For healing diseased or damaged tissues, therapies that use the body's native cellular components may have long-term advantages over go-to treatments, such as steroid injections. With a focus on everyday knee and shoulder arthritis, sports medicine specialist William A. Berrigan, MD, discusses the problems with conventional management and presents the evidence on promising biologics, including an illuminating look at why studies have produced conflicting data on platelet-rich plasma.
Thanks everyone for joining today. Uh, my name is Bill Berrigan. I'm a primary care sports medicine doctor at UCSF. So I have a practice in, in Redwood Shores, and I've also have a practice within the city. Uh, my background is in physical medicine and rehabilitation, and, uh, with the subspecialty in sports medicine, and You know, throughout my training and where I'm at now, uh, a specific interest of mine has been orthobiologics and including some of the research, uh, studies that we're doing here now, which we'll partially get into. But my goal for you today is to, you know, kind of get you to understand what, what biologics are and how they can be applicable to you. So, these are our objectives today. So, define what constitutes orthobiologic, the different indications for these MSK conditions, and to understand the future directions of the field. I don't have anything to disclose today that's at least relevant to this talk, but I am a product of my mentors, so I always mention that, and that's reflected in this talk, including Robbie Bowers, Ken Mounner, and, and Osein Olafade. So what are biologics? Well, you know, we are cellular beings. So we have over 37.2 trillion cells in our body. And at any moment or every second, about 15 million red blood cells are turning over at a specific time point. So, you know, the question is, how can we start to use these cells to help regenerate or heal tissue? That's where biologics come into play. And there's 4 specific generations of biologics that we refer to. One and most commonly, which will be the meat of today is platelet-rich plasma. Uh, 2 is bone marrow aspirate concentrate, where we actually take it from the bone marrow. 3 is lipoaspirate where I take a, take it from the fat tissue itself, like a mini liposuction. And the last one is amniotic tissue and umbilical products, which we won't be getting into much today, mostly because of the current FDA regulations. They took it off the, the market where you need an IND uh to be able to, uh, to use these products. So you need a clinical trial. So, we won't be discussing that. So why is this important to the primary care physician? Well, this is a study that was done out of Canada. It looked over um 12 different countries over 5 different continents with the clinics that were got greater than 20,000 patients and that had reported this info. And the top 4 diagnosis is seen as arthritis, not related to the back. And number 9 is back pain or spinal pain. And then if you just look at the spine, the conditions that patients report, uh, number 2 up there is back pain or spinal pain. And then to number 12 is arthritis is not related to the back. So these are important causes that, you know, that we need to know how to treat. And if we look at the specific MSK diagnoses, and this was some reporting that was done as part of the polar database, the, uh, what's most likely to present to the primary care physician is 57% low back and 11% neck. Now, I will say as a caveat that as we get into this, there's not great evidence in, in the back. And so, I won't be touching on too much of this today, but I will be discussing the shoulder and knee in detail. So our conventional management isn't that great, you know, we think about an injury, even some chronic problems, and we just say rice, rested, ice, compressed, elevated. Over the years, this has transitioned to this peace and love model. So you're protected, you do this uh reloading type program, excuse me, load optimism and excuse me, revascularization, and then you do some exercise as well. But this isn't, you know, really applicable to everything we see, especially, uh, when we think about, you know, arthritis and chronic tendon problems. And then, even though we look at these acute injuries, you know, uh, we don't have good medications to be able to treat this. So, NSAIDs is everyone's go to. But if you think about it, you know, when we have some sort of inflammation or acute process going on, you need the tissue to repair on its own. And part of that is, is this process through inflammation, maturation, and proliferation. So, if the NSAID is a non-steroidal anti-inflammatory blocking that inflammatory phase, we might actually be delaying that process. And there's not really great evidence for these overuse injuries, strains, sprains for these therapeutic properties. And I know I'm speaking to the choir because the NSAIDs are not without their adverse events. You know, we, we have renal cardiac issues, uh, GI problems, and these all need to be considered in our patients with these different comorbidities. And so classically, we've kind of stuck to steroids. So, steroid injections seem to be the answer. That's the next step. And that's what's been, been done for years. But what we need to do is start paying attention to the evidence and that in the long term, these injections aren't really great for our patients and may only offer these long-term harm. And so that's where these, you know, biologics come into play. And, and if we look at steroids and its effect on cartilage, you don't, any steroid, methylprednisolone, dexamethasone, which I use for my injections, betamethasone, all these common ones that are used have a dose-dependent deleterious effects on cartilage morphology, histology, and viability. So they are toxic to that joint. And oftentimes they'll, we'll do multiple injections. But if you look at multiple injections, they actually provide inferior, non-superior symptom relief when we compared to other injectables, such as even placebo, sometimes hyaluronic acid, PRP. And this isn't really shocking or, or anything that is groundbreaking, but it's something to think, you know, that, that we should be reconsidering doing these multiple intra-articular corticosteroid injections. But there's a great amount of the population that lives in this treatment gap, and this treatment gap is those with arthritis that are have attempted conservative treatments, being medications, weight loss, braces, PT and have failed that, but are not ready for knee replacement. So this is that treatment gap that needs to be addressed. And when we look at the economic impact of this treatment gap, it's pretty significant. The cost in healthcare expenditures and loss of work expenses is estimated to be more than $27 billion annually, and $100 billion respectively. So this and the expected number of TKAs, the total knee arthroplasty, is expected to go up by 673%. This was from 2010 to about 2030. So this is uh a little bit older of a study. So the numbers have increased even since this time. And then if you look at that patient that's, you know, waiting for total knee arthroplasty, the average time they spend in that area is about 9 to 12 years. And at the younger patients, this can be about 20 years in average length. And then if you look at the, you know, in terms of the effectiveness, what is highly effective and actually cost effective, the only thing that fits into this area is a total knee arthroplasty. And then the outcomes of total knee arthroplasty, 20% of patients aren't satisfied with that knee. So it's only an 80% success rate, and that's your ultimate end treatment. And so the typical knee osteoarthritis patient, they, they're really only willing to pay up to $5000 to $700 for quality adjusted life year. And so no existing knee arthritis treatment offers this ideal combination of clinical effectiveness and cost effectiveness below this willing to pay threshold. So, what do we do? Do we just scratch our heads just to say you just have to wait, continue to get these steroid injections so they don't work? Well, no, we need something to start to uh to address this treatment gap and bridge that gap. And so, we'll talk about firstly how platelet-rich plasma addresses this. So, what is PRP or platelet-rich plasma? Well, it's this concentrated cellular milieu. So, this, this uh group of growth factors within the blood that happens after you concentrate it down. So what we usually do is take a, like it'll take 60 mL of, of, of blood, spit it down to about, you know, 7 mL that are just the platelets. These are rich in a lot of growth factors. Now, there's different definitions of what PRP is. Say 1.5x, other 5X, other 10x, and we'll get to that in a second. But the goal is to deliver a super physiological level of these growth factors. And if you go by an FDA simple definition, all you need is a larger than your baseline platelet level to constitute as PRP. So, when we look at the platelets, this can actually be quite overwhelming, cause you can get over 1500 different proteins that work in uh within the platelets. But what we need to concentrate on is these alpha granules that help with this regeneration process. So, these granules release cytokines, chemokines. Uh, different proteins and, uh, immuno, uh, modulators and mediators and these complement factors that, that are able to start both a coagulation cascade to activate PRP and then also release these, uh, these different treatments and growth factors to help it heal. And so what do I talk about with this? Well, there's platelet derived growth factor, transforming growth factor, that vaso endothelial growth factor, EGF epidermal growth factor, fibroological growth factor. They all have similar effects. The main player being the platelet derived growth factor. This stimulates cell replication, promoting angiogenesis, promoting the epithelialization of tissue and, and new tissue formation. And as the, and as you get more angiogenesis and blood flow to the area, you're able to help lay down new tissue. And so, when you summarize what PRP does, it activates and releases these proteins, it has anti-inflammatory properties, and this is through the inhibition of NFK beta, which is the pro-inflammatory mediator, the inhibited inhibition of matrix al-proteinases. And it also promotes this extracellular matrix remodeling. So how does this work in osteoarthritis? Well, osteoarthritis is this chronic inflammatory state. So this is led by uh different aspects like IL1 beta, TNF alpha, and this could be through uh nature of metallic proteinases, elastases that lead to this chondrocyte apoptosis. And so when you have the PRP, these growth factors can enhance these cartilage repair and counteract this process. When one of the main players is IL-1RA, uh, that is the interleukin-1 receptor antagonase, which blocks that, uh, breakdown by interleukin-1. And then you have the tissue inhibitor and matrix tauoproteinases, and these matrix tauoproteinases are really degradative to cartilage and different tissue, and you can build up type 2 collagen as well. So these all enhance this chondrocyte proliferation for for the joint itself. So that's more of the pre-clinical or how it works. But where is the evidence now? Well, we have great studies for the joint and specifically knee osteoarthritis. There's, you know, well over 40 clinical trials now that have, that have looked at knee OA and PRP. We have more evidence for the shoulder and hip that have come out. There's some in the ankle, SI joint, and CMC, but we'll go through the higher-level ones today. So, this is, uh, this was published in 2021 in the OJSM and this is a, a systematic review of meta-analysis of PRP for NOA. Now, there's about 15 of them out there now, and 12 out of the 15 show a positive effect with PRP. This included 21 trials. So, PRP was compared to steroids, saline, and hyaluronic acid, and they concluded that PRP injections are beneficial for pain relief and functional improvement in knee osteoarthritis. And if you don't believe me, this is the 4th plot from that study. This is 12 months out, looking at the different comparisons. So, the left favors PRP and the right favors controls. And in 12 months, you could see the difference between hyaluronic acid, corticosteroid, and the saline group all favoring the platelet-rich plasma. And if we compare it to hyaluronic acid, PRP does better than hyaluronic acid every time. There's, there's no doubt about it. There's multiple reviews, multiple, uh, randomized clinical trials that have showed this. And so, this showed that this was in the AJSM published about a year ago. It looked at 18 studies, 811 patients that had undergone PRP, 797 that underground hyaluronic acid at the mean follow-up about 11 months. And they found improvement higher in the PRP group, which is about 45% than in the hyaluronic acid group, it's about 12%. Uh, for the Womack. And then of those that reported pain scales, 6 reported, uh, the PRP patients to have significantly less pain at the latest follow-up when compared to the hyaluronic acid. Some people are combining hyaluronic acid with PRP and, you know, the, this has been shown that it doesn't really provide much benefit. So this is a, a review, 13 articles, over 1100 patients, looking at pain and functional scores, and they found the smallest treatment effect did not reach the MCID or the minimally clinical important difference, meaning that the PRP and hyaluronic acid was not found to be superior to PRP alone. Um, with this treatment. And, you know, one of the thoughts is that if you add hyaluronic acid to the PRP this can actually change what the contents of the PRP is. And this is being looked at by Shane Shapiro at the Mayo Clinic that has found that it actually decreases the platelet numbers by about 25%. So you're decreasing that potential efficacy of your PRP by adding that hyaluronic acid. Well, what we really wanna know and the, the question is, can these treatments delay the need for a knee arthroplasty or knee replacement? And this is a really difficult question to look at. But this group did attempt to do it. So they did a retrospective analysis and survival analysis from 2014 to 2019 and about 1,084 patients with 667 meeting the inclusion criteria. So they had, this is KL3 and 4 osteoarthritis that was eligible for a total knee arthroplasty. So I'm more on that severe side. And 74% of patients achieved a delay in a total knee arthroplasty of more than 1.5 years. And this median delay was about 5.3 years. This is one of the things that I will counsel my patients on is that there's the potential, even though there's severe osteoarthritis, you have a 75% chance of, of potentially delaying that need for knee arthroplasty. And interestingly enough, in these patients, 85% did not undergo TKA for about 5 years of follow-up. Now, one of the things is that not all of these, uh, patients that are registered review only had one PRP injection. Some had multiple others had intraosseous so into the bone. So there was some variability, but it is a good attempt and something that we need to continue to look at. So with all these studies showing that PRP works, you know, there's this argument out there, and I believe it should be true that PRP should be the standard of care for knee arthritis. Yet, you know, that we'll get into the variability, but the, based on the fact that's there's so much variability within PRP insurance companies still aren't covering it. Well, if we move on to hip arthritis, there's less, less trials. This is a review on an arthroscopy, 6 studies uh looking at Womack VS and Harris hip score comparing hyaluronic acid to PRP. They showed that both had a significant improvement at 12 months. Now, if you're looking at hyaluronic acid and PRP based on the knee studies alone, I know, I'm always gonna recommend PRP for my patients. And the reason being is if you pay out of pocket for hyaluronic acid because hyaluronic acid isn't covered by insurances for, for hip osteoarthritis, then oftentimes you're paying about the same amount for HA as you are for a PRP injection. So this is something that's important to consider. And there, there was variability in the PRP content in these studies and some aren't reporting. So, some of this could have been a low-dose PRP which might not have the effect that we would like to see in, in patients with hip arthritis. And so this one was a rand double-blind randomized clinical trial. It was a pilot study to see if we could look at any delay towards either hip resurface resurfacing or total hip arthroplasty over two years. We found that 50% of those that had received low molecular hyaluronic acid converted to surgery versus 15% in the PRP group. So we did see a difference in that between PRP and the hyaluronic acid, even though it was just a small number of hips at 36. Moving on to the shoulder, this was the first clinical trial that came out in November of, of last year. So it was great. Looked at 70 patients with leukocyte 4 PRP or hyaluronic acid, showed improvements in both groups regardless of the OA severity. So, you know, the shoulder is something that we need to do a better job at because when you have a, when you do a shoulder replacement, the longevity isn't as long as, as like a hip, which could be 30 years, 95% success rate. Whereas a shoulder, maybe 1520 years, potentially a little bit more depending on who you talk to. And so, you know, we need to find these ways to help delay the time to the shoulder replacement. And so, you know, when I tell patients that are getting PRP for the shoulder, and I'm not saying that we're alleviating your symptoms completely, but I am showing that similar to this graph, you know, you can see about 25 to 50% improvement in your symptoms with, uh, with PRP. And there's the potential that you could get even more as this PRP was more of a lower dose PRP, uh, within this study. So let's transition. We talked a lot about arthritis. Let's talk to, talk about tendinopathy. So, common things to clear in clinic, tennis elbow, uh, golfer's elbow, rotator cuff tendonitis, you know, hip bursitis, which is really a tendinopathy of the, of the hip. Uh, so these are all things that could be treated with biologics. So, again, we look back to steroids. The steroids is a classic treatment. Let's just inject it around 10 and it'll feel better. Well, long term, that doesn't provide great, uh, great effect. And if we look at the in vivo studies, you know, what we're seeing in the histology is that there's decreased collagen organization, decreased proliferation of fibroblasts, viability, just for decreased collagen synthesis, and you get this increase in collagen necrosis and inflammatory cell infiltrate. So it's not good for cells. And then if you would think, oh, maybe this takes some time to actually have an effect, and this study looking at specifically rotator cuff tendon health and repair, showed that the CSI's decreased cellular proliferation, alter collagen, extracellular matrix composition, etc. as early as 24 hours after the corticosteroid exposure, and this could last several weeks. Again, this is exacerbated by increased dosage, continued medication. And if you look at this, and this has been around for years, is published in The Lancet. Short term corticosteroids can have an effect, but in the intermediate and long term, it's not everything favors the the comparator group rather than the corticosteroid group. And when I talk to my patients about getting a steroid injection, let's say for the rotator cuff, uh, for impingement, then I'll say, you know, if you didn't get the steroid injection about 6 to 8 weeks just doing physical therapy based on some of these studies, you'll be at the same place that you would be if you got the corticosteroid injection. So when I'm talking to them, I'm like, well, how bad is the pain? Is it gonna be painful? Just to sleep at night. Those would be indications to do a steroid injection plus physical therapy. Otherwise, I'm trying to get people away from doing any sort of steroids around tendons. And they continued on this comparing corticosteroids to placebo, NSAID injections, a combination of the two, and all are showing the same effect where you're favoring the corticosteroid in the short term, but not in the intermediate and long-term. And to understand why this is the case, you really have to understand what tendinopathy is, it's chronic tendonitis. You know, it's not just a reaction. It's not this inflammation. Real, realistically, it's some inflammation that wasn't treated appropriately. So didn't do appropriate load modification, rehab, strengthening. And then over time, this leads to tendon disrepair process. So it's more of a chronic condition with less acute or chronic type details, which is why since steroid is an anti-inflammatory, you're not, there's not much inflammatory cells that you're treating in these tendons. And so we need to figure out, you know, how these tendons can heal, and this is what the biologic process follows. So, there's phase 12, and 3. There's inflammation, repair and remodeling. And I'm gonna emphasize this because this is also how I structure my rehab protocols for patients. So the inflammatory phase is this vascular response to this inflammation. So you get some sort of tissue trauma, vascular disruption, the coagulation cascade is activated, you, this uh is able to activate the platelets, then you get all this, the growth factors that are released on this local vascular edema that's able to start the process. And this lasts about 2 weeks. So, the 1st 2 weeks for patients to get like a PRP or or painful, sore, and that's because of this inflammatory process. Between weeks 2 and 6, you have this proliferation phase or this tissue reconstruction or repair. So this can last days to weeks, and you get this cell proliferation, the growth factors that are stimulating fibroblasts, and these can produce collagen, so it's like softer tissue in there. Um, do you have a type 3 collagen, it's not type 1 collagen. So it's starting to build up. So, during this phase of rehab, so between 2 and 6 weeks after an injection, I have patients do a progressive load training to strengthen that tendon, but they're avoiding any heavy loading or eccentric, uh, aspects of the tendon or plyometrics or, or any sport from that 2 to 6 week period. Then at 6 weeks, you start to get remodeling and functional restoration. So, this could last for several months, uh, but it starts at 6 weeks. You start to get type 1 collagen or that ice-like rope-like tissue, which has tensile forces, and you get, uh, some scar tissue that develops as well. And so, this, this part is where you can start to escalate patients to, to, to sport. So, when you, you're counseling and, it's about 2 to 3 months return to sport after any PRP injection for a tendon. So what are the effects? Well, this was a multi-center trial retrospectively looking at different tendons. Patients aged 16 to 7, 70, greater than 6 months of pain, have been diagnosed by imaging, failed conventional treatment options, and then the PRP, most importantly, it's done in our ultrasound. And what they've found is 325 patients responded, about 55% looked at pain and functional measures. And the improvement was pretty good. So 82% reported moderate to complete improvement in their symptoms, which, uh, which means about 50 to 100% relief of their symptoms. 70% reported mostly to complete improvement in their symptoms. So that's 75 to 100%. So 82% success rate of 50 to 80 to 100% relief is pretty good. And then if you look at the pain scores pre and post PRP, it goes from about a 7 to a 1.8, so greater than 74% reduction in the pain levels. Looking at those with greater than 50% improvement, there are some that are really strong data like the lateral epicondyle, so, tennis elbow. Uh, patella tendon is classically, uh, pretty difficult to treat, and that was reflected in this study. Uh, but some of the other ones like medial peondyle gluteus medius, these were also very effective, and we'll show why. So there's higher level evidence. So that was a retrospective study. Now we have several level one studies that proved gluteal tendinopathy, lateral icondyopathy, rotator cuff, and plantar fasciopathy works. And then there's some also Achilles and patella. So looking at the gluteus medius and minimus, so, you know, when you hear about this lateral hip pain, it's usually not a bursitis. I mean, maybe 10 to 20% of cases is a bursitis, but most of the time, it's a degenerative tendon. So, this is what we're talking about treating. And so it's level one evidence, 80 patients to randomized corticosteroid versus leukocyte rich PRP. They single intratendinous injection, about 6 to 7 mill of PRP with kind of some needling going back and forth. And you had about an 82% success rate in this trial. And so we see that over time the leukocyte-rich PRP outperformed the corticosteroid injection, and this is lasting up to 2 years. And the graph on the right is those that had crossed over. So they had the option to cross over at about 3 months. And so, even if they received the corticosteroid injection late, they still had benefits. So it doesn't, so they maybe an initial treatment is try the corticosteroid injection, some physical therapy or try the anti-inflammatory injection plus physical therapy. If that doesn't respond, then they could do the PRP and they'll still have the same outcome. Lateral epicondylitis, so, tennis elbow. We have robust data that that works for this. 26 studies, uh, this looked at, uh, different pain and functional measures, but the important thing is that they wanted to see what met the clinically important difference. And so, when we see this, we look at the visual analog scale or pain score. And, you know, at the 12-week mark, we're escalating to about, you know, 60 to 70% of success and meeting that clinically important difference. And that study is through 52 weeks. And the Q is a measurement of function. We see a similar result. It's 70% at 52 weeks, but that continues to increase at 104. PRTEE same thing, even higher for this specifically for tennis elbow. And the Mayo scale, we also see that improvement at 52 weeks. So, we do have a, a high success rate with lateral epicondyopathy. Some, uh, some people that will argue that PRP doesn't work, will just say, hey, it's just the needle you're bringing, it's just this, this blood flow to the area that doesn't get much blood flow. Well, this has also been looked at. So, if you compare the needle, just the needle tenotomy, success rates for patients at 12 weeks are about 75%. In the PRP group versus 65%, and those are just the needle tenotomy versus at um at, at 24 weeks, you have about an 83% success rate for the PRP group versus 68% in the control group that just had the back and forth needle to the tissue. So if I'm, if I'm having a patient that's like, hey, I'll go, you know, I'd rather do something in office that doesn't cost money, you know, it's not PRP, well, then I could offer them needle tenotomy and the needle, but I do mention that there's about a 67% chance of, uh, that are working, so 2 and 3 versus about 83% chance with the PRP. If we look at improvements in pain, we also see an increased, uh, uh, a difference between the two with PRP having a 71% improvement compared to 56% in the non-PRP group. When we're looking at the rotator cuff, more and more, uh, studies are coming out. There's now 13 non-surgical randomized clinical trials until 725 patients. And it's been, and showed within this uh meta-analysis that was just published within this year that at less than 2 months in the short term, PRP didn't do as well, which is not surprising, and we know that. But then changes in pain and function at 2 to 6 months and long-term rate of 6 months were better in that PRP group with a lower rate of post-injection failure being, uh, being defined as a repeat injection or going on to surgery. And this all met the clinically important difference. And when I talk about uh rotator cuff with my patients, so, it'll be, if you have a partial tear or it's a thickened tendon, you know, you may benefit from a platelet-rich plasma injection. But, you know, if you have a full thickness tear, this is, PRP is not gonna fix that. It, the only thing that it can do is, you know, modulate pain and function, and it's never going to fix this. So that is, when you get to that aspect, it's more about, you know, discussing the surgical options. For muscle injury, there's not much evidence out there that PRP can help, but some will show that platelet po plasma can be helpful for a muscle, uh, for a muscle problem. But in these acute muscle strains, maybe in your elite athletes, so NFL, NBA guys will do a, uh, an injection to get them back a couple of days, maybe a couple of weeks early. There is a A recent study came out of Iowa that showed you, if you do a platelet poor plasma injection, you can get uh quad muscle injuries back in about 28 days. This is like PRP of like 42 and even longer if you wait. So, uh, there is the potential of this, but there's not enough in our, you know, weekend warriors or average uh patients that we see in the clinic to recommend this. So you might have heard of Lukocyte rich, Leukocyte poor, or I want you to kind of just think, kind of put that away and just think it doesn't really matter, and, and it what we're know realizing more and more is that it doesn't. And the reason being is that, you know, it's all, it's more about the platelet dosage. So, this is level one evidence, 192 patients, randomized clinical trial, double blinded, looking at PRP, uh, leukocyte rich versus leukocyte poor for NOA. They did just as well at both 6 and 12 months in both groups. And this is an analysis looking at tennis elbow, lateral icondylitis, a retrospective, um, comparative, uh, systematic review. And they found no difference in outcomes between leukocyte-rich and leukocyte-poor group. And there was also no difference in single and multiple injections. And that's important too, because, you know, very rarely, I'm, I'm recommending more than one injection of BRB. And for what it's worth, I use leukocyte pore products for everything I use. Uh, really, it's a neutrophil pore product because neutrophils can be toxic to different cells. So, the, uh, whereas monocytes can be more healthy to cells. So the, you know, I use leukocyte pore for both tendons and for joints. Well, why is there so much conflicting evidence? So people will say it works, some people will say it doesn't work. Even if you look at the highest level of journals in sports medicine and orthopedics, you know, these both came out in March 2023, and then the AGSM basically said there's not enough evidence to recommend PRP for knee osteoarthritis. And arthroscopy was like the bone marrow and PRP both have better outcomes than hyaluronic acid, and they would recommend it for patients. So, you have these conflicting information all the time and also in high-level journals. And so let's get into that. Well, JAMA, as you all know, is Uh, very reputable journal, but they have had a lot to say about PRP recently. So, this was a trial of a looking at Achilles tendinopathy, a randomized clinical trial, and they said it did not support the use of uh PRP for chronic mid portion Achilles tendinopathy. This was one's called the Restore randomized clinical trial, nice and fancy name, showed that it didn't have an effect when compared to a saline placebo at at 12 months. This was uh looking at ankle arthritis, and they did intraarticular PRP injection compared with placebo, and they should have did not significantly improve ankle symptoms over 26 weeks. So negative, negative, negative. And then if you look at JBJS or the Bone and Joint Journal, this is the peak randomized control trial. Again, another great name, and they said that there's no evidence that a single or multiple PRP had any additional benefit, and this was up to 12 months as well. Finally, this is another one. I mean, there's other trials out there, but it says no clinically important difference with intra-articular PRP for function, symptoms, and quality of life in these patients with hemophilic knee arthritis. So what do we do? That, we have all these studies that I just went over the systematic reviews that show that it works the overwhelming amount, but then now we have these in less high-level journals that say it doesn't work, that are actually well done studies. Well, you know, we don't throw away either of them, but we learn from it. And what we're seeing more is that dosage matters. So, you know, as a primary care physician, you're not going to give an unknown dose of an unknown drug for an unknown period of time. That makes no sense. And that's kind of what was being done with PRP for a while. And so if we actually look at the contents of the PRP that was done and injected in in this first trial in Achilles tendinopathy, they did a 9 cc blood draw, so not much, and they, you got about 476,000 platelets per microliter. This is only about 2 to 3 times the amount, uh, and this is, this is taken from a different trial. So they didn't even quantify their platelet counts, which is the standard now for any publication that has been since 2015. And they also did not use ultrasound guidance to direct the PRP into the area of pathology. The restore randomized clinical trial for knee osteoarthritis, their platelet dosage is about 325,000 platelets per microliter, and this gave you a total of after injection, about 1.6 billion platelets, which, you know, isn't that much more. I mean, it's only about 1 to 1.5 times the amount of your baseline platelets. And then this other one that was looking at ankle syndromes didn't even use true platelet-rich plasma, use an autologous cellular product, which doesn't meet the definition of PRP. They only use about 2 mL, so you're not giving them much of a dose of the PRP there. The JBJS study in the peak randomized trial used about 1.49 billion platelets, or 372,000 platelets per microliter. And then the hemophilic knee arthritis platelets were 3 to 35 3.5 times the amount, but they didn't actually quantify them within the studies. But, you know, what data is coming out is you might need at least 5 billion platelets, maybe 10 billion platelets, so they get the total dose until you have this efficacy. I mean, the trial we talked about earlier, leukocyte rich versus leukocyte poor was a double-blind trial, very well done, and, but they use greater than 5 billion platelets per injection in both groups. So, it's more likely that dosage there. And we are actually uh conducting a systematic review and meta-analysis currently as to with all the clinical trials out there that have used platelet counts and, and actually quantified them in their papers, there's about 33 of them to see and really uh be able to point this out and, and bring this to light in the literature that the dosage is important. And even in the lower back, and I told you we weren't gonna talk about back much, but here we go. Here's something. So, this is a chronic lower back lumbar discogenic pain, and they found that in this retrospective study that those that had received a greater than 10 times the baseline concentration of platelets or for the PRP compared to those receiving less than 5 times the concentration. There was an 81% success rate versus 55% success rate in the lower dose group. So this is called a standardization, and I encourage all of you, if you read these papers to look to see what the platelet contents were, what the, what was, what was out there. Cause again, this has been the standard since 2015 that this needs to be published, and I would argue that, you know, nothing should be published that doesn't have this, or it shouldn't even be looked at. Uh, and so this gives you this one classification system, it's called the PLRA by Mountainner and colleagues, platelet count, leukocyte concentration, red blood cells, and activation, cause all these can affect PRP. And then there's others out there. There's several like probably 1015 others, but this one's the Mars spill method, which looks at that as well. So that was all about PRP. I'll briefly touch on MSCs or these mesenchymal stem cells or signaling cells. So, what are we talking about? Well, you have these mesenchymal stem cells that are found in adipose dermis, uh, synovial fluid periosteum, umbilical cord blood, placenta, amniotic tissue, and they're supposed to be multipotent, you know, differentiating into these different cells. And then you have your hematopoietic stem cells that can convert to MSCs and can orchestrate this bone formation, and some will say that this is a a true driver of these MSCs. But if you listen to the, the godfather, these MSCs, uh, Arnold Kaplan, you know, he'll argue that there's no real stem cells in their body. And so what, what happens is you have these parasites. So if you have some sort of vascular damage or any damage to tissue. You know, then you, uh, then these macrophages and different, um, granulocytes come to clean it up, and they activate these parasites. And these parasites will stimulate these MSCs or the signaling cells, activate them, and then they can become these medicinal signaling cells based on the environment that they're. And so these have immunomodulatory capabilities. They have trophic properties, so anti-apoptosis, anti-scarring, promoting blood flow, angiogenic mitotic properties to create this regenerative type microenvironment, but they're not truly having those multipotent characteristics of stem cells. So he thinks of them more as a drugstore. So, are they really stem cells? No, they're more parasites that could be isolated from vascular tissue. They secrete these bioactive molecules, the immunomodulatory activities. They secrete pro and anti-inflammatory molecules based on the environment. They manage pain by secreting them to oculate opioid receptors, and they also secrete molecules that are mitogenic to tissue intrinsic stem cells. So how do we take these well. We have BMAC. So, this is bone marrow aspirate concentrate. So, I'd go to the posterior ceiiliac spine or that of the pelvis. I use ultrasound guides to mark in a few different places, and then uh numb them up pretty good. Tap into the bone marrow, get 3 separate sites with 10 cc syringes, processing the centrifuge, and you get about 8 cc's of pure bone BMAC. This is the same type of method that you would use in a, you know, in a bone marrow aspiration, uh, in for in oncology as well. Um, but there, uh, uh, we do have to take more, uh, more from these patients to, uh, at, and at different sites rather than just taking it at one site with a core biopsy. And then the microfragmented adipose tissue, this is like a mini liposuction. So we take a 60 cc syringe, we infiltrate all this tumescent fluid, which is this numbing agent. And also the, um, also a lot of fluid to help break up the fat tissue. You take about 30 cc's of fat out, decant it, so you wash it and resize it, and you get about 9 cc's of M fat tissue to inject. Why would you choose bone marrow over adipose? Well, adipose has more MSCs than bone marrow by concentration of volume up to 500 times more stem cells or uh mostly MSCs. There's less decrease in number activity with age. So, in our older patients, you might choose adipose, if they have more adipose tissue, it's easier to get that. Uh, but they all, they may be inferior potentially for both osteogenesis and chondrogenesis compared to BMAC. Um, uh, so, in younger patients, usually less than 55 will favor the BMAC. Um, there's no clinical superiority, though, that's been shown between the two. And, you know, we looked at this in a, in a recent review paper that I'd be happy to send out too. And, but these are the primary trials here, and this is a retrospective review looking at BMAC compared to MFAT, uh, and at 1.8 years out and 1.09 years to the BMAC, there's no difference between the groups, uh, in terms of clinical outcome. And this is throughout all of the CU sub scores of symptoms, activities, daily living, sports, quality of life. They all showed improvement with the um with both treatments. Now, this is important because this is also how I counsel patients, is that uh once they get to the KL 3 and 4 grade of osteoarthritis, to the moderate to severe, it was about a 50/50 shot that it, it provided improvement. Whereas KL1 and 2, KL2 is about 73%, and KL1 is a 100% chance of improvement. And we're talking about at least a 25% improvement in pain score. Now, one of the thoughts is that we can actually get more longevity out of these MSC treatments. So this is an open label study by orthopedic surgery and a regenerative medicine clinics utilizing registered registry data. 75 patients, 120 treatments, older age groups, about 69.6, around 70. They looked at functional measures and um they, they only had 14 treatments that had failed prior to the study endpoint. And we see improvement throughout all groups, uh, whether despite the grade of osteoarthritis. Uh, but you do see that the KL2 osteoarthritis did better than 3 and, and 4, as, as would be expected. But we do see improvement throughout all groups. This looked at 3-year outcomes and similar to what I just showed you, this is 30 patients, one's lost to follow-up. It's a very small number. Um, but if you look at the 1-year outcomes, so in the gray and versus the 3, 3-year outcomes just in the black, they're pretty similar, right? So like, it kind of studies out from that 1 to 3-year mark, but this is showing 3 years of improvement with these uh MFAT type treatments rather than some of the some of the other treatments, which could be less improvement. So. Uh, it is, the average time for PRP, what we're saying now is about 11 year and a half years of pain relief based on some of the studies. And so that's what's that needs to be investigated more within these MSD treatments is like, can we get more of that prolonged benefit? Can it help for more severe, uh, areas of arthritis? Most people ask, well, is it safe? Yeah, it's safe. So there's been the, this is a study of 3000 procedures, 4 2300 patients, 18 different facilities. They only have 325 adverse events. Seems like a lot, but most of it was just like pain post procedure or from progressive disease, which is expected. Um, they only had 7 neoplasms, and this was considered less than general population, so less than the average there. And the lowest adverse events were in BM the BMAC group alone. So some takeaways from this talk. Well, there's good evidence for PRP for certain MSK conditions, that's mild to moderate and EOA, lateral epicondylitis, tennis elbow, glutamy, tendinopathy, plantar fasciitis, fasciopathy. Um, PRP is a generic term, and we need to define what it is in, in all accounts and start to understand the proteins in it. So, we need to know the ideal platelet count, leukocyte counts, number of injections needed, and the ideal rehab. So, dosage really hasn't been established yet for PRP in many conditions. In terms of MSCs, you know, there's a lot of options out there right now that, that lack efficacy and sometimes even logic for the applications in the orthopedics. So, orthobiologics has this opportunity to become the corners cornerstone for these future MSK needs. But we do need to understand these trophic and secretory effects, and we need to know the difference in mechanism of action of these MSCs in, in different environments, soft tissues, cartilage disorders, because they do have different effects based on, you know, where you were treating. And we still don't know the optimal cell source route delivery, scaffolds. Do we, do we use something to hold it in? Are there different rehabilitation protocols? So there's a lot more questions than answers that we have right now. Uh, but this is, you know, going to be very, uh, optimal to, to look at in the future. So thank you guys for your time.
