attention. Well, that's kind of a non-homologous talk. We're not used to the homology, I guess, of these regulations. It's a very difficult subject way to go, Ken. I've been discussing, I'm going to talk about leveraging biology with orthobiologics. And if we talk about regenerative medicine, really the biggest regenerative product right now is probably skin coverage, placenta products for the skin. Those companies actually make money with diabetes being, I think, what, 9% of our culture, double that for the pre-diabetic. So that's probably the best for regenerative medicine. But we're going to talk today about, let me see if I can get this to move forward. We'll talk about my disclosures. Really, we're going to manipulate biology best as possible with orthobiologics, as it was alluded to. And it's really, I'm going to talk about inflammation. The same four days we start medical school, we talk about biologics and we talk about inflammation. And this, we're going to work on inflammation. If we look at the talks that are coming this evening, it's everything's about inflammation. We're trying to manipulate inflammation of all these disease processes that we have. And these are our special tissues in that sense. And I'm not going to talk about spine, but how many of our partners do spine injections? So there's a big market there, but we're going to focus more on sports medicine tissues. I put this slide in here to talk about the volume and the impact of musculoskeletal medicine in our culture. It's demonstrable. We're just really one of the big, we're not as big as heart, because heart admits patients, but clearly the cardiovascular is about 16% of our budget. But musculoskeletal is a huge demand. And we specifically, we talk about the volume osteoarthritis. Osteoarthritis is about 60 million Americans and growing as the boomers get older. So we're really going to talk about some injections today. We're doing injections to decrease inflammation. And if we talk about the complexities of inflammation, we're not going to in details in 15 minutes, but IL-1 is a big one. Of course, TNF is a big one. They have to work a little bit together. We think these are all undecided. IL-1 has been a big proponent lately and there's other non pro-inflammatory mediators. So this whole concept of inflammation is very complex and really not well understood, except for some of those major caveats, if you will. These are the four issues that I'm going to talk about today. PRP, it's already been mentioned by Rachel. And if you look at it, it's a big business. It's not covered by insurance. And really 99% of PRP is given off label. And the understanding of it is difficult because we don't have good nomenclatures. We don't have any good understanding of doses. We don't have a good definitions. And Muenchner and LaPrade has pointed this out in their December or last October in JBJS. So we talk about anti-inflammation and specifically Brian Cole's group has looked at the anti-inflammation effects of PRP. We know that that's pretty strong. So it makes sense to decrease catabolism and inject maybe even multiple times. But if you look at the negative, whether it's a positive leukocyte rich or leukocyte poor, the flavor of the literature is that leukocyte poor is better because the idea that the leukocyte rich PRP increases catabolic cascades, all these things that increase inflammation in generally and it's thought to really increase pain. When in reality, if you look at this study that again, Brian Cole's group came up with, when they looked at six randomized clinical trials and then three additional ones giving over a thousand patients, they found that the studies themselves were difficult. They weren't all double-blinded. They were younger patients and different PRP systems and overall, the available evidence is of low quality for PRP for leukocyte concentration. The idea being that I think it's important to have higher concentrations of white cells against the prevailing thought because white cells aggravate, they give increase in interleukin receptor binding protein. I'll talk about it in a second. They inhibit TNF. They recruit other monocytes and neutrophils that will absolutely help heal in this cascading system. So I think anti-inflammation is really regulated a lot by these white cells. And if you look at IRAP, the idea is that IL-1 is our major culprit for cytokines for inducing inflammation, especially in the joints, obviously. And so cartilage loss and all these types of things. Well, interleukin receptor antagonist protein will competitively inhibit IL-1. So if we turn off IL-1, then we could decrease inflammation. And that's the concept of IRAP. And of course, it's similarly seen in the anacarino for rheumatoid arthritis. White blood cell concentrate, if you use a PRP product with leukocyte-rich, you're gonna increase in picograms demonstrably the amount of receptor binding protein. So the idea is you put this in, you spin it correctly. With the white cells, you're gonna increase of interleukin receptor binding protein. You're gonna competitively slow down the IL-1. That's the concept with white cells, I think. Orthogenes product, Peter Veiling in Germany, he'll give multiple injections. He concentrates greater IRAP in his little bead product. It's not the best evidence to date, but the idea of multiple injections of this will decrease the inflammation in the knee and clearly improve patient functions and reported outcomes. Again, cash business. This can be up to $10,000 for these series of injections. Recently, I reported a paper that we did. We looked at all the level one studies, totaling 57, that over 1,000 patients to really understand what's going on with IRP and PRP. And unfortunately, if you look at it, there's such a mix of heterogeneity that it's hard to make strong statements. Activation, the concentrations, whether you include leukocytes or not, it's really, there's no consensus of indications or preparations. So, and of course, across as we stated before, there's absolutely no dosing to PRP, so it gets very confusing. But from this study, we did find across statistically, when you looked at meaningful clinical differences, that we did have improvement in pain, in pain but not function. Okay, appreciate PRP does not have stem cells or stromal cells, if you will. We'll talk about that in a second. And the future, I think, is the PRP, is the point of service care. The American Association of Blood Banks say we have four hours to play with blood. So in theory, we can selectively isolate components in the future and absolutely have a dosage of this drug, if you will, and then we can start tackling the different products, different procedures we wanna look at and look at inflammation as well as other structural components. I'm sure Jason will speak on this. Hyaluronic acid, a big product in the United States, and I credit it, this rooster chicken stuff. Patients now understand that we can get injections. It's just awareness now. So we all know that we get these injections. If you look at the science, it was mentioned by Rachel, there's clearly some anti-inflammation effects with PRP in different fashions. The Academy, though, makes a statement that they strongly recommend not use it when they went through their meta-analysis. So now we have the latest number, 64 million, almost 26% of Americans who previously had insurance that covered hyaluronic acid are not being covered. So that gives us serious problems. And then if you look in the literature, you look at Banerjee's study, and they debated back and forth about the meaningful clinical differences statistically, and osteoarthritis in college, the ORSI statements, and then New England Journal of Medicine, they all give different opinions about what we should do with this. So with all the statistics, it's very confusing to the practitioner what we should do with and without this with our patients. So for the HA, there's confusion. The American Academy's conflict makes confusion. We're gonna continue to do non-operative care with us. There's no question about that. OA is a growth industry. Hyaluronic acid is a growth industry. There's over a billion dollar industry right now. We'll continue to do HA injections. Steroids, I'm not gonna go into too much. We all know that. The studies at six months, we look at the latest Cochrane studies. It does strong anti-inflammation, but it's poor quality evidence at best. But I wanted to talk about Xelreta, which is the new drug that came out. A six-month follow-up came out last fall, and clearly, it's the first and only extended-release steroid. Their endpoints at three months were kind of mixed a little bit, but clearly, it's less expensive than most, and I think it's pretty exciting to study this in the future for anti-inflammation of the joints. So to finish up on cell stuff, what is an MSE? I'm not gonna talk in front of Arnie Kaplan, but clearly, there's a lot of nomenclature problems, whether it's a stromal cell, a stem cell, or as Dr. Kaplan will tell you, it's a signaling cell. It's very confusing, and the literature, of course, is all over the place. It's very difficult to interpret that in the literature. So bottom line, you cannot inject stem cells in the United States. It's illegal, because if you have stem cells, that means you've done manipulation of that tissue, as Dr. Zavala just went through. So if you've manipulated tissues, you can't do that unless it's under an IND, and there's very little INDs to date for orthopedic surgery. And talk about signaling cells, obviously, MSEs, stromal cells, call them what you want, are good for immune modulatory abilities, and that's what we really like. That's what we're kind of pursuing for anti-inflammation. Dr. Zaslav talked about that 361. 361 is your allograft, 351 is the complex, expensive pathway to get a drug. The idea is that patients want to avoid surges. They don't want to have, let's say, in the knee, a total knee arthroplasty, but we know the restrictions are terrific, so it's gonna be a long time, five years, and millions and millions of dollars to develop a stem cell or a stromal cell drug. So this pressure builds up. They want this, they read about it, we see all the hyperbole, so now we've got the snake oil salesman that we talked about briefly there. And in this JVJS article, they talked about editorial. These stem cells, there's over 350, maybe 400 clinics in the United States, the FDA says. Again, zero evidence, and they are not stem cells. Stem cells today make your problems go away. This is what I get in Los Angeles from the LA Times last year. So we all get this, we all get our patients coming in, and it's very confusing. So what we've got today, these are our choices, either bone marrow, fat, or placenta tissues. Since we can't grow and expand cells, we're gonna talk today, and we'll talk over this meeting, about these are our sources of what we have for these stromal cells to try and inject into our patients. And this is one other point I wanted to make. We talk about stem cell injections. Well, if I invite you over to the house, and I say, come on, I have some wine, but yet I dilute it to one in 100, to 1%, or 20%, and I give it to you, that's really not wine, and you're angry with me. Well, that's what we've got with these cells that we have that we can harvest right now under the current restrictions. In this article, you can see that bone marrow has less than 1% stromal cells. Less than 1%, so it's not a stem cell injection if we aspirate it from the hip or wherever we decide. Adipose tissue of the nucleated cells, 20%. So appreciate that these are not stem cell injections, they're cell injections that have some stromal cells. Now, again, if we look at the literature just for the knee, here's 28 studies, 14 for OA, 14 for focal defects, tremendous heterogeneity. Besides the definition of the cells, it's garbage in, garbage out. We can know it's safe, but at the same time, we need level one studies to really look at efficacy, which is clearly not there. So the FDA says specifically, not based on scientific evidence. Not reliably demonstrated to be effective in stem cell treatments. That's where the FDA sits right now. The future, of course, is gonna be exciting. I wanna touch base as I close out here of these cells. If Dr. Kaplan will tell you they're medicinal signaling cells, which I do believe they are, the cells that they, the exosomes that they release, this is how these cells communicate. And that's what we call self-free therapy. Where the FDA is on this is uncertain at this time, but the idea is that these cells give out these extracellular exosomes, if you will, and this is how these stem cells communicate. So this, I think, is the future of this new drug, if you will, of stem cell biology. We did a little quick study that we've done so far to date. If you take these exosomes from cartilage cells, human cells, we put them in a 2D versus a 3D environment. So just the environment we found, this is the classic cell culture flask that they grow cells on, but if we take it and we grow them in a three-dimensional environment, we see a much robust response of the numbers of exosomes in growing in a three-dimensional situation. And here, you can see a difference in the cell numbers in a three-dimensional environment. So when we take these exosomes, where we're going with them is still undefined. In this case, we got improvement in gang staining with human chondrocytes with a 3D exosome on the right, and then for the COL2, a critical part of the chondrocytes, we had in certain medium three-dimensional environment, we had a different response in vivo. So there's really an interesting future there of what we're gonna do with these exosomes and how we're gonna grow them and how we're gonna manipulate them because they're clearly different in different environments. So the future, biologic injections are here to stay. We're gonna have these biologic clinics. We have to have more improvements of stromal cells to understand what we're doing with the stromal slash stem cells. The FDA, as Dr. Zaslav just went through, is very much involved, and I'm not sure, they're not confused as well. Insurance companies are clearly gonna follow the government. This is gonna be a cash business, so we have to worry about is this really cost-effective if it takes $10,000 to develop an injection that we're paying right now? Is that smart? I don't know. Safety is important, and we clearly need to have more level one studies to really understand what we're doing for our patients. Thank you very much. Thank you.

orthobiologics

regenerative medicine

inflammation

platelet-rich plasma

stem cells