Welcome, everybody. Thanks for joining us today on Saturday. We're going to be having a great group of speakers today, and we're going to be focusing on biologics for the spine and sacroiliac joint complex. We're going to talk about the background, the evidence, and the clinical applications for these. Again, my name is Aaron Yang. I'm at Vanderbilt University Medical Center, and again, appreciate your time to join us today on Saturday. So no relevant financial disclosures. I wanted to let you know I personally do not utilize any biologics in my practice. A quick word about CME credit. In order to claim CME credit, you need to complete an evaluation for each session you attend live or on demand during the assembly. All sessions will be recorded and made available on demand until January 31st of 2021. If you have any questions, visit the Member Resource Center. And lastly, also make sure on the feedback, you let the Program Planning Committee know in terms of suggestive content for future meetings. In addition, if you are tracking CME credit live, we ask that you wait until next Wednesday to enter everything due to heavy traffic volume. So again, we have some great speakers joining us here today. Here's our overall outline. We're going to have Charles discussing molecular and cell biology of biologics. And then Byron's going to be talking about biologics for the intervertebral disc. And Zach's going to be going over the biologics for the SI joint and dorsal ligament complex. And then lastly, Mehul will be talking about practical considerations of biologics. And we hope to save some time at the very end to field some questions. So here's our three main learning objectives. The first is to have a basic understanding of the rationale for use of these biologics. The second is to be able to understand the clinical indications and limitations of biologics based on the available evidence to date. And then lastly, as a result of attending the session, to appropriately identify patients and navigate the various regulatory or cost issues we or the patient may face. So why do we want to discuss this topic? Well, first, it's an emerging area of interest. Patients will ask you about this. They may ask about different types of biologic injections. Other faculty and trainees may have questions about this as they hear about this topic more and more. Now lastly, we want to keep up with the literature and also have an idea of the future direction of spine care. So when it comes to biologics, here are some things that comes to mind for me. It's really the five W's. First, who is the appropriate patient? Second, what are we injecting? Third, when do we actually consider biologics as a treatment option for our patients? Four, where are we injecting this? And lastly, why? What is the rationale for biologics? As I mentioned before, if you take a look to your left, there will be a Q&A box. And if you cannot find it, hit the question mark button. And in this box, I want you to ask any questions that you may have for any of the speakers. And at the very end, we'll try to field as many of those questions as possible. So before we get going, we wanted to ask a poll question for everyone there. We want to know, do you currently utilize any biologics for the spine or sacroiliac joint complex in your practice? So we're going to take the poll here. We'll give it a few more seconds to let attendees respond. All right, so let's take a look at these results here. So we have about 85% of attendees saying they do not utilize Biologics, while 14% say they do. And so without further ado, we're gonna get to our speakers. And we have, again, a great panel that are coming from all over the country, Utah, Nashville, Connecticut, and the Washington DC area. So our first speaker is going to be Dr. Adankor, who is at Yale School of Medicine. Hi, everyone. Thanks for taking time on a Saturday to share time with us and learn a bit about Biologics. So, let's see, adjust here. I do not have any financial disclosures at this time. So I'm hoping that in the few minutes that we have, we can talk about the cellular molecular biology of Biologics, the mechanisms of spine pain, and then also how these regenerative methods for Biologics target the various mechanisms of pain to help solve or relieve the pain induced by these agents. So typically, when we talk about spine pain generators, these are the most common generators that we currently target right now in clinical practice. So the Z-joints are pretty much a common source of pain. We try to treat that with MBBs. Also, we have the disc. And previously, there have been intradiscal treatments. And you also have your ligaments, myofascial pain for muscle, your nerve roots. Typically, we do epidurals and things like that. So these are the most common pain generators. So overall, the main mechanisms for spine pain, these are listed here are the primary mechanisms. There's been a lot written about degenerative wear and tear. So we are gonna go into that a little bit. Primarily, this results in destruction of the spinal architecture. There's also the hypothesis of inflammatory dysregulation. We're gonna review that briefly. And then we have homeostatic imbalance, either metabolic or immunomodulatory imbalance. And you can break that down into catabolic versus anabolic or nutritional dysregulation. You also have some neuronal hyperexcitability. That is a potential mechanism. And then the good old biomechanics, we are pretty much familiar with that. And then the idea of central versus peripheral sensitization. So this schema here basically shows what happens at the molecular level. So a patient is exposed to some kind of stimulus. It could be heat or it could be a mechanical pressure. And this essentially leads to what's called an inflammatory soup. So you have release of all these inflammatory agents, TNF-alpha, TGF-beta, et cetera. And these basically bind to their receptors. These are nociceptors on the cell surface. And continuous exposure to the nociceptor stimulus essentially leads to what's called hypersensitization of these receptors. And that's really the underlying mechanism for peripheral sensitization. On the flip side, you have these nociceptors that map on centrally into the spinal cord. And so as you have C-fibers continue to fire, they activate release of various neurochemical agents. Primary of these are glutamate and BDNF, which is brain-derived neurotrophic factor. And these essentially then lead to release of COX-1 and COX-2. Now, the difference between peripheral versus central sensitization is that as C-fibers continue to fire in the periphery, they essentially lead to the concept of windup. So where you have temporal summation of all these signals coming from the periphery to the point where now when the patient is exposed to a non-noxious stimulus, you still have ectopic discharges in the spinal axis. Okay, next. So here's a schema essentially showing that once the peripheral nerve fiber, C-fibers are activated, they release glutamate. The glutamate essentially then binds to various receptors in the postsynapse region, and then that leads to an influx of calcium. This then leads to altered sensitivity of second-order neurons. And this is like the primary mechanism by which acute pain becomes chronic pain. Patients develop hypoalgesia and then also allodynia. And as I said before, you have ectopic discharges even in the presence of non-noxious stimulus. The interesting thing is that the peripheral fibers also have mapping in the dorsal horn. So here in the upper left corner here is showing different fibers and how they map onto the rectal laminar. So here you can see that, for example, the C-fibers map onto one and two, whereas the A-beta map deeper into three and five here. And this is one way in which the stimulus in the periphery, it's connected centrally. And so this is very important because even currently now, we use medications like SNRIs, anticonvulsants to try to target some of these fibers in the dorsal horn. And this is one approach that we're gonna look at for regenerative biologics. Here is a schema showing the C-fibers in the common so-called degenerative cascade, where you have an insult leading to degeneration. You have tears in the annulus fibrosus. This then leads to inflammatory cytokines. And then it also further leads to damage of nerves that are in close proximity to the disc. So you have a radicular pain. And then in addition, you can also have things like facet hypertrophy that will also then lead to stenosis, whether central or foraminal. So currently, one of the thought process is that for discogenic pain, normally the annulus fibrosus doesn't have, I mean, the annulus fibrosus has all the innervation. So you have fibers coming from the dorsal root ganglion that are innervating the annulus, but then there's no innervation for the nucleus proposals. However, emerging data shows that this is actually incorrect when it comes to discogenic pain. So with release of brain-derived neurotrophic factor, you actually have these nerves coming from the DRG that start to penetrate into the nucleus proposals. And apparently, this is one mechanism by which we have generation of discogenic pain. As a side note, there's currently actually a vertebrogenic pain concept is similar, where you have fibers penetrating into the vertebra. So in terms of biologics, I think this is like the most important slide for today. You have a normal disc where the supply of nutrients from the vasculature into the nucleus proposals and annulus fibrosus. But with degeneration, you have calcification of the end plates, you have diminished nutrient supply. Now with biologics, what we are trying to do is to supply these things that are listed here. So you have growth factors, you're using platelets, we have cell matrix, you have mesenchymal stem cells. And essentially the way this is supposed to work, it's supposed to help regenerate and fix whatever damage has occurred. However, if you look at the degenerative disc, there's already an increased demand for nutrients. And because there's no access to the nucleus proposals and the annulus fibrosus due to lack of vasculature, there's already a nutrition deficiency. And then you add on top of that, these biologics that then also serve as nutrient sinks. And so you end up with a situation where demand completely exceeds the supply. And this is something that we still haven't figured it out yet, even though we are currently now using biologics in the clinical setting. I also just wanted to make sure that I make a note here that when we talk about biologics, we are not really referring to things like tumor necrosis factor inhibitors that are used in the setting, like in rheumatological settings. We're referring to things like PRP, mesenchymal stem cells and adipose derived stem cells. So PRP is basically autogamous plasma that is being used in a superior physiologic concentration above what we normally have in the blood. We just concentrate it in a higher amount and we try to give it back to the patient. And what is the underlying mechanism for this? So typically when you have an initial insult, you have two main phase. You have an inflammatory phase and then you have a proliferative phase that tries to fix the damage that has happened. So in the proliferative phase, usually occurs between days 14 to 21 and then you have remodeling that occurs on day 28. And what happens is that initially you have platelets that arrive at the site and then that serves as a stimulus and recruits neutrophils, macrophages and T-cells to the site, which then leads to a further inflammatory cascade. So with the PRP, what happens is the platelets contain alpha granules, delta granules and lysozymes. And these are the sources of all the different proteins and growth factors that underlie the mechanisms for PRP. So you have more than 300 proteins actually that are contained in platelets. So we've come a long way from thinking that platelets are just responsible for clotting cascade to being an important source of all these different agents that perform different roles in the inflammatory cascade as well as remodeling of damaged cells. However, there are some limitations to PRP. I know some of my colleagues are gonna go into some of those details there, so I'm not gonna belabor the point. But for mesenchymal stem cells, these are pluripotent cells that can become any cell needle age. And the interesting thing is that you can actually have five types switching too. So one cell can switch into another type of cell. And this slide is just basically showing all the different possibilities that one can obtain with mesenchymal stem cells at a molecular level. So you have the inflammatory cascade here. You have neurogenesis. You also have synaptogenesis, generation of new synapses, et cetera. So how do biologics address pain? So primarily looking at the cascade that I showed before, the goal here is to try to reverse the degenerative wear and tear that is happening. And that essentially tries to fix the architecture of the neural axis. In addition, you also want to regulate the inflammatory cascade because what has happened is there's dysregulation. So when you put things like PRP, your goal is you try to reverse this inflammatory process. Importantly also, as I showed before in the other slide, you're trying to balance the supply between nutrient demand and then nutrient supply. And unfortunately, you know, when you add things like PRP and growth factors, with cell proliferation, you have increased demand. And so currently this is still a big problem because we don't understand how we are going to balance, you know, the challenge between demand of nutrients versus supply. And this is one of the current limitations. So overall, there's still a lot that in terms of molecular and cell biology, we do not really understand how these growth factors work, whether it's PRP or whether it's mesenchymal stem cells. Also, the metabolic paradigm that is breakdown versus buildup of damaged tissue, we really do not understand how, you know, to balance the demand between cell proliferation versus breakdown of cells and damage of tissue. And then the other thing also that I kind of glossed over is the difference between peripheral versus central sensitization. You know, with all these regenerative therapies, we really do not address these key features of pain per se. And, you know, central sensitization also underlies how, you know, acute pain becomes chronic pain. And so this is still quite a current challenge to understanding how these regenerative therapies work. With that said, you know, as Aaron alluded to, and based on the survey, we already know that some of us are currently using these therapies anyways, even though we still do not fully understand how they work at the cellular and molecular level. And thank you very much for listening. Again, you can put questions in the Q&A session. So the next presenter is Byron Schneider at Vanderbilt University. All right, it's not good lighting. All right, hi, everybody. I got a lot to go through in 10 minutes. So what I'm gonna do today, there's a lot of anecdotal evidence about whether or not this stuff works, and it's certainly used a lot in clinical practice. My goal today is to simply at least introduce you to the body of evidence that actually exists in support or not in support of this. And I think it's important to realize that unlike many other medicines, interventions, treatments that undergo a very rigorous inspection through medical literature before they're approved by the FDA or approved by regulatory bodies, because this is considered different because it's coming from our own body, we've really put the cart before the horse and have put this into practice before submitting it to the same rigor that we do for many other things. So there is not enough time to go through all of these studies in depth. I've highlighted a key point for each study. This is just to give you a broad overview of essentially what exists. So I don't have any relevant disclosures. I do get some consulting money from some insurance companies that does not pertain to reimbursement for this. And I do have a grant from SIS looking at radiofrequency neurotomy. I also do not offer these to my patients. Also wanna note quickly, some of the slides are supposed to be hidden. So if you see me skipping over slides, it's just for brevity. So we're gonna go over both PRP and stem cell studies for intradiscal low back pain. We're gonna look at both cohorts and RCTs. Then we're gonna try to quickly summarize this evidence. So moving on to PRP, there are a number of cohort studies looking at this that inject it into the disc for the presumptive treatment of disc pain. The first by Levy and Horn, they looked at 22 patients. They had 1.5 CCs of Italius PRP injected into the disc. Patients were selected via discography or a clinical diagnosis. This study did a very nice job at presenting their data in whole. If I can get my slide to advance here. And what they found was that if they considered success, 50% improvement in pain and 30% in function at six months, 47% of the patients reached this threshold. Prior to that, the numbers were not as impressive, suggesting maybe there was a time it takes for this before it takes effect. Sorry, my slides are a little slow here. There we go I'm gonna have to skip over more things here for my connections choppy That's the same slide showing their outcomes at six months So showing that while nine patients were doing better five are also doing worse So again, not everyone is getting better and there's certainly a concern that on what will happen here for the patients You get this treatment and decline in function I Think what I'm going to do if you all can hear me instead of advancing my slides on the screen because of how slow This is I'm just gonna talk Because I have the slides for my own reference So please just reference the slide deck later and you're just gonna have to listen to me and I'll try to make it Doable without seeing the slides so the next study that I that is a cohort study similar to the study by Levy and horn is a study by Ikeda they similarly and did intradiscal injections of about two cc's of PRP and 14 patients and followed them out To 48 months and they had very similar results about 57% patients were doing better According to 50% relief at six months So we have two cohorts very similar design similar results 40 50 almost 60% success in terms of 50% reduction in pain Another study by Navani that also indicted PRP or bone marrow concentrate into 20 into 20 patients Looked at 50% at six months and they found much more profound Increases in pain reduction with reports at 17 out of 18 patients felt better So this is perhaps the most profound cohort But unfortunately, they didn't specify what patients got what inject dates was a little hard to better to further dig into this I think most pertinently relative to PRP There's one RCT. It's well known. It's done by dr. Lutz's group. It was a two-to-one RCT Enrolling patients to either a sham injection or intradiscal PRP and it was done at the time of discography So there was an attempt to really select these patients off the gold standard of diagnosing this pain But after eight weeks the patients were unblinded and crossed over so after eight weeks this similarly becomes a cohort study like everything else I'd also like to point out that 51 of the 58 patients that had discography were deemed positive which is Probably likely higher than the expected incidence of disc pain While this study is touted as being really good evidence that PRP intradiscal injections treat Low disc pain I'd like the audience to consider something here for a minute and that is that they measured Current pain best pain and worst pain at eight weeks so three different measures of pain as well as some measures of function including the SF 36 and When they say there was a statistically significant increase in pain at eight weeks It was only in the NRS best pain So these patients average pain was the same whether or not they got sham worst pain was the same whether or not they got sham It was just their best pain that was better And the reason this occurred wasn't because of this profound treatment effect In fact, the best pain scores in the PRP group went from 2.8 to 2 The only reason that was statistically significant is because the control group actually increased from 2.1 to 2.7 The otherwise didn't provide any categorical outcomes here other than the NAS outcome which found that 56% of patients said they were satisfied with their treatment in the PRP group and that was significantly greater than the sham group They have continued to publish and I commend them for this on longer-term outcomes And when you start looking out at one year You see that the improvements in current pain and worst pain which are now not the same measures of pain of best pain that were touted as positive at eight weeks or now what they Say is is evidence that this works and keep in mind This is now just a cohort study but again when you're looking at the group as a whole the pain scores that the current pain scores went from 4.7 to 3 and The worst pain scores went from 7.9 to 5.9 So while there is an internal improvement within the group these improvements barely or do not achieve MCID I'd also like to point out if this really is going to be the new gold standard for treatment We're still going to be dealing with patients that are coming into clinic Despite having this treatment saying their worst pain on average is 6 out of 10, which is obviously not ideal So the conclusions for PRP studies are that while there's two very promising cohorts The only available RCT is almost a negative study So there's conflicting evidence here But overall if you lump the two positive cohorts that had similar enrollment criteria The success rates ranged between 47 and 57 percent So moving on to stem cells stem cells are a little trickier Well, there can be different preparations of PRP stem cells can come from other tissues outside of our own body from our own tissues They can come from bone marrow. They can be cultured. They can be not cultured. They can come from our fat cells So there's a lot of heterogeneity in what's Injected and I'll try to point those differences out as we go through these studies So the first study by Shug looked at 24 patients They were injected with a commercially available product that also include a hydrogel and these were autologous chondrocyte derived stem cells But they didn't actually look at outcomes They just looked at safety and then biochemical markers and they essentially found that there were no immediate Complications and that people's levels of inflammation tended to go down Another study by the dr. Centeno's group only looked at five patients They said it was relatively successful But this study is worth noting because this introduced the concept that perhaps the amount of relief was correlated with the number of cells Injected but I would like you all to notice later on that this necessarily doesn't hold true Another study by dr. Centeno's group, which again touts intradiscal stem cells as being a positive study or showing that they work Is really difficult to really hang your hat on that because out of a registry of 1800 patients 53 had intradiscal injections only 33 were Included as meeting inclusion or exclusion criteria in this study and then baseline data was included only on 25 of these 53 injections So from an evidence-based medicine perspective, you're really already starting with less than half of the patients that got this so it's clearly not consecutive patients and there's probably a lot of selection bias but more importantly when they followed these patients out the Touted success of an improvement of pain scores by two or more Didn't occur until three years post injection and then when you look at three years post injection, which is one statistical Significance is achieved. They're down to only following 10 patients. So now we're down to 10 out of 50 patients who had the procedure So probably not a scientifically valid way to look at this Moving on a couple studies one by a Roscoe that looked at autologous mesenchymal bone marrow cells had very good improvements on mean data, but only with 10 patients showing pain went from 7 to 2 and And similarly a study by court what looked at 15 patients looking at allogeneic chondrocytes from cadaver tissues similarly showed improvements in pain scores from about 5.7 to 3.9 so less robust but still overall Improvement similarly, there's 30% improvement in ODI a a Study by Kumar also looked at adipose derived mesenchymal stem cells and these were cultured up to 2 or 4 million cells that were Injected these were collected from abdominal source again Only 10 patients were injected and and while you look at the pain scores The improvements were modest improvements of pain score overall by about 2 to 3 But they also noted that 6 out of 10 at 50% improvement in BAS. So that's a quite a robust a success rate limited by a small sample size and these same patients had 30% improvement in ODI and however Only three of the six that showed clinical improvement had radiographic improvement I only point that out because many of these studies show or claim that well the clinical improvement wasn't there There's robust radiographic evidence that this works and yet in one of the studies that shows clinical improvement in these patients It actually wasn't correlated with radiographic improvement the last adipose cell that Study the adipose stem cell study was by Camilla They looked at 15 patients and again, there was mean improvements in pain score on the order of about 2 So maybe technically MC ID but not overly powerful. So the pain scores went from 5.6 to 3.6 So I know this is probably hard to follow without my slide So I'm just gonna really quickly close here in three minutes or so on perhaps the three most important studies So the first two are done by patina and wolf. They both used bone marrow aspirate concentrate, which is now really the only form of Stem cells that are allowed in the u.s. They're no longer allowed to be manipulated being culture or anything else. So this is what's really Applicable clinically and in the study by patine they took 26 patients and they inject one or two levels with two or three cc's of BMAC and their categorical data at 12 months looked fairly good 61% success rates and This seemed durable according to the mean scores over two or three years now These patients were selected clinically so you would perhaps think maybe things were better if you had better patient selection And that's where the study by wolf comes in. So wolf did a very similar study They injected one or two levels with a bone marrow aspirate concentrate in 33 patients And yet all of these patients were selected via discography but perhaps surprisingly the results were much less robust with success rates at 24 weeks as defined by 50% improvement in pain as low as 24 percent and At 52 weeks less than 40 percent. So that brings us to the last study I want to talk about which is by Noriega This is the only Prospective randomized control trial looking at intradiscal C Intradiscal stem cells it enrolled 24 patients They had one or two discs injected and they followed patients at 3 6 and 12 months I think it's very important to note here that this is a prospective Randomized sham controlled study and that if you look at the difference between the groups They didn't report categorical data, but they reported mean pain scores There is no statistical significant improvement between groups and BAS or ODI at any of the time points So while this study was written up as showing proof that intradiscal stem cells work because the stem cell group itself got better Compared to the sham the improvements were identical So if you do a controlled trial with the sham group You can't then report the outcomes as a cohort study saying our stem cell group did well the whole point of doing a controlled trial is to compare it to the sham study and In this study the sham arm did just as well as the intradiscal stem cell study So my conclusion is on stem cells is there are a number of favorable cohorts That all are limited by 5 or 15 patients and they all use Forms of stem cells that are no longer available or lawful in this country The two studies that use BMAC, which is the currently available form of stem cells in this country did have Variable success rates between 40 and 60 percent at six months or one year However, it's interesting that the study had that had better selection criteria had poor outcomes But then most importantly we have a single RCT showing no clinical efficacy that this works So in a way, this is high level evidence arguing against the use of stem cells in All of these studies I will point out there were no major complications But in all of these studies, there were only 200 patients or so enrolled So our entire body of literature looking at whether intradiscal Stem cells or PRP injections work for disc pain is Limited to a total of 200 patients being studied in the entire world So overall I would conclude that there are observational studies that show promise for both PRP and intradiscal stem cells, but that the RCTs really Diminish the optimism here, especially considering one of them's a negative study So I hope you all could follow that. Thank you very much, and I'll pass the baton on to the next speaker Good morning, everyone. I'm Zach McCormick. I practice at the University of Utah All right. I think we're going to circle back to Dr. McCormick when we get to technical issues sorted out. So I am, my name is Mehul Desai. I live in Washington, D.C. I think that's why I got asked to give the regulatory talk because as you can all imagine, we like to regulate everything in Washington, D.C. I don't believe these are actually my slides, but I'm going to sort of scroll through real quickly and get to my slides. I think we talked a little bit about, there's a lot of excitement around biologic therapies and I think with that excitement and exuberance sometimes comes, you sort of start to, some of the rules start to get put to the side in some cases at least and sometimes the federal government certainly can't keep up with the pace of all the innovation that's going on in this space. So something to keep in mind and so I'm going to talk a little bit about that. The other clarification I wanted to make is we're not, you know, there's a tendency for people to talk about injecting stem cells and using the word stem cells over and over again. In fact, based on the current regulatory environment and the way that, um, these, the tissue-based products, now some of those tissue-based products or cells may have, um, may have a greater amount of stem cells in them or have stem cells in them, but not all of them, uh, have stem cells in them. And we're going to talk a little bit about that as well. So with that, I'm going to get into it. This is, these are my disclosures, none of which are relevant to the current, uh, the current talk that I'm going to be giving. So my objectives are to review patient selection for biologics of the spine, uh, to understand cost and patient burden for spine biologics and to elucidate regulatory issues with regards to spine biologics. Now, truthfully, there could be an entire talk, an entire hour could be just dedicated to who's the right patient and the regulatory issues surrounding, um, surrounding biologics. So I want to be, I want to be conscientious of this and sort of hopefully guide people with regards to resources that may be available, uh, that you can dig into on your own. And I certainly think that if you're interested in biologics, you should read as much of the FDA guidance that's available so that, um, so that you're aware of it, but also so that, uh, don't get yourself into trouble. It's also easy to go down a rabbit hole with, with this information because there's a whole host of folks out there who have a lot of opinions and who are commenters on, um, on some of the regulations and rules and some of the new products that are out there. But, uh, if you, if you sort of sift through that information, there's actually some really valuable, uh, information out there. So I think, you know, and this is an opinion, I actually do, uh, biologic therapies in my practice. I provide, uh, as much as possible, uh, informed consent. And I talked to the patients about the heterogeneity and, and really frankly, the lack of really robust data. And I, I really enjoyed Dr. Schneider's talk on that because I think that's, uh, he always does such a great job talking about the statistics and the data itself. And I think we have to be cognizant of this. Um, uh, I'm not interested in selling anyone a therapy. I'm really interested in talking to them about the options that are available to them and the pros and cons of those options. In fact, just, just last week, I saw a patient who came to see me as a third opinion and had seen a, um, another practice where they, this patient has had six back, six spinal surgeries is fused from, uh, L3 to S1 bilaterally. And the most recent thing offered to them was by a stem cell practice. I could use air quotes, I guess, um, where the patient got two sets of PRP injections throughout their dorsal spinal column for $2,500 a pop. I mean, so, so what you have is such a huge amount of variability in terms of what people are offering their patients and why they're offering these options to their patients. And also the reality of any of these things actually working for these patients based on, um, uh, based on some of these, some of these, uh, confounders or variables. Like if you've had a four level fusion is our biologics even really truthfully an option for the most part. We don't know the answer to that, but when you look at that, when you break into the data at Dr. Schneider did, it seems unlikely. One of the things I think that makes these therapies really attractive to patients though, is that the alternatives are pretty challenging. I mean, we all, uh, I mean, I'm certainly, I'm certain that the folks who are speaking today are aware, and I'm, uh, I'm also certain that the folks who are listening are aware of the challenges we face with regards to the traditional therapies we offer, right? So we have corticosteroids, local anesthetics, uh, saline, we've got developing technologies such as intra, uh, epidural clonidine, uh, but really none of those things have shown long-term robust data. And we know that we're limited in terms of what we offer. The other end of the spectrum is surgical remediation. And we know those are also really, really challenging because for the most part, surgical outcomes have not been all that promising. And when you really dig into the data, uh, if you look at the Swedish registries, which are what some of the better registries, because every patient in Sweden goes into the registry when they have back surgery, uh, all comers, first surgery outcomes are sort of like, uh, maybe 60, 40, second surgery, 40% likelihood of success, third surgery, 10%, uh, fourth surgery, 5% and a fifth surgery, 2% likelihood of success. Yet all, most of us in our practices have encountered patients who've had multiple spine surgeries. Uh, so I think it's, it's a really interesting, uh, conundrum. So who's the right patient? I wish I knew the answer to that. I don't know that anyone so far knows the answer to that. Probably it's better to figure out who the wrong patient is and who not to offer this to. So if you look at the studies that have, uh, that have been done in, in interarticular facet injections and offering biologic therapies there, it's typically patients who have fairly straightforward or simple facetogenic pain or zygoporphysial mediated pain. So probably not five, six, seven levels of, uh, uh, Z joint pain, probably not folks with instability. Um, really as a first step, we're looking at patients who have fairly, uh, sort of limited geographically, but also in terms of pathology, uh, symptoms and pain, uh, if possible, if we can, if we can correlate this to radiographic findings or physical exam findings, I certainly think that that helps our case. But, but for facetogenic symptoms, at least, I don't think these, the patients that have diffuse, uh, arthropathies or certainly autoimmune disease, such as ankylosing spondylitis or a problem such as that are really the candidates for this kind of therapy. Similarly, uh, challenges remain when it comes to identifying the right, identifying the right patient for sacroiliac joint pain. Uh, do you inject interarticularly or periarticularly? Have you, uh, ascertained whether your patient is hypermobile versus hypomobile? Uh, are you doing these procedures in patients that have any sort of inflammatory arthropathy? Uh, is it unilateral versus bilateral? Uh, is there any confirmation on pathology on x-ray, MRI, CT scan, or even bone scan? Uh, what physical exam maneuvers are you using to identify whether this is actually indeed sacroiliac joint pain? So all these things, all these questions remain open. And in our practice, we really try to identify patients who are not good candidates, right? So to exclude those patients, um, to frankly talk them out of these therapies, because the last thing I want is for a patient to undergo an out of pocket, relatively expensive therapy. We, we don't charge an arm and a leg, but even still, uh, what might seem inexpensive to us might be a big chunk of someone's savings. So we sort of really careful about that and identifying patients, especially, um, those who were looking at injecting their facets or SI joints. And, and again, trying to find out who's not a candidate. I think that's part of thinking about this, this whole area as, as much as possible is excluding patients appropriately. When it comes to intradiscal procedures, you know, one of the questions I actually submitted just a few minutes ago is, should we be doing simply intradiscal injections, or should we also consider interosseous injections? What we know is based on the studies that, that Dr. Schneider talked about is typically when there was, let's say any success or nominal success, these are patients that had modified Fireman scores, most commonly between four and seven. Although when you look at all comers and all the studies, um, folks were injecting people who had scores as low as three and as high as seven. Uh, we're going to, I'm going to show a couple of images of what those, what those scores really look like. And then also Adam's stage two and four, and that's sort of more of a, uh, provocation discography finding. And we'll talk about that as well. So this is just a slide that goes through all the great, the Fireman score, uh, uh, or grades, pardon me. So you can see here, grade one, grade two, not really great candidates for any sort of therapy for the most part, uh, or any treatment, um, or it's certainly not an interventional treatment. And then you start getting into grade three through grade seven, where you have maybe a reasonable chance of helping this person and, um, and, and working on the, uh, working on mitigating their disc, discogenic symptoms. And then grade five is probably so far for degenerative that they're probably not a great candidate for any, uh, biologic therapy, uh, either. So things to keep in mind when you start thinking about which patients to intervene in, this is just a histologic sample of what those discs kind of look like. So on the far left, you've got healthy discs, uh, with great hydration, good, um, hydrostatic pressures. The nucleus is nice and concentrated in the middle and the far right, you've got fairly degenerative discs. Um, when it comes to Adam stage here, you can see the middle two through four is where we really look at patients for interventional options. Uh, again, these slides are going to be available. So feel free to look at these. This is, these are cross sections of patients where, or, or discs where dye has been injected and, and then the, uh, the disc has been examined. Cost. I mean, that's one of the things I was asked to do or talk about. And I think it's really challenging to tell you much about costs. I'll say that there's an incredible amount of variability. There's a broad, broad range of costs and pricing structures that are all over the place. I see patients who get told that they can have bone marrow injections for $10,000 and others that get offered it for a couple thousand dollars. Uh, in some ways, this lack of data and sort of this wild, wild West mentality, when it comes to biologics has beget this unstructured cost structure where it's sort of anything goes and it's what the market bears. And in some cases, in some places you have these stem cell clinics that are charging in order and amounts of money. Uh, I'm going to, I know we're a bit short on time. I want to make sure we get to Dr. McCormick. So from a regulatory perspective, I would strongly recommend folks check out this, uh, this link that's on the bottom of this slide. It really, there's a really great document that goes through and talks about guidance with regards to, um, uh, biological substances. And really, again, I want to reiterate, these are human cells, tissues, and cellular and tissue based products. I think we really do need to do a good job getting away from calling them stem cells. Um, cause there's a variety of options, plate leveraged plasma, bone marrow concentrate. We know that fat derived cells, I think there's one FDA approved product. There's been a lot of conversation about exomes and amniotic substances recently. And even so far as where, where people are claiming that amniotic cells are paid for by Medicare. That is not true, at least not to my, my knowledge. Um, so, uh, you know, at the, at the risk of being really short with this, and I apologize for running out of time, I would strongly advise folks, uh, folks check this stuff out and understand that there's a difference between, um, cells that are structural cells and cells that come from cells themselves and how, what minimal modification is considered or minimal manipulation and how that's defined. Um, I really have a really nice group of slides about that, but in the interest of time, I'm not going to go into all those. Uh, I think with that, I'll pass it back to Dr. McCormick, uh, so that he can talk about, um, BSI joint and dorsal ligament structures. Hey everyone, we're going to take two on this. Um, go ahead, Allie, if you can just send me a message and let me know that the audio is coming through all right. Okay, perfect. Um, so thanks so much for the invitation to be on this, uh, you know, this excellent panel of speakers and thanks very much to Dr. Yang for, for putting this together. Um, so I am going to talk about biologics for the SI joint and dorsal ligaments. Um, as mentioned, I, I do have, I'm a co-investigator on a grant from the RNSA found a research foundation that, uh, I don't actually get any salary support for, but this is a, is a study that is looking at PRP for the thoracic joint. I am a section editor for the rehabilitation and regenerative medicine section of the pain medicine journal. Um, so I'm briefly going to talk about, um, essentially what is in more detail, uh, described in a recent publication, uh, from pain medicine with some of my colleagues, uh, definitely need to acknowledge Dr. Burnham, Samson, Speckman, Conger, and Cushman. Um, I'm simply representing this work, but this was very much a team effort. So, um, we, we did a true systematic review. This was registered in Prospero. Um, and these were our pre-specified, uh, eligibility criteria, uh, for studies that we would consider. Um, these are our PICO criteria, which you can see here. Um, we, our, our primary outcome was at least 50% reduction in pain at three months. Um, and we also were interested in secondary outcomes of function. We took a look at randomized and non-randomized comparative studies and cohort studies, but we excluded expert opinion, um, in case reports. So, before I even move further, what I'll tell you is that not a single study met our inclusion criteria for, uh, as it relates to stem cell therapies. So, all we had to go off of from our, our lit search was Pivotal Rich Plasma. And, um, this is the, the Prisma flow chart, um, that shows the studies that we identified. And then, uh, ultimately only three qualified. And I'll briefly run us through those in a minute. We use the American Academy of Orthopedic Surgery minimum reporting standards in order to appraise the, um, the methodologic rigor of these studies. We also use, or intended to use the Cochrane Risk of Bias tool, but what you'll see is that there's only one, uh, RCT that, um, even met inclusion criteria. So, it ended up not really being particularly relevant. So, many may not be familiar with the AOS, um, minimum standards tool. This is it here, and I won't go through every line. Um, but it, you know, if you take a peek at this, what it really boils down to is, these are just standard, um, methodologic sort of tick boxes that you would want to see in any good clinical study. Um, but then they also talk about what should we, um, what information should the authors provide to us, um, to make us confident that, uh, we actually know what's going on with the biological substance. If it's PRP, how many platelets are, were there, and how, are they quantified in the whole blood sample, um, how is the PRP processed, um, and then what factors were present, and at what concentrations, um, in the actual, um, uh, injectate itself, uh, if we're talking about PRP, for example. So, these are the three studies, um, and I'll spend the most time on the single study. This is the one, um, standalone randomized control trial. So, this was an open label study. Um, participants knew exactly what they were getting, whether it was, uh, an, an, an, um, inter-articular steroid injection or pituitary rich plasma injection. They had 40 patients, so 20 in each group, which, um, you know, as you would guess, one might think this is a bit underpowered. I'll just throw that out there. Um, the inclusion criteria are interesting. So, it actually did not require a diagnostic block, whether it be, uh, an esacro-lateral branches or an inter-articular injection in order for a patient to qualify. So, simply unilateral sacroiliac joint or, or region pain, um, potential imaging findings, and then, uh, at least three, uh, provocation maneuvers of the sacroiliac joint complex. Um, and as mentioned, group one was allocated to, um, what, what, what, what, what, what they claim to be a leukocyte-free PRP preparation. Group two received methylprednisolone with, um, uh, with lidocaine mixed in. They use ultrasound guidance, notably not fluoroscopic guidance. I think it's probably just important to comment that we can likely be confident that the injectate got into the dorsal ligaments, whether it truly got into the inter-articular portion of the joint, the sacroiliac joint. Um, unclear. If we look at the best cadaveric studies, um, the success rates for, um, ultrasound guidance with true inter-articular, uh, flow of, uh, contrast or dyes within cadaveric dissection, they're not high. They're less than 40%, uh, when ultrasound guidance is used. Um, and then finally, the, um, these authors did not report, um, on the contents of the whole blood, um, or PRP analysis. So we really don't know exactly what was in the substance that was being injected. Uh, these are, are the, the characteristics of the participants in the study. And what I'll, um, what I'll highlight is, uh, this is generally a young population. So both groups, mid to late 30s. Um, and if you take a look at the causes of pain, these may not represent the typical patient that you see in your clinic. Um, so some of these patients, actually a good portion, nearly half had ankylosing spondylitis, or at least the diagnosis that was listed, uh, by these authors. And then a good portion of them had trauma. We don't know more about exactly what the nature of the trauma was, but, um, you know, I can say that in my practice, this is not particularly representative of the usual patient with sacroiliac pain. That is probably what's represented in this idiopathic category. That's listed in table one here. Um, and, and so here are the, the main findings. Um, they, the authors, uh, the investigators follow patients out to three months. You can see that the blue line represents the, the, uh, mean VAS scale, uh, pain, pain, change in pain. Um, and the green line represents, um, excuse me, the green line represents the mean change, uh, within the PRP group and the blue, uh, in the steroid group. So both groups improved initially, and then you see a regression back towards baseline in the steroid group. Whereas, um, pain scores remain lower, um, in the, the rich plasma group out at three months. Uh, they do show us categorical data and, uh, we see similar, similar pattern where, uh, both groups, uh, improve or will have a relatively high proportion of responders. If we define a responder as pain reduction, um, early on, then by three months, um, significant regression where, um, only 25% of patients in the steroid group were, um, reporting at least 50% pain reduction. Whereas 90% were reporting that threshold of pain relief in the rich plasma group. And then we, we only have, again, mean data, um, no categorical data with regard to function, but we see a similar trend with improvements in, uh, ODI, um, in both groups early on, and then a regression back towards baseline in the steroid group, uh, with persisting relief out to three months, uh, or persisting improvements in function out to three months in the PRP group. Here are complications. So really the, the only difference between groups, um, that was meaningful was post-injection pain and stiffness. Um, probably not surprising, um, where the steroid group had a lidocaine injected along with the steroid, uh, the PRP group had, uh, uh, only that injected. So perhaps not surprising. There were no significant adverse events that were reported. The other two studies I'm really going to breeze through because ultimately, as you'll see, um, they're very low quality. These are probably not much more than proof of concept studies. Navani looked at 10 patients, um, required a single intra-articular block with 50% relief threshold. So not a super high bar for diagnosing sacroiliac joint pain. We don't know much about the inject date. Um, there was no whole blood or PRP analysis. And these authors reported that every single patient of the 10 had at least a decrease of 50%, um, in their pain score and, uh, improvements in the physical and mental components of the SF-36 at 12 months. Uh, they didn't provide any categorical data. And then Koh and colleagues, uh, reported on four patients, um, again, very loose inclusion criteria. Um, they did note that they did not intend to inject the intra-articular portion of the joint, uh, but rather the dorsal ligaments, uh, via ultrasound guidance. We also don't really know exactly what was injected. There's no literature to date, at least that I've seen, and as of the writing in the systematic review on other biologics, predominantly stem cells, for sacroiliac joint and dorsal ligament pain. So we very much need better research in this area, and we need higher quality research. So I think that AOS standards nicely outline it, but ultimately we need larger samples, we need appropriate blinding, we need appropriate diagnostic. And again, you know, as I alluded to over and over, we really need whole blood analysis and this if it's related to stem cells so that we actually truly know what exactly is being injected. So thanks so much. You know, apologies for the technical difficulties there. Hopefully this was an interesting session. People come away with some new good information, and I believe there is some time for Q&A, so I'll turn it back to Dr. Yang. Thank you guys. So in true 2020 fashion, we just have to roll with the punches, and I really appreciate everyone being a part of this. We try to answer as many of the questions as we could in the Q&A chat box, so please take a look at that if you've asked a question. We have a couple minutes, but Mehul, I just wanted to pass back to you because I know you were about to address about the FDA regulations and stem cells, but the audio cut out. Can you just address that again for us? Yeah, I think what I was saying, and I want to make it very clear, we probably shouldn't be calling these things stem cells when we talk to our patients, nor when we use information on our websites or post things about it, because we're not, based on the way that these cells, these human cells produce cellular and tissue-based products are collected and prepared, they're not necessarily stem cells. Some of the cells that we're collecting or parts we're injecting, they contain some cells, some stem cells in them, but they're not a stem cell that we're injecting. So I think we need to be really cautious about that because that implies a lot of things to patients when we start saying we're injecting stem cells, because that's a big, big part of this and it's a big potential no-no. Also there's a lot of companies out there that are making a lot of claims about what's in their products, whether it's frozen products or like what we're talking about exosomes and amniotic products, and there's a lot of concern about what's actually in those products and the FDA guidance is kind of evolving all the time, so I do think it's really important for folks to keep an eye on the FDA's position statements about these things and to use the appropriate nomenclature. Great. Thanks, Mehul. Thanks for clarifying that. I also wanted to ask Dr. McCormick and Dr. Adancor, I know both of you guys are in an academic institution. Can you speak briefly, if you guys are using any biologics at all, any barriers to implement that into your practice or if you did, were there any, what's your experience been? Sure. So, yeah, I currently do PRP injections in the periphery. I have not really done any neuroaxial PRP quite yet. Our institution is currently undergoing a study for PRP injection in the facet joints, but in my own practice, I do PRP for tendon injury, commonly lateral epicondylitis, and then also for arthritis, so knee OA and then also for CMC joints, but I have currently not started doing anything for the neuroaxis yet because our institution has not approved that. And then in terms of payment, as everywhere, just like in private practice, it's pay out of pocket, and so that's most patients who come to my practice, if they are not Medicare or Medicaid patients and they can afford it, we do offer that to those patients. What about you, Zach? Yeah. I'm happy to speak to that. So, yeah, a few things, we have a number of studies ongoing, and so I'd say that the majority of the time, if I'm using a biologic, it's a part of an IRP-approved protocol, so there's a proprietary agent that's been developed at the University of Utah by one of the cell labs here, and I probably actually can't say that much. It's not PRP. It's not stem cells, but it's a biologic agent, and we are using this for radicular pain in the context of spinal stenosis, and that's purely investigational. It's a part of a randomized controlled trial. I mentioned the Sacred Iliac Joint PRP study that is a collaborative between ourselves and the radiologists at the U. It's also IRP-approved. We do have a cohort, an open cohort study related to intradisacal PRP, so, again, this is IRP-approved research. Outside of those three studies, I do very little with biologics. There is a very occasional patient who I will do it for, and, you know, we have a system set up. Obviously, you know, as everyone knows, it's not reimbursed by insurance, so it is a cash pay procedure. I do them very, very rarely when there's a good reason to do it and to not offer usual standard of care. Occasionally, there will be a patient who I can think of just offhand, a patient who was managed well for a period of time with epidural steroid injections, and then ultimately started having shingles outbreaks, and she was not my patient at the time, but was receiving epidural steroid injections and having shingles outbreaks every time she had an epidural injection, and so ultimately, you know, came to me asking if I would do an epidural PRP injection. I agreed to do it, but, you know, this is sort of these unique situations. So for the most part, in my practice, it's a part of clinical research. You know, I think someone brought up a really good point about, you know, when we think about set joints, for example, there is a regenerative process like PRP, or there's a destructive process like radiofrequency ablation. We also have other options like peripheral nerve stimulators to affect nerve. I mean, Mehul, what are your thoughts on these different types of ways to approach and treat pain? You know, we're used to hearing about radiofrequency ablation, where it is a destructive process, but now we're starting to get into some other ways of treating pain that may not be destructive. What are your thoughts on that? Yeah, that's a great question. I think, you know, in my practice, there's probably been a paradigm shift. So, you know, we joke, our practice, we call it privademics. So we do, we're a private practice, but we're affiliated with a couple of university programs. Not in any specific formal way, but we publish a fair amount and have eight to ten clinical trials going on at any one time. So with that in mind, we often sometimes, we often get exposed to certain therapies earlier on, maybe in the continuum, we get, you know, some therapies in the meantime. I think, in my personal experience, peripheral nerve stimulation has become potentially transformative for my younger patient population. So the number of patients under the age of 50 or 45 that I used to previously ablate, like their lumbar facet joints, I'm really reconsidering that, I'm really considering other options and other alternatives for them, specifically peripheral nerve stimulation. But some of the data, it's still pending. We don't have great gobs of data yet, but it's compelling and it's promising. And there's a restorative component to it. So I think that, I think things are going to change potentially with regards to how much we use RF. And, you know, not that RF is not a good therapy for our patients, but I think there's other alternatives that now provide options for us as well. Okay. I wanted to ask, oh yeah, go ahead. I was just going to ask one more question before we all end this session, but, you know, for people who are starting to look into some type of biologic injections and they're just starting out and they're trying to find out information about it and also trying to find some level in terms of a standard of preparation or care, I mean, what would you say to someone who's like thinking about biologics and they don't know where to start, they don't know where to say what kind of preparations or what types, I think it'd be very daunting to navigate this for somebody. Any quick advice, we'll start with you, Charles, and we'll go to Zach and Mehul. Yeah. I think that, you know, there are different companies out there with different products. And so normally I would say that start with the literature. So Dr. Mautner at Emory wrote a paper a few years ago proposing a classification system that includes, you know, clarifying whether the content of your PRP is platelet rich, platelet poor, how many leukocytes are present, you know, and so he proposed this PRLA system that really helps you know exactly what is the content of your PRP because currently that is part of the problem. There's so much variation, you know, from practice to practice in what is being done that I think that, you know, if you follow at least what has been proposed in the literature, which is evidence-based, then, you know, you have something to stand out. So that would be my first thing. And then, you know, you should always investigate all these different companies and the claims that they make before, you know, you give in to the products that you're using. And then also just check with your colleagues, you know, folks that are currently doing PRP and all these regenerative biologics, ask them which companies they're using and, you know, they probably already vetted them. And so, you know, if you're somebody who's starting from scratch, I think that's sort of the approach that I would take. And then always make sure that, you know, everything that you do, you can support it with what's in the literature at the end of the day. Great. Thank you, Charles. What about you, Zach? Yeah. So I would echo all of that. And I would also just add that I think you absolutely have to commit to learning a literature in this area. And mainly because the literature isn't great, you know, there's nothing that's absolutely convincing about any of this stuff outside of animal studies. And there are elements that are absolutely promising. And I'm hopeful that there will be more data, better data forthcoming. But if you don't know the literature, like the back of your hand in this area, you can't really appropriately counsel patients. And then you're ultimately just hopping on a bandwagon. I think that it's, as I mentioned, there are situations where it's not unreasonable to use these things. I mean, overall, the safety profile appears, you know, quite reasonable with very few exceptions. The bigger burden is cost. And, you know, Dr. Desai alluded to this. For some people, they might be really excited about the therapy and they're ultimately going to do it. But it's a financial hardship for some folks. And so I think, you know, helping them understand their options is really vital. And if they ultimately choose to proceed, that's fine. But you know, Dr. Desai I think said the same thing. I had people come to me and ask for biologic treatments, I talked more of them out of it than actually agree to, you know, proceed. I think after we present the, you know, best evidence across the spectrum of options for what might be useful for a given patient, you know, many of them understand that the biologic treatment may not really be the ideal solution for them. So I'll just, you know, I guess preach that I think transparency is important. And it's not that you shouldn't use these things, but there should just be, you know, good transparency. Okay. Great. Thanks, Zach. You got 30 seconds, Neho. We're up against the time limit. What do you think? Yeah, no, I completely agree with Dr. McCormick and Dr. Vankar. I mean, I think that what it comes down to is in my practice, I look at this as one part of the toolbox. Like, it's part of my armamentarium. It's not the only thing. I think when we start getting into these areas where it's the only thing that we're starting looking for reasons to use it as opposed to reasons not to use it, right, so it's sort of like everyone gets prolo or everyone gets PRP, and I think that's a really dangerous way to practice, in my opinion. I think if it's too, if the company's making claims that are too good to be true, they probably are too good to be true, right? So there's a few really great, reputable companies out there that are contributing to the science and are part of the process in terms of learning and exploring how these things work and what the right formulation is and what the right centrifuge speed is, et cetera, et cetera. And go with the stuff that's out there that you know your colleagues and friends have had success with. Keep an eye on the FDA, that website I told you about. I mean, that website is constantly updating with new things, and they're responding to things about amniotic cells and exosomes and all the biologics. So I think that's going to be important in addition to the science, which I completely agree with the other speakers, but there's also the regulatory component here that I think is really key for people to keep an eye on. So that's what I would say. Awesome. Thank you, guys. Thank all of you and those attending for your time and patience through this period. So great job. I hope you have a wonderful Saturday and just filling in with the other sessions that EAPMNR is offering. Have a great day, guys. Thank you. Thanks, everyone.

patient selection

biologics of the spine

regulatory issues

FDA guidelines

cost of biologics

insurance coverage

open discussions

informed consent

stem cell injections

specific joints

pricing structures