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 U CS F. So I have a practice in, in Redwood Shores and I've also a practice within the city. Um 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, a specific interest of mine has been or the biologics 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 Ortho biologic, the different indications for these MS K 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 within this talk, including Robbie Bowers, Ken Mountain and, and, and so what are biologics? Well, you know, we are cellular beings. So we have over 37.2 trillion cells within our body. And at any moment or every second, about 15 million red blood cells are turning over at a a specific time point. So you know, the question is how could we start to use these cells to help regenerate or heal tissue? That's where biologics come into play. And there's four specific generations of biologics that we refer to. One and most commonly, which will be the meat of today is play the rich plasma. Uh two is bone marrow aspirin concentrate where we actually take it from the bone marrow. Three is lipo aspirate 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, was this important to the primary care physician? Well, this is a study that was done out of Canada. It looked over um uh 12 different countries, over five different continents with the clinics that were got greater than 20,000 patients and that had reported this info and the top number four diagnosis is seen as arthritis not related to the back and number nine is back pain or spinal pain. And then if you just look at the spin, the conditions that patients report, you know, number two, up there is back pain or spinal pain. And then toward 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 MS K 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 position 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 pro problems and we just say rice rested, ice compressed elevated over the years. This is transition to this peace and love model. So you protect it, you do it, this uh reloading type program, excuse me, load 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 when we look at these acute injuries, you know, uh we don't have good medications to be able to treat this. So NSA 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 NSA is a non Australian anti-inflammatory block, blocking that inflammatory phase, we might actually be delaying that process. And there's not really great evidence for these overuse injury strains, sprains for these therapeutic properties. And I know I'm speaking to the choir because uh nsaids are not without their adverse events. You know, we, we have renal cardiac issues, uh G I 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 do, 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 know, any steroid methyl Pernis index, which I use for my injection, it's 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 will do multiple injections. But if you look at multiple injections, they actually provide inferior, non superior symptom relief when compared to other injectables such as place, even placebo, sometimes Hyaluronic acid P or P and this isn't really shocking or, or anything that is groundbreaking, but it is something to think, you know, that, that we should be reconsidering doing these multiple intraarticular corticosteroid injections. But the 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 on health care expenditures and loss of work expenses is estimated to be more than $27 billion annually and $100 billion respectively. So the 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 the 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 50 to $700 for quality adjusted life year. And so no existing neo art arthritis treatment offers this ideal combination of clinical effectiveness and cost effectiveness below this willing to pay 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 first with how platelet rich plasma addresses this. So what is PR P or plate rich plasma? Well, it's this concentrated cell amilia. So this this uh group of growth factors within the blood that happens after you concentrate it down. So we usually do is take a, it'll take 60 mL of, of, of blood, spin it down to about, you know, 7 mL that are just the platelets, these rich, a lot of growth factors. Now, there's different definitions of what PR P is, some say 1.5 x, other five x, other 10 X 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 constitutes PR P. So when we look at the platelets, this can actually be quite overwhelming because 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 immuno uh modulators and medias. And these complement factors that, that are able to start both a coagulation cascade to activate PR B and then also release these uh these different treatments and growth factors to help the heal. And so what do I talk about with this? Well, there's plaid dried growth factor, transforming growth factor that vasal athelia growth factor, EGF abdominal growth factor, Fibroplastic growth factor. They all have similar effects. The main player being the plaid dried growth factor. This simulates cell replication, promoting angiogenesis, promoting epithelization 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 PR P does or 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 inhibit inhibition of matrix alpin. And it also promotes this extra cellular matrix remodeling. So how does this work in osteoarthritis? Well, osteoarthritis is chronic inflammatory state. So this is led by uh different aspects like I and beta TNF alpha and this could be through uh nature mental proses elastosis that lead to this condo site apoptosis. And so when you have the PR P, these growth factors can enhance these cartilage repair and counteract this process when one of the main players is il one R A, uh that is the interleukin one receptor antagonist which blocks that uh breakdown by interleukin one. And then you have the tissue inhibitor matrix to pros and these matrix to proses are really decorative to cartilage in different tissue and you could build up type two collagen as well. So these all enhance this chondrocyte proliferation for for the joint itself. So that's more of the preclinical or how it works. But where is the evidence? Now? Well, we have a great studies for the joint, specifically knee osteoarthritis. There's you know, well, over 40 clinical trials now that have, that have looked at knee O A and PR P, we have more evidence for the shoulder and hip that have come out. There's some in the ankle, I join C MC, 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 PR P for Neo A. Now, there's about 15 of them out there now. And 12 out of the 15 show a positive effect with PR P. This included 21 trials. So PR P was compared to steroids, saline and Hyaluronic acid and they concluded that PR P injections are beneficial for pain relief and functional improvement in knee osteoarthritis. And if you don't believe me, this is the fourth plot from that study, this is 12 months out, looking at the different comparisons of the left favors PR P and the right favors controls. And in 12 months, you could see that the difference between the Hyaluronic acid corticosteroid and the saline group all favoring the platelet rich plasma. And if we compare it to Hyaluronic acid, PR P 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 AJ SM probably about a year ago. Uh looked at 18 studies, 811 patients that had undergone PR P 797 that underground hyaluronic acid at the mean fall about 11 months and they found improvement higher in the PR P group, which is about 45% than in the Hyaluronic acid group which is about 12% uh for the and then of those that reported pain scales, six reported uh the PR P patients to have significantly less pain at the latest follow up when compared to the Hyaluronic acid, some people are combining Hyaluronic acid with PR P. And you know, the this has been shown that it doesn't really provide much benefit. So this is a a review of 13 articles over 1100 patients looking at pain and functional scores and they found the smallest treatment effect did not reach the MC ID or the minimally clinical important difference, meaning that uh the PR P and Hyaluronic acid is not found to be superior to Pr P alone um with this treatment. And you know, one of the thoughts is that if you add Hyaluronic acid to the PR P, this can actually change what the contents of the PR P is. And this is being looked at by Shane Shay 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 PR P by adding that Hyaluronic acid. Well, what we really want to 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 1000 and 84 patients with 667 meeting the include criteria. So they had, this is KL three and four 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 things that I will counsel my patients on is that there's the potential even in the severe osteoarthritis, you have a 75% chance of uh potentially delaying that need for knee arthroplasty. And interestingly enough in these patients, 85% did not undergo TK for about five years of follow up. Now, one of the things is that not all of these uh patients that restrict review only had one pr P injection and some had multiple others had intra aus over 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 PR P works, you know, there's this argument out there and I believe it should be true that PR P should be the standard of care for knee arthritis. Yet, you know that we'll get into the, the variability. But the based on the fact that there's so much variability within PR P 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 six studies. Uh looking at Woma Ds and Harris hip score comparing Hyaluronic acid to PR P. They showed that both had a significant improvement at 12 months. Now, if you're looking at Hyaluronic acid and PR P based on the knee studies alone, you know, I'm always gonna recommend PR P for my patients. And the reason being is if you pay out pocket for ionic acid, because Hyaluronic acid isn't covered by insurances for, for hip osteoarthritis, then oftentimes you're paying about the same amount for H A as you are for APR P injection. So this is something that's important to consider. And there, there was variability in the PR P content in these studies and some weren't reporting. So some of this could have been a low dose PR P which might not have the effect that we would like to see in, in patients with hip arthritis. And so this one was a ran double blind randomized clinical trial. It was a pilot study to see if we could look at any delay towards either hip resurfacing, resurfacing or total hip arthroplasty over two years. And they found that 50% of those that had received low molecular Hyon acid converted to surgery versus 15% in the PR P group. So we did see a difference in that between PR P and the Hyaluronic acid, even though it was just a small number of hips at 36 moving onto 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, Lecy poor Pr P or Hyaluronic acid showed improvements in both groups regardless of the o A 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 is like a hip, which could be 30 years, 95% success rate, whereas the shoulder maybe 15, 20 years, potentially a little bit more depending on who you talked 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 PR P 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 PR P. And there is the potential that you can get even more as this PR P was more of a lower dose PR P uh within this study. So let's transition. We talked a lot about arthritis. Let's talk to talk about tenon opathy. So common things so clear in clinic, tennis, elbow, uh golfer's elbow, rotator, cuff, tennis, 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, steroids is a classic treatment. It's just injected 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 proliferator, fiberglass viability, 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 cup tendon health and repair showed that the C SI S decrease cellular proliferation, alter collagen extracellular matrix composition, et cetera 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, and let's say for the rotator cough uh for impingement, then I'll say, you know, if you didn't get the steroid injection, about 60 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 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 cortico steroids 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 or this chronic tendinitis. 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 a tendon disrepair process. So it's more of a chronic condition with less acute on chronic type details, which is why since steroids 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 three, there's inflammation repair and remodeling. And I'm gonna emphasize this because this is also how I uh 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 two weeks. So the first two weeks for patients to get like APR P or are painful, sore. And that's because of this inflammatory process. Between weeks, two and six, you have this proliferation phase or this tissue reconstruction or repair. So this can last days to weeks and you get this cell proliferation of growth factors that are stimulating fibroblasts. And these could produce collagen. So it's like softer tissue in there. Um Do you have a type three collagen? It's not type one collagen. So it's starting to build up. So, during this phase of rehab. So between two and six weeks after an injection, I have patients do a progressive load training to strengthen that tendon, but they're avoiding any heavy loading or e centric uh aspects of the tendon or Plyometrics or, or any sport. From that 2 to 6 week period, then at six weeks, you start to get remodeling and functional restoration. So this could last for several months. Uh but it starts at six weeks, you start to get type one 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 pr P injection for attendance. So what are the effects? Well, this was a multi center trial retrospectively looking at different tendons. Patients aged 16 to 7, 70 great and six months of pain have been diagnosed by imaging failed dimensional treatment options. And then the PR P, most importantly, it's done in our ultrasound. And what they found is 325 patients responded about 55% like the pain and functional measures and the improvement was pretty good. So 82% reported moderate to complete improvement in their symptoms. So 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. It pretty good. And then if you look at the pain scores pre and post pr P, it goes from about a seven to a 1.8. So great in 74 per percent reduction in the pain levels. Looking at those with greater than 50% percent improvement. There are some that are really strong data like the latter oon. So tennis Obbo uh 10 is classically uh pretty difficult to treat and that was reflected in this study. Uh but some of the other ones like Melius mec, these were also very effective and we show why. So there's higher level evidence. So that was a retrospective study. Now we have several level one studies that prove gluteal tendinopathy la later oath, the rotator cuff and planar fay 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 level one evidence, 80 patients to randomized corpus steroid versus leuco rich pr P, they single intratendinous injection about 6 to 7 millis of PR P 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 leucocyte rich pr p outperformed the corticosteroid injection and this is lasting up to two years. And then the graph on the right is those that are crossed over. So they have the option to cross over at about three months. And so even if they receive 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 uh anti inflammatory injection plus physical therapy. If that doesn't respond, then they could do the PR P and they'll still have the same outcome. Lot of opis. 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% as success and meeting that clinically important difference. And that study is there 52 weeks and the Q dash was a measurement of function. We see the a similar result at 70% of 52 weeks, but that's continues to increase at 104 P RT ee same thing even higher for this, specifically for 10 tennis elbow and the mayo scale. We also see that improvement at 52 weeks. So we do have a, a high success rate with later. Some uh some people that will argue that PR P doesn't work will just say, hey, it's just the needle, you're bringing it this, 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 to an success rates for patients of 12 weeks are about 75% in the PR P group versus 65%. And those are just the needle tenotomy versus at um at, at 24 weeks, you have about a 83% success rate for the PR P 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 pr P well, then I could offer them needle toomy and the needle. But I do mention that there's about a 67% chance of that. A that a working A two and three. This is about 83% chance with the PR P. If we look at improvements in pain, we also see an increased uh uh a difference between the two with PR P having a 71% improvement compared to 56% in the non PR P 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 seven or 25 patients. And it's been and showed within this uh meta analysis that was just published within this year that at less than two months in the short term, PR P didn't do as well, which is not surprising that we know that but then changes in pain and function at 2 to 6 months and long term rate of six months were better than that PR P 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 a rotator cup with my patients, so it'll be if you have a partial tariff or it's a thick intended, you know, you may benefit from the plate, the rich plasma injection. But you know, if you have a full thickness tar, this is PR P is not gonna fix that. It's it, the only thing that it could do is, you know, modulate pain and function and it's never going to fix thickness. 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 PR P can help. But some will show that platelet poor plasma can be helpful for a muscle uh or 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 weeks early. There is a recent study came out of Iowa that showed you if you do a P platelet poor plasma injection, you can get a quad muscle injuries back in about 28 days. This is like pr p of like 42 and even longer if you wait. So you know, 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 Lucy Ridge Lucai 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 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 pr P uh Lucy rich versus leucocyte poor for EO A. They did just as well at both six and 12 months in both groups. And this is an analysis looking at tennis ali a respective um comparative uh systematic review and they found no difference in outcomes between leucocyte rich and leucocyte poor group. And there was also no difference in single or 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 leucocyte poor 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 leucocyte 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 A GSM basically said there's not enough evidence to recommend PR P for neo osteoarthritis. And arthroscopy was like the bone marrow and PR P both have better outcomes than Haar 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, Jamma, as you all know, is a very reputable journal, but they haven't had a lot to say about Pr P recently. So this was a trial of a kid looking at achilles tendon, a randomized clinical trial and they said it did not support the use of uh PR P for chronic midportion achilles tenon. This was one that's called the restore randomized clinical trial. Nice and fancy name showed that it didn't have an effect when compared to a placebo at, at 12 months. This was uh looking at ankle arthritis and they did intraarticular PR P 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 JB Js or a bone and joint journal, this is the P randomized control trial again, another great name. And they said that there's no evidence that a single or multiple PR P had any additional benefit. Uh 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 intraarticular pr P 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 learned from it. And what we're seeing more is that dosage matters. So, you know, as a primary care physician, you're not gonna 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 PR P for a while. And so if we actually look at the contents of the PR P that was done and injected in, in this first trial in achilles 10, they did a nine CC blood drop. So not much. And they, you got about 476,000 plates 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 PR P into the area of pathology to 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 of 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 using a uh atto cellular product, which doesn't meet the definition of Pr P, they only use about two ML. So you're not giving a much of a dose of the PR P. There. JB Js study in the randomized trial used about 1.49 billion platelets or 372,000 platelets per microliter. And then the hemophilia knee arthritis platelets were 3 to 353.5 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. Leucocyte rich vers lucy poor was a double blind trial very well done and but they use greater than 5 billion platelets for injection in both groups. So it's probably more likely that dosage there. And we are actually uh conducting a systematic review of me analysis is currently as to with all the clinical trials out there that are from 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 talking about back much, but here we go. Here's something. So this is a chronic lower back lumbar dysgenic 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 PR P compared to those receiving less than five 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, what the platelet contents were or what the, what was, what was out there. Because 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 that. Uh And so this gives you this one classification system. It's called the PLR A by mountain and colleagues platelet count leucocyte concentration of red blood cells and activation because all these can affect PR P. And then there's others out there, there's several like probably 10, 15 others. But this one's the Mars Spill method which looks at that as well. So that was all about Pr P. I'll briefly touch on MS CS or these meal stem cells or signaling cells. So, what are we talking about? Well, you have these meal stem cells that are found in adipose dermis, uh synovial fluid, perio umbilical cord blood, placenta, amniotic tissue and they're supposed to be multipotent. You know, differentiate into these different cells. And then you have your optic stem cells that can convert to MS CS and can orchestrate this bone formation. And some will say that this is a, a true driver of these MS CS. But if you listen to the, the godfather of these MS Es 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 granu sites come to clean it up and they activate these parasites and these parasites will stimulate these MS CS or these signaling cells activate them. And then they could become these medicinal signaling cells based on the environment that they and so these have a moo modulatory capabilities. They have trophic properties. So, anti aosis, anti scarring, promoting blood flow angiogenic mitotic properties to create this regenerative type micro environment. But they're not truly having those multipotent characteristics of stem cells. So he thinks of them more as a drug store. So are they really stem cells? No, they're more parasites that could be isolated from vascularized tissue. They secrete these bio active molecules through the meal modulator activities. They secrete pro and anti inflammatory molecules based on the environment. They manage pain by secreting them to opioid receptors. And they also secrete molecules that are mitogenic to tissue, intrinsic stem cells. So how do we take these as well? We have the mac. So this is bone marrow aspirin concentrated. So I'd go to the post a spine or that of the pelvis. I use ultrasound guys to mark in a few different places and then uh numb them up. Pretty good. Tap into the bone marrow. Get three separate sites with 10 CC syringes process in the centrifuge And you get about a CCS of pure bone B mac. This is the same type of method that you would use in a, in a bone marrow aspiration uh in for in oncology as well. Um But there, you know, 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 micro fragment, 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 ccs of fat out decant it. So you wash it and resize it and you get about nine ccs of M fat tissue to inject. Why would you choose bone marrow over adipo? Well, adipose has more MS CS than bone marrow by concentration of volume up to 500 times more stem cells or uh mostly MS CS, there's less decrease in number activity with age. So, in our older patients might choose adipo 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 chori genesis compared to B MAC. Um uh So in younger patients usually less than 55 a favor the B MAC. 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 to. Um but these are the primary trials here and this is a retrospective review looking at B MAC compared to M fat. Uh and at 1.8 years out and 1.09 years to the B A, there's no difference between the groups uh in terms of clinical outcome. And this is throughout all the subs courses 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 three and four grade of osteoarthritis to the moderate to severe, there was about a 50 50 shot that it, it provided improvement. Whereas KL one and two, KL two is about 73% and KL one is 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 MS C treatments. So this is an open label study by orthopedic surgery and our regenerative medicine clinics utilizing registration registry data. 75 patients, 120 treatments, older age groups, about 69.6 around 70 they look at functional measures and um they and they only had 14 treatments that have failed prior to the end point. And we see improvement throughout all groups, uh, whether despite the grade of osteo arthritis, uh, but you do see that the KL two osteoarthritis did better than three and, and four as as would be expected. But we do see improvement throughout all groups. This looked at three year outcomes and similar to what I just showed you, this is 30 patients, one's lost the follow up. It's a very small number. Um But if you look at the one year outcomes, so in the grave and versus the 33 year outcomes just in the black, they're pretty similar, right? So like it kind of stay out from that 1 to 3 year mark, but this is showing three years of improvement with these uh m fat type treatments rather than some of the, some of the other treatments, but could be less improvement. So, uh, it is the average time for pr P. What we're saying now is about a year, year and a half of pain relief based on some of the studies. And so that's what's in, that needs to be investigated more within these MST 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, 423 100 patients, 18 different facilities. They only had 325 adverse events. Seems like a lot, but most of it were just like pain post procedure or from progressive disease, which is expected. Um They only had a seven neoplasms and this was considered less than the general population, so less than the average there and the lowest adverse events were in BM, the B MAC group alone. So some takeaways from the stock. Well, there's good evidence for PR P for certain MS K conditions that's mild to moderate eo a later oitis, 10 glue tenino plantar fasciitis fay. Um PR P 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, leucocyte counts, number injections needed and the ideal rehab. So dosage really hasn't been established yet for PR P in many conditions in terms of MS CS, you know, there's a lot of options out there right now that that lack efficacy and sometimes even logic for the applications in orthopedics. So Ortho biologists has this opportunity to become the cornerstone cornerstone for these future MS K needs. But we do need to understand these trophic and secretary effects and we need to know the difference and mechanism action of these MS CS and, and different environments, soft tissues, cartilage disorders because they do have different effects based on, you know, where you were treating and we're still in an 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 to, to look at within the future. So thank you guys for your time.
