allograft. I picked obviously more than manipulation and then I get this result which basically is telling me because I'm manipulating this product, it's currently you need to think about it and gives me some references for that. So it's pretty straightforward. It's not as straightforward as we'd like it to be perhaps, but you can go through and kind of figure out where you're at. By name it's a little more challenging because AOS wanted you to have to think a little bit about what you're doing. So for example, I just put Regenitin. I have nothing to do with this. I don't like or dislike Xenograft protection of tendons, ligament of tendons, you can tell this one, that gives me a green light. It's OK to use this. This is an approved product. So that can be extremely helpful when you're trying to sort out what's going on. And we've all gotten emails from an FDA-approved consultant that says it's legal to use amniotic product, for example. And I would just caution that's not true. So I think with that, so we have plenty of time for questions. I'd like to get the faculty back up here. And we'll take questions from the audience. So please, I don't know, we have mics to go to. So holler out if you have questions or concerns. I know it's hard to be inspired this early in the morning. I put everybody to sleep with the last talk, so that's all fair game. Yes, sir. For the PRP studies, are we talking about one injection, a series of injections over time? That's a very good question. Yeah, so the early studies mostly were being compared with HA. And so I think for that purpose, they started to do them with three injections, compared to three HA injections. But now, as we're coming to understand that dose seems to be the important thing, my own opinion is that if you can get a high enough dose, which in my mind at the moment, based on literature, is greater than 5 billion platelets in a single injection, that that's just as good as getting 5 billion or 6 billion over three injections. So we don't have a lot of data. There's one study that did show that three injections were better than one, but again, that was with the earlier low dose PRP. So right now, I think it's more about the dose, and if you'd rather take it three times to do that. But for the patient, it's $1,000 or whatever you're charging per time. So the way I do it now is one injection with a high dose, 5 to 10 billion, and we see how they do. And in a few months, if they're doing pretty well, but not as good as I'd like, we may talk about a second dose. But that's a very good question. The earlier data was all on three injections. Now we have a lot of what those last two studies I showed you were one injection. Well, I think most of the studies will show that KL2-3 do much better than KL4. So KL4, once you have big time malalignment, I mean, I do treat those patients sometimes because they don't want surgery for whatever medical reason or social reason. But I do make sure that in those patients with KL4 and the malalignment, I put them usually in an unloader brace. We have both unloader braces that unload in the standard way. There's now a new brace by this company, Icarus, that actually jacks open the joint more. There's patella femoral unloaders. So I think unloading along with the injection may get you better. But all the studies show KL2-3 do better than 4. Would you agree with that, Jason? Yeah. Yeah. And then, you know, if you allow a little bit of anecdotal medicine, and that is if you look at how PRP works, one of the biggest benefits are the anti-inflammatory properties of it. And we now know that there are many subsets of osteoarthritis, right, in our different presentations of arthritis in our group, in our patients. And the ones that have an inflammatory component anecdotally, because we haven't studied, it's hard to subset these studies like this, but anecdotally do better with PRP-type biologics than bone dry. They're non-reactive. They just hurt. It's the soreness. You know, that's been an okay anecdotal experience for, I'll just speak on behalf of my patients, but then the ones that have an inflammatory component, they have a reactive knee, they're sore the next day after activity, have had a much better response. And that kind of makes sense from the perspective of what PRP can be delivering for us. So just one way, in addition to their grade of arthritis, to quite possibly seek out patients that may be suited better or are less likely to respond. But this whole bar repository, we're looking into all those factors. So to be able to report back to you guys on more specifically the patients that are going to be more likely to respond versus not. So there's, you know, something we didn't talk about today is for those bone dry patients who then on MRI have subchondral edema, you know, we found that whereas BMAC intra-articular injections do not seem to be any more successful than PRP, and of course it's much more expensive and painful to take, but if you're doing intra-osseous injections, it seems that the IRAP and the BMAC may have more stimulatory effect, and it may be that those patients need both an intra-articular and an intra-osseous injection. Again, more studies have to be done, but Hernagel has a whole bunch of studies showing incredible effectiveness of BMAC with bone intra-osseous injection, you know, under fluoroscopic guidance. Actually, you make as much out of just the decompression of the intra-osseous pressure when you're needling, and whether or not you've got to put in BMAC, I don't know how you can do that. You're right. One of the, well, in fact, I'd add this important question about degree of arthritis. We talked about PL2, 3, 4. Alignment's important. You heard that. But importantly, I look at, once you see the architectural remodeling of the condyle, the flattening of the condyle, I think it spools out. That means too far gone. So, once you see that flattening, I don't think it's going to respond as well. What's the status of insurance coverage for the orthopedic doctors? It doesn't exist. I mean, they keep, there are some insurance companies that tell their patients, their clients, that they cover this, and they say, oh, you know, they can call a, then the patients tell me, you know, please call. I'm told that this is covered. But I've never once gotten a payment for it. So, I don't know what to tell you. They talk about, it's really just not, it's like, you know how they say these things don't need predetermination? But then on the back end, they don't pay you for it. So, I will say, however, there are a few work comp groups and some military insurances that will pay. But it's really a small number. I think the military's changed, if I'm not mistaken. They used to, to TRICARE to pay for PRP injections. I think they flipped it back to a single PRP injection. And that's caused some strife in the military population, as they've had good results in trying to have re-dosing. And then the TRICARE says no, only once. Don't quote me on that, because I'm not sure. But that's been more recently over the past six months. It's been very difficult for a second dose. Jay, could you comment a little bit more? You know, the right to try is interesting. I know it's out there. I've heard of it. But the process, there is, for example, some of these humanitarian exemptions have a limit to the number of patients they'll even let do it. Do you know much about it? How do you initiate that process? Yeah, well, and again, probably Scott would be a better resource than this. I'm just learning about this. But right to try trials are, by the design of the law, meant to protect patients and for the patients to have option if and only if their disease is severe. So that's the part of it. And then there's no watchdogs with cancer and things. It's like, of course, you get to have a choice. With osteoarthritis, I think we have to be a little more careful. That it can't be, hey, I just ran a triathlon. I need a right to try to regrow my cartilage, because that's not necessarily a severe disease. My understanding of the paperwork flow is that this is not FDAA regulated, meaning that the FDA is going to be looking at your paperwork with any sort of scrutiny. B, have any limits to it. This is a company reporting necessity where they have to have the paperwork. They, on a yearly basis, have to register this paperwork or send it to the FDA. And so then that pathway is there. But it's not that the companies are limited. The companies can charge for their products. So there's a little bit of regulation. But it's not that this means that the patient gets the therapy for free. So it is a way to treat our patients that really need it. And that's what the law is designed to do. But there has to be some paperwork. And so then, obviously, this does mean in the same way, this law does not allow you, as a practitioner, to have your own little lab set up, and your own culture area, and to give patients back. These are companies that have had the structured trials with the FDA, the safety trials, etc., that set up the underpinnings of being able to use this, not you in the garage or your office to be able to start doing this. And I wasn't there yesterday, but I think Scott talked about it. These other lawsuits or new laws, depending on which one, especially in Florida, same thing. It sounds like, oh, now you can use stem cells in Florida. That's not exactly, but paraphrasing it. But not true, right, because you have to, again, have the structure of the laboratory that's FDA-approved and regulated. So, again, there's a little more leeway in a couple of states going forward, but it still prevents the use of improper technique and improper laboratory conditions to protect the patients. You know, I believe, Scott, you can comment if you're here, but I think the right to try is only for those things that the company's already done a phase one study. So that's an important issue, too. There has to have been a safety phase one study. It's not for things that have had zero study yet. So they may not have completed the full phase three or phase two and three studies, but they have to have phase one. I can use my 53 New York Giants. Nothing else has worked. Thank you very much. All right. Thank you.

orthopedic biology

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rotator cuff repair

cell therapy

matrix synthesis

inflammatory mediators

bone marrow

adipose tissue

Platelet-Rich Plasma

osteoarthritis

cartilage restoration

umbilical cord cells

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