We started past the 75-minute mark on the way down, so we're gonna go ahead and get started for the afternoon session. You're in What to Tell Your Patients When They Want the Truth About Regenerative Medicine for the Spine. And my name's Jim Acheson. I'm just gonna be the moderator. After presenting at the academy for a number of years, I finally figured out it's a lot easier to come to the meeting and ask them to do all, get your experts to do all your presentations, and then you can sit back and listen to the things you want to hear about. And I will introduce them in just a second, but I would tell you that my concept and idea for this session came about because I practice in the state of Florida, which is technically the wild, wild west, except we're on the east coast. And the issue is people come in every day to Mayo Clinic and say, you know, I've had stem cells done. Really, okay, well, where did they put them? What do you mean? Well, there's different structures in your spine. Did they tell you where they were putting them? No. Okay, how, you know, other than the cost, they really don't know much about the story of what's going on, right? And I always ask them, I said, well, what did they tell you they would do? Fix me, okay? So, I don't know if all that's true. And so what I thought is I'd like to hear people who have looked into this and done a lot of work with it and studies to help me be able to talk better to those patients. I'm gonna have a better response for some of them as we get going down the road, a little bit to see. But let's kind of move forward. Oh, last one, somewhere in there, all right. So, our three presenters are gonna be Dr. Jay Bowen, who is from the New Jersey Regenerative Institute, and then gonna be followed by Mary Ansbach, who's out here in San Diego and just started a new practice at BioEvolve with San Diego Orthobiologics and Sports Center. And then Dr. Wen-Chun Hsu, who is a physiatrist. He practices at the Mayo Clinic in Florida in the Department of Pain Medicine and has ongoing trials with some of the areas in terms of regenerative medicine in the spine. And so, we're gonna lead off with Dr. Bowen talking about the basic principles of the use of orthobiologics, including some of the history and kind of really what areas have had some research or study done in terms of structures. So, when that patient says, I have no idea where they went, and you're thinking, was it the disc, or was it the joint, or some people are getting them intermuscularly at this point to see, what is it that's really been looked at up to this point from there? Then Dr. Ansbach's gonna come in and talk about a little bit more of the systematic reviews in different areas that actually would show more data to support use in particular areas and with particular types of problems in the spine. And Dr. Hsu's gonna finish up with perhaps a little bit more about what's the future and what else could we be looking at or what else should we be looking at and also where else would using these orthobiologics and the principles that go along with this, different substances that may be in development, which is part of his area of expertise from there to see. So, I'm gonna move a little quickly, get forward. So, Dr. Bowen will come up and get us started and we'll switch sides out of there. Did work if it skipped one. I just went back one and then it came back on. Okay, so I think we're good from there. Thank you. All right, so first I'd like to thank the Academy for having me here. And as a little homage to my partner, Dr. Malanga, who's been passed, he usually had 120 slides for 10 minutes talk and I would help him wean it down. So, I just have 60 for 20 minutes. So, hopefully this is not too fast. I'm a New Yorker, so I speak a little fast. The good news is that these slides should be for you and there are a lot of references. So, some things I'm gonna blow over so you can look back at them as a reference later and look up what you think is pertinent or you wanna know about or more about. Two is that it's not just me making a statement, there's actually something behind what I made a statement of. And so, we'll try to move forward. My disclosures, I'm a partner and founding member of Data Biologics, a company looking at real world evidence for these things we're gonna talk about as well as others. With this disruptive and novel technologies out there that we can advance our patient care and outcomes. I have sort of a tough task to go over everything in a 60,000 foot view. So, hopefully you come away with actually some points, maybe not some specifics, but the gestalt of different things. Introduce the topic, give some definitions as I go through. The history of things that are probably gonna be definitely different than what you thought you were gonna hear when you walked in. The quote products that are being used. Regulation, just touch on it a little bit. Resources and training so you know there's stuff out there for you. You can look back and get those. And then just a little tiny comment on cost. So, definitions, let's define at least what we're gonna talk about. And that is the field of regenerative medicine and sort of what is that. Initially, some people said it's restorative and then maybe it's not. And are we really regenerating anything? Is it just a pain treatment? Well, I mean every day we're regenerating the skin and our gut and our skin sloughing from our body. So, we're regenerating ourselves from everything. So, that's sort of what we're trying to do is get us back from the diseased tissue healthy versus what our bodies do every day with just replacing normal tissue with aging tissue. So, it's a field of the science of repair, restoration, and regeneration of diseased or injured cells, tissue, or organs to restore homeostasis or balance. So, often the regenerative medicine is really not discussed in different disciplines that we learn. And it probably should just be incorporated in that continuum along the care that we deliver, whether it's for a tennis elbow or radiculopathy or something else. The other thing is let's just step back a little bit. I know we're focused in on let's hear about regenerative medicine, but let's talk about the most important person in the room, the patient. So, we as physiatrists are biased in a good way, I think, and that is we're looking at impaired function and quality of life. And that's ultimately what we want to do is improve both of those factors. So, looking at the whole patient and thinking about what is their mental, physical, spiritual aspects, what medicines are they on that may be detrimental to what we're trying to achieve? What are the supplements they may or may not need? Supplements are supposed to supplement thing, not just 50 that they brought in a bag that they take. And then what is their goal? I talk to my patients and say, how you doing when they come in for follow-up? And I usually tell the story of two patients. One is, I think they're a failure, and I sort of, in the back of my head, and the patient says, no, this is the greatest thing since sliced bread. I can walk up and down my split level, I can get on the floor and play with my grandkids, I love it. I'm like, okay, success. On the other end, I have somebody who's active, and they come in, I go, they're like 90, 95% better. And they go, this failed, this sucked, this is horrible. I go, really, what happened? Like, well, I can't hella ski out back country, I can't do CrossFit. I'm like, well, you weren't doing those before. He's like, but this was gonna give me that opportunity. I'm like, okay. So know your patients and their goals. We don't wanna medicalize patients. That's what we do, right? We have our white coat, you need me, come in and see me. My goal is to get these people independent, empower them, and get them out of my office. I don't wanna see them again. Unless they send me a card and say, I love how well you did, but. So we think about their general health. Maybe we need to precondition them with good exercise and modify their bad biomechanics, why they have this knee pain or back pain. And then maybe one of the most important things that, again, bias in this room, I hope, is good rehab protocol that we define, not just the black box of physical therapy. So we're gonna start back in the 1500, or the 1350 BC, right? But we'll go a little faster. You look at Aristotle, looked at animals and the limer generation. It's like, wow, you lop this little lizard's arm off and it pops back, or the tail. That's cool. Can we do it in humans? Well, now I'm gonna start with something called prolotherapy. So some people may have heard about it, and I think this is the grandfather term and treatment of all of what we're talking about and the future. It's stimulating your body to heal itself. We first reported animals in 27. They thought it was a sclerosing agent, and they had a society, they started a medical group of people for treating hernias. Then you fast forward a little bit. In the 50s, you have a general surgeon who started looking at things, and they had the Dyssyndrome, looked at management of hypermobile SI joint, started looking at sclerosing syndromes in the back. And then you started another group outside the hernia group that looked more at just sclerosing pain management. And you advance till today. In 2009, they switched to the Prolotherapy Sclerosing Society that exists still today. And what's the mechanism of action? Well, dextrose, which is a typical thing in prolotherapy, is mobilizing the proliferation of growth factors to promote healing of soft tissues and potentially other structures. So then you have George Hackett, one of the fathers, and he was looking at injecting things in 35, and then wrote a book and coined the term prolotherapy, or proliferative therapy, in the 50s. And there's no data, right? But he looked at over 1,800 patients for 20 years to get over 80% improvement, and no complications. No complications, right? Above all, do no harm. So people are like, oh, that's a bunch of bunk. Yeah, they don't really want to learn about what may help our patients. But so why isn't this present-day use and paid for by everybody and everything? We could debate that, but at the same time, Mixter and Barr was talking about the disc and starting to do spine surgery, and all of a sudden, we know how spine surgery has exploded. Maybe that's the reason, who knows? So as I said, classic prolotherapy is using sugar water, or P2G is phenol, glycerin, and glucose. And most of the things people talk about, they would be dextrose prolotherapy. So we want to look at this specifically for one thing, and that is people were treated with saline and with dextrose prolotherapy. And the important thing in this is they both did well. So saline is not a control. It's maybe a less effective therapeutic treatment, but it's not a control. So this study has impacted me quite a bit because of the technique. I've modified what they do, but this person in the UK looked at 21 people, did dextrose prolotherapy, and looked at the spine with the red being where they inserted it through the skin and the black being where they actually injected it at the bone interface. And he looked at two groups, very long pain, eight years, and long pain, but not so bad at eight months. Being quite disabled, between 12 and 44 on the ODI, Osteosteroid Disability Index. Higher it is, the worse you are doing. 18 patients had over 86% improvement. Define how. Over 70% improvement in pain, and over 80% improvement in the disability or patient report outcome scales. And that's in a year. Two of them were unchanged. One has a little bit worse, and as we look at medicine, everything won't cure everybody. And if they do, then you gotta question why that's happening. So you can look at low back pain that radiates down the leg, potentially radiculopathy, do caudal epidural injections, about five a year. And listen, people are like, it's too expensive, it's not covered by insurance, it's gotta be, I don't have fluoro. I learned in a third world country, with a 25 gauge needle, how to do a caudal epidural injection with no guidance. You can do it, and you can make it really inexpensive for patients to put in their office. So if you're in an indigent area, you're in an inner city, you can do this. There's a will, there's a way. And in one year, it improved disability and pain. Coding, people love to get creatively coding for all these things we're gonna talk about. Don't do it. Or take the same amount of money you got paid and put that into the bank account for the lawyer. So there's a HCPCS code not covered by Medicare. You can't put dextrose in something as a primary treatment and code it as an injection of a joint, a tendon, a ligament, because that looks, that's by definition prolotherapy. And that should be knocked out, and it's fraud. Internally, we use a Medicare guidance of that figure you see up there, how we code sort of our stuff internally. So depending on where we're treating it, how we charge. Ozone, well, Pericles said that all things are poison and nothing is without poison. The dosage alone makes it such a thing that is not a poison. So devil's in the details, as we heard earlier. I got stem cells in my back. What the heck does that even mean? And dose, devil's in the dose, right? That's also important. So ozone first discovered in 1785. As you can see, lots of things that'll be there to look back if you don't believe me or agree. And around 2006, Spanish Society developed a group, and it's the Spanish Society that made a really dense article to sort of cover the soup to nuts on ozone. Made a Madrid documentation. And the important thing is the bottom, right? Ozone's practiced in more than 50 countries, and there's more than 40 medical societies. So nobody may have heard of this, except maybe Dr. Rogers, in this audience, but it's being used a lot around the world because it's cheap, it can't be patented, and it's effective, and it's safe. We wouldn't want that in the United States, would we? All right, but we said, FDA says, no, no, no. Ozone, by definition, is a toxic substance with no medicinal use. However, sorry about the error. It's not contraindicated, it's conflicting, right? So contradictory by the vasogen studies that FDA certified and approved, phase one, two, three, that they agreed it was safe. The effectiveness wasn't looked at because it wasn't a study for the spine, but we do know that ozone is safe, and the FDA knows that too. Again, it's used in general dentistry where they actually have continuing medical education, articles on infection, and other things. And with the new administration, depending on who's there, I have some inside information, we may hear more about ozone. So if you take proliferant therapy, dextrose prolotherapy, and you switch it up a little bit, you get prolozone, proliferant therapy with ozone. Dr. Schallenberger registered this term. I was luckily enough to be on the founding group in 2010 of the American Academy of Ozonal Therapy, and essentially it's using a different stimulus of gas, ozone gas, instead of dextrose. Gas flows completely differently in the tissue under ultrasound than everything else you think about from magic pixie dust that's liquid. Ozone for the spine, right? We all know, or hopefully we know, that you can take two groups of people to disc herniation and radiculopathy. Follow them out if you can manage their pain. And at one year later, not statistically relevant, but the non-surgical group is a little bit better. So you can get there. Well, how about we just take these people who are having a tough time and we do ozone? So half have ozone, half have surgery. 71% of people that had the ozone avoided having surgery. That's pretty good odds to me to try. There's other studies. So you look at ozone in the back, 70 to 80% improvement. Ozone in the neck, 70 to 80% improvement. Less studies, but they're out there. Again, some summaries if you wanna go back and look. There's some there. So another definition. Regenerative medicine. It's a new branch of medicine that will develop, that attempts to change the course of chronic disease, and in many instances will regenerate tired or failing organ systems. So that's what we're trying to do with what we're talking about. We get so enamored by technology and this magic pixie dust called stem cell. And it's gonna cure everything. It's gonna be the wonderful thing. But we have to remember, Bruce Lipton wrote a book called Biology of Belief. I always tell my patients, what's the most important thing in your healthcare? And they're like, I go, your mindset. Because if they go, ah, this stuff might work, guess what? More difficult for me to help them. Or as you hear about, I know how much money it costs, so it must work. So I'm already in on this. So that's beneficial. I mean, use everything we can to make someone better. Adjust their suffering, invest their quality of life, get them better. Again, I treat patients, not pictures. I have to register that. But we know you can image a lot of people with no back pain, no back injuries. 66%, there's a disc abnormality. We can look at people that are younger, image their necks. Lots of disc abnormalities, right? But we follow them for 10 years, and guess what happens? They advance, much more incidence of abnormalities, but only 34% actually develop symptoms. So we have to treat patients. Hopefully, anybody doing spine in this room, all right, you don't look at an MRI or an x-ray and go, well, their facets look fine, so it must be something else. We do diagnostic medial branch blocks, and then we make a diagnosis of facet syndrome. Nothing to do with imaging. So to me, I always say to my patients, I go, you know, imaging is pretty much useless. I go, if you don't have a tumor, fracture, or something else, you're just gonna feel bad. Your bad looks horrible. So what? You're hiking, you're running marathons, doing whatever. Don't worry about it. Take time to listen to the patient. Evaluate them functionally. Figure out their movement patterns. See if they just need rehab, good rehab, not just rehab. Well, think about the fascia, right? The surgeons will cut through the fascia and then screw up the entire chain, and then we wonder why they're even more problematic after. So we have to think about the victim and not the culprit. We have to think about the source of the problem, not the symptoms. We have to, forget about this sort of search for the pain generator, because we don't really care about a disc herniation a lot of times, right? That happened why? You had a bad posture, bad loading, ultimate fail years later, you herniate a disc. When the disc compresses on a vital nerve root in a structural area that has no give like that, now we care because you have an acute radiculopathy. But the problem was the posture 20 years ago. Because everybody sits like this, right? I've got another definition from the National Science Foundation. So you can see the theme. There's a lot of definitions, and they're somewhat close, but we need to make sure that we understand what we're talking about together. Another reason I got into this field was I got annoyed with the connotation of inflammation in med school and residency. Inflammation's bad. I'm like, well, what I learned, if you cut yourself, God gave us this inflammation as a gift to heal. So why is it always bad? And then you hear about, in the very beginning, when we talked about regenerative medicine, people brought up this wound curve. I was like, that doesn't make sense. That's BS, right? You have an open wound. I'm like, we're not doing that. And so you look at Dr. Kaplan's comments and whatnot, and that wound curve probably doesn't apply at all. So you take a tennis elbow, and there's no opening. It's under there. Has anybody looked at the microductional catheters to see the phases, and when you put PRP, what happens? Not that I know of. So we're probably looking at modulation. And if we remember back to med school, the immune system and the pain system are intimately connected, and we forget about that. If we look at someone who gets better, they might get better in three to four weeks, and plateau around 12 to 14 weeks. Or Dr. Centeno just looked at this thing at six years, and people were still improving with their spine injections at two years. And so if it was really healing, it may take 12 to 14 months for people to get better, and yet they're getting improvement clinically at three, four weeks. It's probably an immunomodulatory phase that's happening. So PRP, the next lecture's gonna go in much more detail, but it was sort of started in 54, used in cardiac and dentistry quite a bit. First sort of regenerative side was around 1998. And then it really took a lot of traction to the mainstream when Heinz-Ward in 2009 got it before the Super Bowl. And all of a sudden, it's like everywhere. It's like, wow, what's this PRP stuff? And then people ask you, like, hey, that thing that Heinz-Ward got, can I have some of that squirted in my knee? The problem is these studies you may have read, like they don't work at all. Well, they work great. Who knows? I'm gonna do this study, and I'm gonna do antibiotic for pneumonia, and it works, or not. Well, I didn't tell you the dose, the frequency, or the duration. Well, of course, who's gonna publish that? But that's exactly what's been happening in PRP, is that we don't know what's actually being administered to the spine or otherwise. Now, we have some inkling on some of it, where we can split it out, where we know a higher dose of PRP might be better, but we have to be better, and part of it is we developed a classification system, Magellan developed a great classification system, so it's incumbent upon the editors not to publish something unless we know what's in there, and not just like it's cool, let's publish. We have enough of that crap. And then stem cell, well, that term thrown around, magic pixie dust, 1908, Dr. Kaplan really looked at the whole lineage in the 1980s and coined the term mesenchymal stem cells, but he said he missed the boat a little bit, which I'll bring up in a second. The problem, again, is just like PRP, what's the nomenclature, what's the definition? Well, on one side, you have the International Society for Stem Cell Research in 2002, but they're mainly basic scientists. They have different goals, and they have different reasons for saying what they say, and most of their stuff is an in vitro model, and we're looking at in vivo outcomes, so we need to have a consensus on terminology, so Kaplan in 2010 decided to change things, and he said, you know what, I screwed up a little bit. Number one is I didn't get the precursor to stem cells, the pericyte, that lives in all the vasculature in our body, so if you cut your little finger, you release that off, and it modulates the way things happen, and then they shouldn't really be called mesenchymal stem cells, but let's keep MSCs and call them medicinal signaling cells, because that's really what these stem cells are doing, is they're modulating your body's ability to heal. They don't really become that target tissue, so he's like, listen, I can put these stem cells in a petri dish, and I can make them dance, and they can do the jig. He goes, but if I give them the right stuff, I can push them to cartilage, I can push them to skin, I can push them to nerve, I can push them to fat. That's not what happens in your body, so the whole mission until he passed away recently from 2010 was to get everybody to understand that this is the way they work, not the way everybody talks about. So, three-quarters of my consults are done doing misinformation from what they've heard from TV, or even my peers and other physicians. So, like I said, the pericytes, and then how they actually function in the body versus in the petri dish. Orthobiologics, there's a whole bunch of names, right? They come from blood, bone marrow, fat, peri-umbilical, perinatal, and some are more than minimally manipulated, so they might fall in a different category, so there's a lot of stuff out there. The field of regenerative medicine has grown enormously, in part due to the failures of standard traditional care and surgery. Either they don't get the outcome they want, or they're laid up a lot longer than they want. Unfortunately, a lot of our peers or just people out there have said things in sort of hyperbolous fashion that everybody gets better, and so people are going after it. Have to give kudos to Dr. Centeno. He started some of this early on, and he put a lot of effort into money, time, and work, into collecting data, and that was really the first thing, and he collected data. We pound that, data, data, data. That's what I think is one of his greatest legacies, although he's done a ton of stuff. We ended up doing the same kind of thing, is we started a company called Data Biologics that's open to anybody that wants to look at novel treatments that don't have to just be regenerative medicine focused. To get real-world evidence. Why? Because those kinds of things that you're doing and seeing in your clinic that you think are working are disruptive technologies. They change the status quo, and I'm a conspiracy theorist, and I get everybody to agree with my conspiracy theories. The conspiracy of the status quo. If I could do something and flick my fingers right now and eliminate breast cancer, nobody would want that. You'd put half the country out of business, right? So things have to evolve slowly, but we don't want this from research for 17 years until it gets adopted in clinical practice. We want to get it adopted at a much faster pace with good evidence in four or five years. So despite people adopting a lot of these treatments, unfortunately with these great claims, they don't put effort into collecting their data to tell me with the data that they actually made a patient better. And define those kinds of things like, yeah, I went to X and I got stem cells. And you get the notes from it and it says, this is truly stem cells, not what I just said. This is how many were alive. This is the number. This is exactly where I put them. I mean, I get stuff from dermatologists and cardiologists who are treating spine pain, and I look at their notes and I'm like, holy crap. So to me, it's lazy. It's unethical. It's just not acceptable that people are doing novel things and they're not collecting their data. So there's a lot of sort of, people are like, there's no data. And there's a lot of data. The problem is we don't have that data, which you're sort of here today for, is what can I do to my patient on Monday morning? And that translational data, that phase three data, is what do we know? Well, Dr. Chu's gonna tell a little bit about the future coming, so we will have some of this. The good news is we're getting a groundswell of data. So for decades, three decades, we've had a lot of research, but nothing yet to really tell us this is exactly what I need to do for this patient yet. Part of this is research problems. Unlike, say, a product that you have that's got a company behind it or it's got an industry behind it that figures out how they can monetize it, this is everywhere. It's various fields. Nobody's really got a common voice. There's different terminology, nomenclature, different focuses for research, different financial supports and interests, different ways of collecting data you can't compare across. Like, look at all the PRP studies. They all have different outcomes data. So how do you even compare two people who looked and did the same thing for knee arthritis? And then we make bad assumptions about these things and then priorities. My priority is to make a lot of money. My priority is to get this guy's knee better. My priority is to help the spine. So I'm not a lawyer, but this is the most important part of the lecture. A lot of stuff for your slides, but I'm gonna try to break it down into two general categories. On one side, you have 351 and 361, division in the code that talks in details about what that means from the government. So on one side, you can think about it as this thing has whatever characteristics that is a drug. If it's a drug, it's under FDA purview and needs to go that route. If it's not, it's the practice of medicine and therefore it's unregulated, right? Nope. We all have a state board of medical examiners that regulate it. So you still have to do the right thing. And then remember, there's a lot of regulatory terms that people talk about. You should know what IRBs are and INDs. And it's like, well, you can use our product because we have an IRB. No, that doesn't necessarily mean it. So remember, you're on the hook. You need to know what's going on. Don't trust the drug rep. Don't trust some other guy because when the FDA comes knocking on your door or some other governmental agency, you're on the hook, they're gone, they're out of business. Words matter. So be very careful about what you put, like stem cells on your website because that's FTC purview and you might get in some big regulatory problems with that. Be careful in your notes. Make sure you're not documenting putting stem cells in when you're putting something that's been irradiated and everything's been killed and it's just growth factors. So I want to put out also two major cases, we'll call it. On one, the regenerative sciences, they were culture expanding bone marrow and that essentially got put out as that's a drug. That doesn't mean you can't get it. It just means that now has to go through the FDA pathway and that has to be then regulated by the FDA as a drug. You can do that and the Cures Act has allowed a potentially expedited way to do that more efficiently versus the antiquated way to say put an antibiotic chemical through that pathway. And Dr. Chu will probably talk a little bit about those kind of drug pathways. And then fat, is it a drug or not? Well, probably not fat as a tissue as a drug, but if you do something like SVF, stromal vascular fraction, that is a drug now with the last decision just recently came out, that's a drug. So as I said earlier, State Board of Medical Examiners, so you need to read this document, the Federation of State Board of Medical Examiners because that's their overall of all those different states and it has a lot of good information on regenerative medicine and how you should do certain things. I mentioned the 21st Century Cures Act. Important thing is that it allows an expedited potential way for biologic cellular treatments to get through the FDA, even though it's still a little antiquated because they're still looking at sort of getting a chemical and going through the chemical pathway and then making a Botox or an antibiotic or whatever. Oops, sorry, going back. Right to Try is a fantastic thing that was signed in 2018 and that essentially allows someone who's got end stage disease, could be whatever, to allow to have some novel treatment. Doesn't just apply to our field, but we particularly can apply it here for someone who may have end stage knee arthritis. They've had everything you can think of except surgery. They're too old or too sick to go through surgery because it might kill them and then they're a potential patient for Right to Try using stem cells or something else, true stem cells. Guidelines here, something for you to look at if you want some guidelines. From the AALS, their guidelines on PRP as well as on stem cell therapy. Societies, there's a bunch of societies out there. The Academy is doing some work here. They actually put out a recent publication that was fantastic about what you should learn in a stem cell fellowship, Regenerative Medicine Fellowships. They did a lot of work with collaborative other organizations. We're one of the few people we actually have a Regenerative Medicine Fellowship, so if anybody's interested. Data Biologics collects real world data, so that's always a good place to go to do it hopefully simply for you. There are books out there, a couple written by my partner who passed away, Dr. Malanga. The ACIP has some big books for references. Cost, so a quick little comment. This is disruptive technology we're talking about. This is gonna have a lot of resistance, so we need to prove this and prove it well. We need to have overwhelming data. First, safety, and second, efficacy. We need more data, we need more data for everything, but this is really important for this particular field to go. Hopefully I've given you some ideas to think about, expand, and not just shut down and take a nap. This will hopefully get you thinking about the next thing that you can do and try novel for your patients. Then the conclusions, hopefully I've addressed, it says that regenerative medicine that we can term as orthobiologics for this particular lecture and field is it consists of lots of, quote, products or treatments. Some of these treatments have a long track record, or a lot of history, but we haven't really translated some of that yet into exactly what problem and what treatment to do. The research is growing with real world evidence hopefully leading that charge, and then it can help us define what we can do RCTs on. And then this is safe, or at least safer than the traditional treatments that we give. And there's a significant and dramatically changing regulatory landscape that you guys need to keep apprised of, because that's where you're gonna get most hurt. And there are a lot of resources that are also really starting to explode over the last couple of years. So hopefully I didn't go too long, but we can take questions at the end, and it should be hopefully a lively discussion. Thank you. Good afternoon, everyone. I generally talk very slow, so coming after Jay, who talks 250 words per minute, that will be more highlighted. I'm Mary Ambach. I'm a physical medicine rehab physician. I did a orthopedic spine and sports fellowship. And I'm here locally in San Diego. My practice has been predominantly focused on orthopedic regenerative medicine for the past at least decade. And thank you so much for inviting me. So this afternoon, I'll be talking about the current evidence of PRP for low back pain. And Dr. Chu will be talking about mesenchymal stem cell evidence. So why orthobiologics? There has been increasing use of orthobiologics for chronic spine pain for several reasons. Unfortunately, the standard treatments that we currently have is not very effective, or it doesn't last very long. So patients are trying to look for other alternative treatments that has the potential to improve their condition. Also, they want an option for chronic opioid therapy, which is usually what a lot of these chronic spine patients end up with. Back in 2018, this was the first systematic review that was published, which became the foundation for ACIPS, American Society of Interventional Pain Physicians, guidelines with regards to the safe and effective use of orthobiologics for spine pain. And at the time, there was level three evidence for the use of PRP for lumbar disc injections, and level four evidence for the use of PRP for lumbar facet and epidural injections. So fast forward five years, 2023, I was a part of this group, which perform another systematic review on specifically on PRP for low back pain. 40 studies were included, 13 RCTs. There was a high compliance rate for the minimum information that is needed to report studies on orthobiologics through a Delphi consensus. And we found level two evidence for the use of PRP for low back pain. So there's definitely better studies that are ongoing. We still need a lot more, but this is a step in the right direction. So let's talk about intradiscal PRP. This is one of the topics that physicians are interested in, because there's really not a lot of options that we have to treat degenerative discs. The first RCT, randomized controlled clinical trial that was published was by the late Dr. Lutz at HSS and his group, wherein they compared a single injection of PRP versus a contrast, or I'm sorry, an intradiscal contrast injection, which was their control group. The PRP was three to five times more than baseline, which was estimated to be about one to two billion injected per discs. And they were able to show that the single injection of PRP had a statistically significant improvement in pain and function compared to the intradiscal contrast, up to the one year follow up that they did for this initial study. More importantly, there was no side effects within that time. They then did a follow up study at two years, at three years, which they published their results on, and the latest one was this five to nine year follow up study, wherein the patients, the 19 patients who continued with the study and who received intradiscal PRP continued to have a statistically significant improvement in their pain and function that met the MCID criteria, Minimum Clinically Important Difference criteria, of all the patients that were treated with intradiscal PRP. Less than half of these patients required pain medications, and less than a third of them required additional spine injections. They went on further to show Dr. Lutz's group that the higher the concentration of the PRP, specifically 10x group in this study, which means 10 times more than baseline, actually did better than their original group of patients in the RCT trial, which was less than five times more than baseline at 18 months. And so you're gonna see these studies that will be showing more granular data with regards to platelet dosing and patient outcomes. One of the studies that was earlier published was by Jane, showing that less than 400 million per ml of platelets actually did not do so well. And they were also able to show that increasing PRP concentration resulted to, and correlated to increasing improvement in pain and function. So there's a lot of this data now with regards to the peripheral extremities and the tendons and the joints, and we're now arriving at specific platelet doses. That will result to better outcomes, and you'll see that trend will show as well in the spine studies. We also did another randomized controlled clinical trial on the use of PRP and bone marrow concentrate for degenerative disc disease. And this was a multi-center trial, four centers across the country. And this was interventionally spine trade payment art physicians, anesthesia pain physicians, with a total of 60 patients that were enrolled, 15 at each site. There was a crossover design, wherein the patients who did not do so well in their treatment arm had the opportunity to cross over to the other treatment arm at certain time frames. And we followed these patients for one year. Our 12 month results show that both the PRP and the bone marrow concentrate resulted to statistically significant improvement in their pain score and their oswestern disability index at one month compared to baseline. Although the raw data for bone marrow concentrate was actually better, there was not enough power in our study, in our data to show that there was statistically significant difference between the two. We found them to be equally effective in treating discogenic low back pain with one injection, with or without leg pain. And all the patients who crossed over from the placebo or from the other treatment arm also showed significant improvement in their pain and function at one year. And most importantly, there was no complications that were found in both the biologics that were used. So not all of the RCTs that are published resulted to positive outcome. This is one of them, wherein they didn't show any significant difference between one cc of intradiscal PRP versus the control that they used. It was a low blood volume to begin with. It was a 32 cc blood draw, which most likely resulted to a low concentration of platelets. And the control that they used was an antibiotic with the saline. And if you look at some of the data with regards to the pathogenesis of degenerative disc disease, there is some data out there with regards to an overgrowth of C. acnes, which is a gram-positive anaerobic bacteria, which they think to be a possible contributor to the pathogenesis of degenerative disc disease, wherein an overgrowth of the bacteria or a dysbiosis in the normal flora of degenerative disc could contribute to the pathogenesis. So probably doing that as a control might have, may not, but it might have influenced the results of their outcome. So now moving on to epidural PRP, a lot more physicians are actually doing this procedure in spine orthobiologics, because there's a lot more physicians that are trained to do epidural injections more than intradiscal injections. This was the first, one of the first RCTs that was published comparing a single injection of PRP versus the same volume of steroid injection injected through a caudal epidural injection approach. This was a leukocyte-rich PRP formulation versus a 60 milligram of Celestone injection. And if you look at the graph on your right side, on the first month, the steroid actually did better. There was better pain relief during that first month, but after that one-month period, the PRP had a more sustained response, and it had continued improvement in the VASA score, pain score, and the short-form survey. So the patients actually did better up to the six-month follow-up of the study. Another RCT on PRP epidural versus steroid epidural injection. This time it was a transferaminal approach wherein they injected three cc of the PRP on each level. It was a three to five times baseline concentration PRP, and they also had a six month follow up, and same graph that you just saw on the other RCT, I'm sorry, wherein during that first month the steroid group actually did really well in decreasing the pain, but the effects did not get sustained past that one month period. And so this is something that you will see as a trend if you look at all the randomized controlled clinical trials comparing PRP epidural versus steroid epidural injections, wherein the patients actually do really well during that first month, but after the month one to three period the PRP starts kicking in, and it has a more sustained effect. So I included this for your reference. These are four other randomized controlled clinical trial comparing PRP epidural versus steroids, and most of them are six to 12 month follow up, and you'll see the same results, consistent decline in the steroid effects after the first few months. The PRP offered a more sustained and superior benefits up to the six months follow up. There were two studies that actually follow up to 12 months, and during that 12 month period they didn't show any statistically significant difference between the PRP and the steroid group, but much more need to be studied with regards to platelet dosing and what kind of PRP formulation was used in those studies. So now moving on to facet joint. There's not a lot of high quality studies in facet joint. There's at least two randomized controlled clinical trials. This is one of them, a WUS group, compared PRP versus lidocaine and steroids to facet joint and capsule injection, and they used 0.5 cc of volume of PRP, four to five times baseline concentration, follow up of six months. Same thing as the epidural steroid studies, epidural steroid versus PRP studies, wherein there was significant improvement in the pain scores and the functional outcome scores at one month in both groups. However, the PRP had the more sustained improvement past that one month period. And more importantly, it was a safe injection. There was no adverse events. So with the advent of orthobiologics and regenerative medicine for spine, there is a resurgence of this concept of a functional spine unit when we treat spine with interventional procedures. And the thinking is that because the spine almost always is a multifactorial complex etiology for the cause of the pain, why not treat all the structures that contribute to the stability of the spine and have a better outcome? And so we tested this hypothesis, and I was a part of the group that did a prospective case series on a multi-target PRP injection for chronic low back pain. And it was a total of 46 patients. We did follow them up for one year. We included facet joints, intervertebral discs, epidural space, and paravertebral muscles. And we devised some clinical criteria on how to identify which structures to include in the injection. All of the patients had more than one injection. About 75% of the patients had more than three, at least three structures that were injected. And we were able to show statistically significant improvements using this approach in both the pain and Roland Morris Disability Questionnaire. At one year, almost 66% of the patients reduced, of the number of patients were reduced who were taking opioids. There was a good satisfaction. NAS is scored to good to excellent, and 82% of these patients would repeat the injection if they need to. So Dr. Bowen was talking about data biologics. We use data biologics as well to follow and track our outcomes. This was with my San Diego Orthobiologics Medical Group with Dr. Chris Rogers, who's here as well. And using the personalized multi-target PRP approach, we were able to show that out of the 100 patients that participated in the survey, 61% of them improved in their average disability index at one month, I'm sorry, one year. And out of the 84 patients that participated in the survey, 43% improved their pain score at one year. There's one RCT that used multi-target PRP injection. This was PRP injection versus lidocaine injection for mostly the posterior column, ligaments, tendons, facets in the lumbosacral spine. But they also added a layer of prolotherapy injection to the two treatment arms. And the results showed that the PRP and the prolotherapy group actually had better outcomes, better pain improvement at six months compared to the lidocaine and prolotherapy group. However, both had the same outcomes when it comes to the functional scores. So this is where we are now. With regards to intradiscal PRP, we have at least four. I think there's about five or six now. That have favorable outcomes with intradiscal PRP. There's two that are published that did not have any favorable outcome. One of them we discussed that used a antibiotic for control in a low platelet whole blood dose. And also, the other one was Zelensky's study, which they had to stop a very early one at eight weeks due to a futility analysis. It's hard to draw conclusions from that study. With regards to epidural PRP, there's five randomized controlled clinical trials showing favorable outcomes. One that did not show any favorable outcome, no significant difference. And it was an 18 ml blood draw, which most likely resulted to a low platelet concentration. And the epidural was done through an ultrasound guided approach and not the fluoroscopically approach, which is the standard of care. Two RCTs on PRP facet and one RCT on multiple target injection. So how much data does one need to proceed to a treatment that's still considered experimental or novel? That's really up to each and every one of us. That's where real world data comes in. That's where evidence based medicine comes in. But the take home point is that there is increasing evidence of good quality data on these studies. Chronic low back pain is just very, very hard to treat. For all of you who are treating spine, I'm sure you would agree. It makes it challenging to create PRP protocols, much more to design studies to standardize the methodologies to do high quality data studies. But in spite of that, there's still increasing evidence, high quality data on the safety and efficacy of using PRP for chronic low back pain. And more high quality studies along with real world evidence is needed to move this field forward. These are my references. Feel free to contact me if you have any questions. So we have Dr. Bowen talked about that a variety of biologics and body, and meanwhile Dr. Omba talked about the PRP. I'm gonna talk about cell therapy, gene and cell therapy, and what we're doing in the laboratory at this point for the future. So I hope that's mine. Yeah, we'll talk about. So I'm gonna give a couple of examples. Matter of fact, so this is not relevant. So first, cell therapy and gene therapy. What about the gene and cell combined therapy? That is the future. And cell therapy, apparently Dr. Bowen talked about that the MSC therapy, we still use the terminology MSC regardless of exactly which word we're using. MSC therapy, MSC, it is falling into the category of a drug. So therefore that cannot be used without FDA approval. At this point you're gonna have to get a IND like an investigational drug license for that. So otherwise you won't be able to. So hopefully sometime soon we're gonna have a product that is gonna be approved. I know there are products that's in the process of being applied for licensing for that. So that's cell therapy. But cell therapy, mesenchymal stem cell therapy, a lot of the time people use the bone marrow-derived mesenchymal stem cell therapy, adipose-derived mesenchymal cell therapy, plant placenta tissue-derived mesenchymal cells, you know, MSC therapy. These are the common ones. There is another type that is induced pluripotent cell derived MSC. And then why do we do induced pluripotent MSC? Because that is one cell line with the master cell bank. You're gonna be able to derive unlimited number of MSCs. That takes away of the interpersonal differences between your drug. If you get one batch of drug from one patient, one donor, another batch of drug from different donor, everybody's different. You know, the phenotypes are kind of different. So one cell line that gives unlimited number of cells is very desirable. So the characterization is gonna be easier. And then the effects can be monitored a little bit better. So that's the types of cell therapy. And I'm gonna give a couple of examples of what cell therapy has been doing. But what's the future? Future is gene and cell therapy. And cell and gene therapy, CGT, a lot of time people use the terminology for, is either you use gene, you put a piece of gene in the cell, and then for that, you augment a particular type of activities of the cell that is desirable according to the target you have found. So if you are finding a particular type of, for example, published data by Dr. Alba Zuber of Milton, Florida, he targets interleukin-10, which is a anti-inflammatory cytokine. So you put a gene in a cell, the cell produces a 100-fold increase of the interleukin-10, and then you put this cell in where you are gonna treat. So that you know what's going on, particularly you know there is a increased dosage of interleukin-10 that is gonna modulate the microenvironment in the anti-inflammatory direction. That is the gene and cell therapy. Otherwise people put particular genes using a virus into the cell, and that is another type of it. We're gonna go over some of that, but also non-cell therapy, extracellular vesicles, which is a vesicle that is produced by the cell. A lot of time people call it exosomes, which is a smaller portion of that with a particular size of the particles. So that's another part of it. I'm gonna give some examples on the cell therapy and the EV therapy. So I'm gonna give two examples on the cell therapy. First, spinal cord injury. So we all know the pathophysiologic processes with spinal cord injury, but of the cell therapy for spinal cord injury, we are taking advantage of the cell's immunomodulatory effect, particularly on the top of it you see the cytokines, and then you're producing anti-inflammatory cytokines, interleukin-4, interleukin-10, all that. And also some trophic factors from it. But also in modulated T-cells, you decrease the proliferation of the T-cells, and then also on astrocyte. Astrocyte, we know in spinal cord injury, astrocyte and the microglia, these are the two major categories of cells. Both cells has a pro-inflammatory state and anti-inflammatory state. You're gonna have to polarize that to one state or the other. Cell therapy helps the astrocytes, as well as the microglia, to change from one state, the pro-inflammatory state, to the other state, the anti-inflammatory state. So therefore it's changing from A1 to A2 and M1 to M2. So these are the basic reasons. So a hypothesis how cell therapy helps in the spinal cord injury. So we have done a clinical trial on a cell therapy for a spinal cord injury. We had 10 patients that has been finished. That's the phase one study published. The phase two study is 40 patients, randomized trial. 20 patients get the cell, 20 patients get the placebo, but six months crossover is possible. So the phase one published, so here's the data. Of the 10 patients, the cell is autologous, adipose-derived MSC. So essentially the patient comes in, within two weeks to a year, that's the inclusion criteria for a patient to be included. So a patient comes in, you take a piece of fat, then you culture the MSCs from this piece of fat, and then from this fat, after all this quality control has been performed, there's no contamination, all that, and number and viability, all that is proper, you inject back into the intrathecal space, 100 million cells per patient, one injection. So at the end of the day, seven out of the 10 patients got improvement in motor and sensory function, at least one level. And so there's improvement. However, we all know that the natural history of a spinal cord injury is the improvement. I'll bet all these patients are in the later part of the one year timeframe. So therefore, the natural history part, we passed most of the case, that the rapid, like a hockey stage of the improvement, however, we have to screen out the confounding effect of the natural history, therefore a controlled trial is ongoing. We actually just got the 40 patients, but the follow-up needs to be done, and then data will be published in the next couple of years. So that's cell therapy. What about cell therapy for disc and for lumbar facet arthritis? So for disc, there has been a phase three trial that has been sponsored and done by industry. The trial was done actually is 2020, and then we're still yet to have the publication that is released. There is no peer-reviewed protocol that has been published, but there has been a news release that says the pain and function has improved. So that's the cell therapy for disc, and cell therapy for lumbar facet arthropathy, we did a trial, we did a phase one trial, 10 patients, one loss to follow-up, nine patients of that, three-thirds of the patients did have much improvement, it was good, but however, that's a open-label trial, we don't know yet. So we are currently conducting a phase two trial, randomized trial, so that's a six-month crossover, same idea, but we're yet to finish this recruitment by probably by the end of the, no, by mid-2025, we're gonna finish that recruitment. We'll report the outcome of that. So looking into the future, so here is a non-cellular therapies, is the extracellular vesicle, what is an exosome? It is a small bubble at about 100 to 300 nanometers big that actually comes from the cell, and then this bubble actually used to be thought to be garbage from the cell, but actually it contains, number one, a lot of genetic materials, number two, particular type of proteins. So is that, at the beginning people have been reporting that this extracellular vesicle, the EV, has anti-inflammatory immunomodulatory effects, just like MSCs, I was suspicious of that, and we conducted those studies in my laboratory. As a matter of fact, I would say I was pleasantly surprised that they say there has been a strong signal of the immunomodulatory effects of the EVs, but also the next step, of course, is we are genetically modifying the EVs, and then genetically modifying the cells. We put genes, just as you said, Dr. Soubir's work, we put a particular type of gene in the cell, the cell produce the target molecule where we use it for treatment. So I'm gonna give an example of how the EV has been demonstrating is some of the immunomodulatory effects. So first, the EVs, here we are seeing that the EVs are uptaken by the cells. So this is just a staining to show that if you culture the EVs, in this case, I'm doing that with the spinal cord injury, this is an individual spinal cord injury model, and here we are working on the microglial cells. So culture the EVs with the microglial cells, they are uptaken from this. But next, so I have a lot of the data, but I was advised to present the conclusion of it rather than the raw data, it will be published so that you can see, just follow my publications on that. So essentially, if you culture the microglial along with the control, and then along with LPS, LPS stimulates the cells into a pro-inflammatory state. So after, that's another arm, another one, actually, the last arm is LPS plus EV. That's derived from IPS-derived MSC. So of that, so you can see there is a down regulation of the pro-inflammatory molecules, including ionized, and interleukin-6, interleukin-1 beta and TNF alpha, which we have confirmed from two different PCR study as well as the ELISA studies. So also, the EVs promotes the migration of the microglial cells. So this early migration of the microglial cells is important for spinal cord injury, because it goes there to clean up the dead cells. In astrocytes, pretty much the same thing happens that is well uptaken, and also in astrocytes, it shows that it down-regulates the interleukin-1 alpha, interleukin-6, interleukin-1 beta, and TNF alpha. And that can be tested on both the protein as well as the genetic studies. There's another slide that's not here. So also, EVs prevents the astrocytes from apoptosis. So what about degenerative disc disease? Degenerative disc disease involves cell death, so there's apoptosis of the cell. In our disc cell, in the nucleus pulposus, you have 4,000 per cc of tissue cells. That is not a whole lot. Once you go through the degenerative process, your cell population decreases. So with that, there's information, but also with the pro-inflammatory processes, your enzyme for the matrix degradation goes up, and then also the synthesizer of the matrix molecules is down-regulated. Therefore, you lose matrix. With loss of matrix, of course, you lose the attraction of water, so you've got a black disc disease. So for that, the cell therapy, the idea is that because of the immunomodulator effect, it protects the cell population, but in the meanwhile, slows down or protect the matrix from controlling the matrix MMP family and also increase the matrix production with the type two collagen and so forth. And this is our study design. We have the nucleus pulposus cell. There's a human cell. We stimulated the cells with interleukin-1. With interleukin-1, then, of course, the cells get into a pro-inflammatory state. Then we provide the EV, and then the EV shows that it actually controls the cells in a sense, and let me see if the data is here. So the EVs are uptaken pretty well, and here's the result. So with the EV treatment, the MMP-3, MMP-13, they go down. These are the enzyme, degrading enzymes, but also the interleukin-6 goes down, TNF-RFR. These are the pro-inflammatory cytokines, but also they do increase the collagen-2 production, so that's the matrix production. So remember, so these products, because of the regulation, has to be produced in the GMP facility, good manufacturing practice facility. What it is, it's just like a hyper-clean facility. It is in the ISO 7 room and ISO 5 hood, which is very, very difficult to maintain, and it is very expensive to do that. So every product has to go through a process development, manufacturing, quality assurance, quality control. All these are very expensive, so this is our facility for GMP manufacturing, and for these cells also, they cannot be just used. If a patient comes in, I got stem cell from somebody, I'd already got it from the Caribbean and otherwise, in the United States, it's not possible, because none of them has been approved by FDA so far. So the summary is that the EVs has a strong immunomodulatory effect, and EVs demonstrate anti-inflammatory trophic effects, but also we need to be aware of the regulatory guidance that's come from the FDA. So that's our team, and if you have any questions, I think we're gonna enter the question state. Let everybody know we're streaming, so there's some questions coming in from that side also, but I thought I would take one moment and think back to my patient again to start with, but they're often told they are going to regrow the disc, especially, as part of the marketing, and I didn't notice there was any discussion about any changes in radiologic issues, disc height, other structures, and things like that as we're doing things. Is that something we should be able to share with our patients, that that's probably not going to happen? Well, you've heard a little bit about my comment regarding imaging, so I have a bias, and when I go with our research team, there's always that push and pull. Right now, we're trying to look at disease-modifying agents for NeoA, and they wanna do X-rays and MRIs, and we're gonna do some cartilage mapping. I don't really know on the disc how valuable it might be, but there is that push and pull. Mainly, I'm trying to appease my orthopedic colleagues who all they care about is how it looks, but we know how many surgeries have happened, and it looks a lot better, and it functions a lot worse. There are a few studies on PRP and intradiscal BMAC that showed before and after MRIs with increased disc hydration. Good. The one other thing I'd like for you to comment before we go on is, if they're having intradiscal or facet or the other areas injected, when do you consider restarting them into an exercise rehab program? How quickly or how much do you wait after a procedure before you think it's appropriate to begin doing those things for our colleagues? Yeah, I mean, I would say that generally, I recommend relative rest for about four days. Usually, one week after the procedure, they're back to doing generally what they wanna do. On the spine, generally, things take a little longer. So, as you saw, some of the data, four weeks. So, generally, you can do therapy, and you're not hurting anything. The problem is they might have too much pain to adequately participate and fire off everything and retrain. So, I will usually see them back in about four or five weeks, and they just sort of keep active and aren't laying around. And then, around six weeks is when I usually institute a rehab program. Yeah, after the biologic injections, the patients go through an inflammatory phase, which usually lasts about seven to 10 days. It could be longer in some. So, just like the extremities, we usually wait about a week for them to start PT if they're getting an epidural injection or a facet joint injection. However, for intradiscal injections, these patients are usually pretty sore for about two weeks. So, we wait at least two weeks if they can. They can start that early. Otherwise, it's usually two to four weeks before they can start rehab. Great advice. Questions? Oh, yeah, thank you. So, thanks to the panel. I really appreciate. I'm gonna start out with venting a little bit, just because it's healthy for me. I've been doing the regenerative medicine maybe for about 10 to 15 years. And so, we see a lot of literature has come out since we first started. I'm in the Los Angeles area. The comment was made that it's the wild, wild west in Florida. No, it's the wild, wild west literally out here. And so, my question is, and comment, is originally I was doing bone marrow stem cell, and then the literature came out that said no, no, no. The stem cell's not good for older people. So, then we have vendors coming with packages and selling us stem cells, and then selling exosomes. And so, I just wanted for you just to clarify for me, where are we now with the evidence? My understanding is if we're gonna do stem cell, we should get it from the patient and adipose. And we're not ready for this packaging exosome stem cell stuff, is that the consensus? Yeah, the first thing I would say is let's be mindful about terminology and words. We have to be specific. I mean, cell therapy. Yeah, so cell therapy's good, because we're not, as we heard from Dr. Chu, that there really is no stem cell therapy being delivered in the United States. That is a little caveat. There are some potential areas we can get it through the right to try, but you can call up those clinics and talk to the medical director to know what that patient got, and they're gonna be legit and have a lot of information, versus I get it one page and there's a couple Xs on it. So that's the first thing. Second thing is, is I would say still as of today, exosomes, extracellular vesicles are mainly allogenic, and therefore would be in the drug pathway side. So they have to be approved, and right now, I don't know of any approved. There's been at least 14 letters that say cease and desist from the FDA. So you have to be very mindful. There's a lot, as you said, the wild, wild west. There's a lot of things being said and promoted. The things that you have to do is find reputable sources like potentially us to help you, or organizations I put up there to vet what those products actually are and what they're not, because a lot of people go, I got X, and I'm like, well, they irradiated it to make sure you didn't get a disease, and therefore, if there was a cell in there, it just killed it. Doesn't mean the product may not work, but it's not what's in there. So it doesn't exactly answer your question other than we really have to delve in to figure out what are these people getting, and then, even I said, PRP, there's some things that they don't define the dose. Dr. Ibeck said the same thing, is that we're having some dose of where it's getting, but we don't quite know. We have general guidelines, but the question is how many people that are doing this in their office actually have a cell counter, are counting those cells, and saying, yes, I'm giving it. The company says, you do this, and you get 400 million cells or more per cc, but if your tech draws the blood incorrectly, you process incorrectly, and you have a pristine way to put that in, who cares, because maybe you put one platelet in, even if that was the perfect technique to do it, and if you're not doing QC and QA, you don't know what you're putting in. So, we still don't know the answer to your question specifically. Clutch. Yeah, thank you for the presentation, and in the studies in particular where there was multiple structures being injected with PRP, and they made reference to epidurals, or in your clinics, when you do epidural with PRP, must that always be lysate, or is there actual PRP being injected epidurally? Yeah, if you look at all the epidural PRP studies, they're all different kinds of PRP formulations. There's releasate, there's lysate, there's poor in WBC, there's rich in WBC, so we don't really know. All the studies are all kind of mixed. I used a formulation that's low in WBC, only because it does, sometimes it does tend to flare out some of my patients, although some of the newer devices are now very good at not creating that inflammatory response, even with a very high number of platelet count. Intradiscally, it's a little bit of a gray area. There's now more studies on leukocyte-rich formulations and high-dose PRP intradiscal, especially with the data on the C-acnes, and possibly dysbiosis as a contributor to the pathogenesis of degenerative disc disease. And so, yes, I share your concern and your feeling with regards to what kind of PRP should I use. Definitely no RBCs, especially epidurally, but with regards to leukocyte-poor, leukocyte-rich, we still really don't know what's the best. And specifically, lysate, it needn't be lysed to get into the epidural space. That's what I was under the understanding for a while, that to do it epidurally, it had to be lysate, but that's not true, apparently. Not necessarily, yes. So there's a question from the audience online, too, about why do we think there would be a significant improvement in leg pain after doing the epidural with this? Any thoughts on that? There's a lot of studies on the different growth factors actually helping with nerve repair. There's actually animal studies showing improvement in myelination, in axonal regeneration, myelin sheath formation with the growth factors in the PRP. And so the thinking is that you'll help, not just in the anti-inflammatory aspect, but also in helping with the nerves getting healthier. Excellent, question? Hey, y'all, thank you for the informative and engaging talk. My name's Sager, I'm a fourth-year medical student from PCOM South Georgia. If you need a pronunciation help, it's Sager, like logger, but with an S. My main question was about kind of understanding the data collection and a little bit about data biologics. So my question being that, as a medical student, especially from second year to fourth year, a lot of times I think about what's the best treatment. As I've gotten into clinic, I've learned a lot about the cost and the treatments and how we can get there with insurance. So my question is kind of wondering, as we improve data collection, do you guys think there's a timeline to thinking when we may get some more general insurance approval for this? I don't even know if we want insurance approval, but that's a longer story. Number two is, at least our focus is to get enough data to make a convincing argument, and what are insurance companies in the business of doing? Managing risk. So not only do we have to prove that it's beneficial, but we also have to look at, in reference to standard of care, and show that, we've already shown, I think, that it's safe. And then look at, is it as effective, if not more effective, and then is it cost-effective for that? So the sections that are actually worried about direct costs would be, say, workers' comp, because they actually care about saving money and not just increasing premiums. So our probably first goal would be to try to get self-identified companies to look at comparison and even sharing risk about trying to treat people, thinking of more data to maybe have it translate to commercial or even Medicare. I'd throw in one comment on the slides we're up to about what people are told about their pain may go to zero, and you saw even in the studies where there was significant difference between the PRP at levels. They were dropping four to two, six to two, three, and patients go with the expectation that when you're gonna have a procedure, I'm gonna be zero, right? And so I think, once again, what do we tell our patients about this is be realistic with what the expectations are going into the procedure, and that's something good practitioners are going to share with them, too. Thank you all. Yeah, actually, thank you, great presentation. Just a quick follow-up question on that. So let's say in an academic center, we're trying to get this involved. I've actually had a good amount of patients trying to ask about Facet PRP, and there's some decent data on that now, and just trying to, how did you come up with the cost? Because I know you're still doing the procedure, and you're, how many levels bilateral, you know, how many levels you're gonna do. How do you break up the cost in terms of what you're gonna charge the patient, because the kit's costing money for knees, we have stuff, you know, we're doing it, we have some data, but how do you do that for the spine? If you can help, like, help us create something. Well, I think there's two sets, right? Private practice and academics. So I'll speak to the private practice point, and that is that I know how much my cost is with my staff, my overhead, my insurance, et cetera. I don't think many physicians know that, number one, because they're not running the business. So you need to know how much it costs you per half day to run your business. You need to know how many patients you have. And you can't just go, well, PRP should be five bucks. Why, just because the guy down the road charges six? I mean, I charge more than most people in my area, and some people shop, and that's fine. I go, you're looking at my expertise, my training, my research, et cetera. You wanna go somewhere else, you go somewhere else, that's fine. In an academic center, the hardest thing is getting it through the administration. Then the second thing is administration has no idea to handle the cash. Then the third thing is, how do you get what your actual cost per hour or per unit is to then break it down and say, it takes me 30 minutes to do a PRP procedure, and it costs us to run this clinic $400 per half hour. That's how you should truly develop it, not like, hey, the guy down the road said it's 400 bucks. So what? Maybe your cost is cheaper or more. You have to go with what makes business sense for you. And you have to prove value to your patients in multiple different ways, and then you can justify whatever you're charging. Completely agree, and just for a practical standpoint, the way that I charge my prices is that, for spine, especially, there's a limited spine cost, and then there's a comprehensive spine injection cost. Usually my comprehensive spine is anything more than three structures that you inject. That's, I would consider that comprehensive. Most of the spine cases are comprehensive. And then, in addition to that, there's the additional kit. So you can charge for the additional kit, and it depends on what kind of kit you're using. But completely agree with Jay. You gotta know what your overhead is. You gotta know what your cost is, and then what you charge for your time, and how long it takes you to do the procedure. Great, thanks. We got time for one last question. One quick thing is we also use anesthesia, so that's a potential added cost, too, you don't wanna forget about. Oh, I'm glad you let me sneak in. Byron Schneider, Vanderbilt, no disclosures. Um, my question would be, and I might have missed it, but I don't think we're, when you think of complications here, so like with PRP, there's no RCTs that fall up over eight weeks that show benefit to placebo. And what's surprised me most in the papers with the PRP, their stem cells, is we have small RCTs that are multiple studies capturing risks of dischitis osteomyelitis. That risk in the published data is like 3%, and that's a major complication. So how are you balancing, like if it was me, I wouldn't want it, to be honest. I don't want a 3% of a disc infection. So how are you balancing that with your patients, or do you feel just anecdotally the risks and complications aren't that high? Because if you look at RCTs for things like epidurals, we know there's complications of paralysis. Like those things don't get captured in RCTs, because there's such low incidence of those major complications. And yet, all these RCTs are showing that dischitis osteomyelitis occurs with these injections. So I think that you gotta look at the details a little bit. We've learned quite a bit. If you use bone marrow in the beginning, you add more of the dischitis. You use PRP, and that's a lot less than you're getting. And two, I think the most important thing is, while we're doing this, you be honest with your patient. You're gonna undergo surgery, you have a 0.1% chance of dying. I tell the people, you're not 0.1% dead, you're 100% dead. So I always tell them with everything I do, the worst complication I think we can get is an infection, whether it's disc or otherwise. Like to me, this scares the crap out of me, and keeps me up at night. And it's why I'm very, very, very cautious about sticking needles in discs. I mean, I think the preferred method, which we may be able to get to, is actually doing the intervertebral body, and injecting it to get to the end plate, and not actually sticking needles in discs. But that's sort of the future, potentially. All right, so I apologize. They want us to kind of finalize things, because of the next session coming in. But I want to thank the panel once again. I hope you all enjoyed it, and hearing their thoughts as much as I did. Thank you.

regenerative medicine

spine conditions

stem cells

PRP

Jim Acheson

Dr. Jay Bowen

prolotherapy

ozone therapy

gene therapy

cell therapy

patient outcomes